Michael R. Lauer
Stanford University
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Annals of Internal Medicine | 1995
Hanno L. Tan; Charles Jia-Yin Hou; Michael R. Lauer; Ruey J. Sung
Antiarrhythmic drugs that exert their therapeutic effects primarily by delaying cardiac repolarization and prolonging the QT interval have, in recent years, become the favored drug treatment for life-threatening ventricular arrhythmias. Such drugs are presumed to have greater clinical effectiveness and a lower risk profile than more traditional antiarrhythmic drugs, which primarily slow the action potential conduction velocity and prolong the QRS duration [1, 2]. Although agents that prolong the QT interval may be useful in treating arrhythmia, they may also provoke a unique form of proarrhythmia called torsade de pointes [3, 4]. Torsade de pointes (twisting of points) is a characteristic form of polymorphic ventricular tachycardia in which the mean electrical axis of the QRS complex within any single electrocardiographic lead appears to twist around the isoelectric line [3]. Quinidine is the most widely used antiarrhythmic drug that can induce torsade de pointes; the reported incidence of torsade de pointes in patients receiving quinidine is 1% to 8% [5]. Antiarrhythmic drugs such as procainamide, disopyramide, and sotalol may also cause torsade de pointes, although amiodarone, which also prolongs the QT interval, is much less likely to do so [6, 7]. However, torsade de pointes is more than simply an unusual cardiac curiosity; numerous noncardiac agents or conditions may also precipitate it. The acquired and hereditary long QT interval syndromes and the form of polymorphic ventricular tachycardia associated with them have now become a model of the ways in which identifiable cellular electrophysiologic abnormalities can cause clinical cardiac arrhythmia. With the development of new cellular and molecular biological techniques, the cellular mechanisms of these syndromes are now the subject of renewed research interest. In this review, we 1) classify the forms of the long QT interval syndromes; 2) discuss proposed explanations of the cellular electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes; 3) outline the causes of the acquired long QT interval syndromes, placing particular emphasis on torsade de pointes caused by antiarrhythmic drugs; 4) briefly review the hereditary long QT interval syndromes and torsade de pointes; and 5) summarize the available short- and long-term treatment options for the acquired and hereditary long QT interval syndromes. Classification of the Long QT Interval Syndromes and Torsade de Pointes As seen in Figure 1, the QT interval recorded on the surface electrocardiogram corresponds to the relatively isoelectric plateau phase of the action potential. The broad T wave is inscribed as a result of the rapid repolarization occurring nonsimultaneously throughout the ventricles. The QT interval is prolonged by any agent or condition that delays repolarization in the ventricular cells. Various agents and conditions cause these long QT interval syndromes (Table 1) and initiate the characteristic torsade de pointes tachyarrhythmia (Figure 2). Table 1. Classification and Causes of the Long QT Interval Syndromes Figure 1. Relation between phases of the cardiac action potential and the surface electrocardiogram. Figure 2. Electrocardiogram showing the typical short-long-short RR interval initiation sequence triggering an episode of torsade de pointes. The long QT interval syndromes have been classified as acquired or hereditary on the basis of the conditions that appear to trigger the polymorphic ventricular tachycardia associated with the syndromes. The acquired long QT interval syndromes are also typically classified as pause-dependent because the torsade de pointes associated with them generally occurs at slow heart rates or in response to short-long-short RR interval sequences. The hereditary long QT interval syndromes are typically considered adrenergic-dependent because the torsade de pointes associated with them is generally triggered by adrenergic activation or enhancement of sympathetic nervous system tone [5]. However, the acquired and hereditary syndromes overlap somewhat; adrenergic-dependent forms are more likely to occur in response to pauses or short-long-short RR interval sequences or during slow heart rates. As seen in Table 1, causes of the acquired long QT interval syndromes include antiarrhythmic drugs, severe bradycardia, electrolyte disturbances (notably hypokalemia), various nonantiarrhythmic drugs, and numerous unrelated clinical disorders. The hereditary long QT interval syndromes include the Jervell and Lange-Nielsen syndrome [8], which is associated with congenital deafness, and the Romano-Ward syndrome [9, 10], in which hearing is normal. As mentioned above, initiation of the acquired, pause-dependent form of torsade de pointes often (although not invariably [11]) involves a short-long-short RR interval sequence [5]. As seen in Figure 2, a premature ventricular depolarization closely coupled with the last normal QRS complex is followed by a long pause after extrasystole that precedes another closely coupled premature ventricular depolarization, which constitutes the first beat of the tachycardia [5, 12, 13]. The tachycardia has a rate of 150 to 250 beats/min and is usually self-terminating. It is usually nonsustained and produces either no symptoms or only mild symptoms of presyncope, but it can occasionally degenerate into ventricular fibrillation that may be fatal. Although the initiation of torsade de pointes in patients with the hereditary long QT interval syndromes does not require pauses or bradycardia, adrenergic activation or enhanced sympathetic nervous system tone does appear to be necessary to produce the bizarre QT or QTU prolongation characteristic of this form of the disorder. Cellular Mechanisms of the Long QT Interval Syndromes and Torsade de Pointes Normal Cardiac Action Potential The action potential of the ventricular or Purkinje fiber (Figure 1) results from the transmembrane movement of ions through channels in the cell membrane. The normal resting potential of most cardiac cells is about 80 to 90 mV. Membrane depolarization results from the net influx of positive charges (inward current) and repolarization occurs secondary to the net efflux of positive charges (outward current). The major ion currents responsible for the action potential in ventricular and Purkinje fibers are listed in Table 2. During diastole (phase 4), the membrane remains polarized near the K+ equilibrium potential ( 90 mV) because the inward rectifier K+ current (IK1) is normally the only current of significant magnitude activated at this membrane potential. In Purkinje fibers, diastolic depolarization results from a combination of the decay of the outward delayed rectifier current (IK) and the activation of the inward pacemaker current (If) and the inward Na+ background leak current (INa-B). The rapid upstroke of the action potential (phase 0) results from the inward fast Na+ and L- and T-type Ca2+ currents (INa, ICa-L, and ICa-T). Initial repolarization immediately after the overshoot (phase 1) is mediated by activation of the transient outward current (ITO) carried by K+ ions. The plateau (phase 2) results from a balance between inward currents, primarily the slowly decaying ICa-L and possibly the electrogenic Na+-Ca2+ exchange current (INaCa) [14] and the outward currents IK and ITO.Repolarization (phase 3) develops as the outward currents, especially I (K), overwhelm the decaying inward currents. An inward window current is responsible for the repetitive depolarizations at plateau levels of potential that are characteristic of early afterdepolarizations (see below). This current appears to be generated by the slow inactivation of ICa-L [15] and INa [16]. Table 2. Major Ion Currents Underlying the Cardiac Action Potential* Role of Early Afterdepolarizations in the Genesis of Prolongation of the QT Interval and Torsade de Pointes The study of torsade de pointes is confounded by the transient nature of the condition and the unpredictability of its occurrence and because it generally cannot be induced by programmed electrical stimulation during electrophysiologic study [17, 18]. Thus, animal studies form the basis for the current understanding of this arrhythmia. It is believed that prolongation of the QT interval and torsade de pointes are caused by early afterdepolarizations, defined as single or repetitive depolarizations or oscillations of the transmembrane voltage, that occur at low levels of membrane potential because of a failure of normal, complete membrane repolarization (Figures 3 and 4). Early afterdepolarizations may occur during the plateau phase (phase 2 early afterdepolarizations) or the early rapid repolarization phase (phase 3 early afterdepolarizations) of the action potential (Figures 3 and 4) [19, 20]. Because these afterdepolarizations delay repolarization, they may result in significant prolongation of the QT interval. Figure 3. Schematic drawing illustrating transmembrane action potentials from a Purkinje fiber, a ventricular muscle fiber, and a surface electrocardiogram. dotted line dotted line Although direct evidence that early afterdepolarizations cause torsade de pointes is lacking, considerable indirect evidence supports this hypothesis. Specifically, conditions that induce early afterdepolarizations initiate torsade de pointes [21, 22], especially at slow heart rates [23], and conditions that suppress early afterdepolarizations prevent torsade de pointes [24]. Furthermore, endocardial monophasic action potential signals (which reflect transmembrane electrical activity generated by action potentials) recorded under clinical and experimental conditions have shown that torsade de pointes is associated with voltage deflections resembling early afterdepolarizations [25, 26]. Early afterdepolarizations probably arise from the Purkinje fibers rather than from working myocardial cells because interventions that induce e
American Journal of Cardiology | 1996
Kathy L. Lee; Michael R. Lauer; Charlie Young; Wen-Ter Lai; Yau-Ting Tai; Hingson Chun; L.Bing Liem; Ruey J. Sung
Abstract Verapamil-sensitive ventricular tachycardia (VT) is a well-recognized clinical entity that some authorities believe may result from triggered activity. Despite its uniform response to verapamil, however, there is evidence that this uncommon form of VT may not be as homogeneous as first believed. Standard intracardiac electrophysiologic techniques were used to study verapamilsensitive VT in 32 patients (aged 38 years ± 20 years) without evidence of structural heart disease. More than half of these patients (69%) exhibited VT with a right bundle branch block-type QRS pattern, with the remainder (31%) displaying VT with a left bundle branch block pattern. In 31% of the patients the VT could be induced by fixed-cycle length atrial pacing, whereas in 59% of patients fixed-cycle length ventricular pacing was necessary. A critical range of cycle lengths for VT induction was required in 66% of the patients. Ventricular tachycardia was initiated with single atrial premature extrastimuli in 16% of patients, single ventricular extrastimuli in 50% of patients, and double ventricular premature extrastimuli in 9% of patients. Ventricular tachycardia displaying cycle-length alternans was observed in 28% of patients. In only 19% of patients was it possible to entrain VT during pacing from the right ventricular apex. Isoproterenol infusion was required for tachycardia induction in 50% of patients, 44% of whom had VT with a left bundle branch block QRS pattern, with the remaining 56% exhibiting VT with a right bundle branch block pattern. Beta-adrenergic blockers suppressed 53% of verapamil-sensitive VT in patients tested, whereas adenosine terminated VT in 50% of patients, with 81 % of these patients exhibiting either a left bundle branch block QRS pattern or isoproterenol dependence. Ventricular tachycardia exhibiting a left bundle branch block pattern was more likely to be isoproterenol dependent (p 0.5). Verapamil-sensitive VT exhibits properties expected of both a reentrant and triggered arrhythmia, and it is inconsistently dependent on both exogenous catecholamines for induction and intravenous adenosine for termination. Verapamil-sensitive VT encompasses a heterogeneous group of tachycardias that may result from multiple cellular electrophysiologic mechanisms.
American Heart Journal | 1996
John Yu; Michael R. Lauer; Charlie Young; L.Bing Liem; Charles Jia-Yin Hou; Ruey J. Sung
During radiofrequency catheter ablation of slow atrioventricular node pathway conduction in patients with atrioventricular node reentrant tachycardia, an atrioventricular junction rhythm is frequently observed. The origin and relation to ablation success of this junctional rhythm was examined in this study. By using standard intracardiac electrophysiology techniques, we studied the radiofrequency energy-induced atrioventricular junctional rhythm in 43 consecutive patients with atrioventricular node reentrant tachycardia undergoing selective ablation of slow-pathway conduction. The frequency of atrioventricular junctional activity was correlated with successful and unsuccessful attempts at ablation of slow-pathway conduction. Also, we compared the sequence of retrograde atrial activation of radiofrequency energy-induced atrioventricular junctional beats in a subgroup of 22 patients with the retrograde activation sequence observed during pacing from the right ventricular apex and the site of successful ablation of slow-pathway conduction. A total of 201 radiofrequency-energy applications was delivered in 43 patients with > or = 5 atrioventricular junctional beat(s) induced during 110 (55%) of 201 ablation attempts. Atrioventricular junctional activity was noted during 98% of successful ablations but only 43% of the unsuccessful attempts (sensitivity, 98%; specificity, 57%; negative predictive value, 99%). The mean time to appearance of atrioventricular junctional beats was 8.8 +/- 4.1 sec (mean +/- SD) after the onset of radiofrequency-energy application. In 22 (100%) of 22 patients in whom detailed atrial mapping was performed, the retrograde atrial activation sequence of the radiofrequency-induced atrioventricular junctional beats was earliest in the anterior atrial septum, identical to that seen during pacing from the right ventricular apex. Earliest retrograde atrial activation was at the posterior septum in all patients during pacing from the successful ablation site, a markedly different activation pattern compared with that seen during either radiofrequency ablation or ventricular pacing. Whereas the occurrence of atrioventricular junctional activity during radiofrequency ablation does not necessarily herald a successful ablation of slow atrioventricular node pathway conduction, its absence strongly suggests that the energy is being applied in an unsuccessful fashion. Furthermore, it appears that radiofrequency energy-induced atrioventricular junctional beats originate not from the endocardium in contact with the ablating catheter tip but instead appear to exit remotely from the anterior atrial septal region. This finding supports the existence of specialized tissues in the atrioventricular junction that preferentially transmit the effects of radiofrequency energy to an anterior exit site, possibly identical to the atrial exit site of the retrograde fast atrioventricular node conduction pathway.
Pacing and Clinical Electrophysiology | 1994
Ruey J. Sung; Michael R. Lauer; Hingson Chun
With the advent of RF catheter modification of AV node conduction for the treatment of AV node reentrant tachycardia, considerable advances have been made with better understanding of the AV junctional anatomy, electrophysiology, and mechanism responsible for AV node reentrant tachycardia. Future studies should be designed to uncover the basic cellular electrophysiological mechanisms responsible for fast and slow AV node conduction, to define the exact tissue components of the reentrant circuit in order to make ablative procedures safer, and to study the long-term effects of RF catheter ablation on AV conduction. Special caution should be directed toward pediatric patients with more stringent indications for catheter ablation of the AV junctional area in these patients.
American Journal of Cardiology | 1994
Michael R. Lauer; Charlie Young; L.Bing Liem; Linda Ottoboni; Jan Peterson; Phoebe Goold; Ruey J. Sung
Many of the newest implantable cardioverter-defibrillators (ICDs) provide the option of programmable low-energy cardioversion for monomorphic ventricular tachycardia (VT). Whereas these devices may provide less myocardial damage and increased comfort in patients receiving frequent shocks for VT, the proarrhythmic effects of low-energy cardioversion from ICDs in patients with structural heart disease are not clear. The purpose of this study was to determine prospectively the per-patient incidence of ventricular fibrillation (VF) induction after low-energy cardioversion of VT by ICDs in patients with coronary artery disease. The estimated cardioversion energy requirement was determined during the course of routine predischarge ICD testing in 40 patients with newly implanted ICDs. Two groups of patients were identified during determination of the cardioversion energy requirement: (1) a non-VF group consisting of 26 of 40 patients (65%) without VF induced by low-energy shock and, (2) a VF group consisting of 14 of 40 patients (35%) who developed VF during low-energy cardioversion. There was no difference between the 2 groups in terms of patient age, sex, concurrent antiarrhythmic drug therapy, VT cycle length, or type of ICD system implanted. Compared with the non-VF group, the VF group was more likely to have both a lower ejection fraction (25 +/- 5% vs 33 +/- 8%; p = 0.005) and a cardioversion energy requirement > 2 J (79 vs 27%; p = 0.005). Our results suggest that low-energy cardioversion is associated with a high per-patient risk of VF induction, and the risk is higher in patients with poorer left ventricular function and, possibly, higher cardioversion energy requirement.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Cardiovascular Electrophysiology | 1998
Kathy L. Lee; Hingson Chun; L.Bing Liem; Michael R. Lauer; Charlie Young; Ruey J. Sung
Multiple AV Nodal Pathways. Introduction: Multiple AV nodal pathway physiology can be demonstrated in certain patients with clinical AV reentrant tachycardia.
American Journal of Cardiology | 1994
Michael R. Lauer; Charlie Young; L.Bing Liem; Ruey J. Sung
The purpose of this study was to determine if adenosine is equally effective in terminating catecholamine-dependent and independent supraventricular tachycardia (SVT). The effect of adenosine on termination of SVT was studied in 21 patients: 12 with atrioventricular (AV) reciprocating tachycardia, and 9 with AV node reentrant tachycardia. Group 1 comprised 13 patients who had SVT induced in the absence of exogenous catecholamines, whereas group 2 comprised 8 who needed isoproterenol (1.6 +/- 0.4 micrograms/min) for induction. There was no statistical difference between the 2 groups regarding age, weight, mean arterial pressure during sinus rhythm and SVT, cycle length of SVT, or norepinephrine and epinephrine levels during sinus rhythm and SVT. Cycle length during sinus rhythm was significantly decreased in group 2. The mean dose of adenosine needed to terminate SVT was 52 +/- 6 micrograms/kg of body weight in group 1, and 61 +/- 12 micrograms/kg in group 2 (p > 0.05). In addition to isoproterenol not altering the minimal dose of adenosine necessary to terminate SVT, there was also no correlation between the dose of adenosine (mean 55 +/- 6 micrograms/kg) of each patient, and the corresponding endogenous epinephrine (273 +/- 59 pg/ml) (r = -0.19) and norepinephrine (400 +/- 58 pg/ml) (r = 0.01) levels during SVT, or cycle length of SVT (323 +/- 9 ms) (r = -0.35). The results show that adenosine is equally effective in terminating catecholamine-dependent and independent SVT; higher adenosine doses should not be needed to manage catecholamine-dependent SVT.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of the American College of Cardiology | 2001
Michael R. Lauer
On October 1, 1999, the U.S. Food and Drug Administration (FDA) approved dofetilide (Tikosyn) for the treatment of persistent (nonparoxysmal) atrial fibrillation and flutter. However, the FDA cautioned: “Because Tikosyn can cause life-threatening ventricular arrhythmias, it should be reserved for
Journal of Cardiovascular Electrophysiology | 2005
Ruey J. Sung; Michael R. Lauer
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults and is associated with significant morbidity and mortality.1 AF frequently not only causes symptoms of palpitations, but can also precipitate angina, syncope, myocardial infarction, congestive heart failure, and thromboembolism including stroke, and may also produce tachycardia-induced cardiomyopathy. Unfortunately, medications aimed at suppressing AF and maintaining sinus rhythm (rhythm control) or at controlling ventricular rate (rate control) are usually not effective.2,3 They may cause intolerable and/or serious adverse effects and may not prevent systemic embolization.1-3 Finally, despite its efficacy, the Maze surgical procedure is not widely accepted because of its invasive nature and associated morbidity and mortality.4 Encouraged by the high success rate of the percutaneous radiofrequency catheter ablation (RFCA) technique for curing a variety of supraventricular and ventricular tachyarrhythmias5 over the past 15 years, a number of investigators worldwide have attempted to extend the RFCA technology to cure AF. Traditionally, the high efficacy of RFCA against its target arrhythmias has been based upon a fundamental understanding of the electrophysiological mechanisms and anatomic substrates underlying these arrhythmias. However, in the case of AF, the exact electrophysiological mechanism and anatomic substrate remain elusive, despite an extensive body of animal and human research.6-8 Reportedly, current techniques of RFCA can achieve a 60–80% improvement in selected patients with medically refractory AF.9-12 It is believed that the muscular sleeves and antrum of the pulmonary veins may contain both the electrical trigger required for the initiation and/or the critical substrate necessary for maintenance of AF. While the details of the RFCA procedure vary from laboratory to laboratory (i.e., ostial vs antral vs wide-area ablations), the fundamental principle of these procedures is that mapping of the culprit triggering focus causing the arrhythmia is not performed (or even possible). During the ablation procedure, the application of radiofrequency energy is guided primarily by anatomy with secondary assistance provided by local electrical activity (so-called pulmonary vein potentials). This anatomic ablation approach has evolved precisely because of the failure of mapping techniques to localize the trigger for AF, as evidenced by the long-term failure of this technique to provide a durable cure for AF patients.
Journal of Cardiovascular Electrophysiology | 1992
Michael R. Lauer; L.Bing Liem; Charlie Young; Ruey J. Sung
Verapamil‐Sensitive Ventricular Tachycardias. Ventricular tachycardia (VT) due to reentry is often associated with organic structural heart disease, such as coronary artery disease with previous myocardiai infarction, and primary or secondary cardiomyopathy. Treatment of this form of VT generally requires the use of potent antiarrhythmic drugs such as procainamide, quinidine, and amiodarone, or nonpharmacologic interventions such as endocardial resection and implantation of cardioverter defibrillators. Some forms of VT, typically occurring in younger patients and not associated with structural heart disease, may be due to a mechanism other than reentry and may be terminated or prevented by Ca2+ channel or beta blockers. Because these tachycardias are often so effectively treated with these rather benign agents, all patients with sustained VT undergoing an electrophysiologic study should be carefully evaluated to rule out the possibility of having these forms of VT. These tachycardias may be induced by treadmill exercise testing, programmed electrical stimulation, and/or catecbolamine infusion. While it appears that the mechanisms of these tachycardias may be caused by triggered activity related to afterdepolarizations or enhanced automaticity, there is evidence that some may in fact be due to reentry involving Ca2+‐dependent slow conduction. The cellular mechanisms of triggered activity and enbanced automaticity, and their relation to clinical ventricular arrhythmias, are discussed. (J Cardiovasc Electrophysiol, Vol. 3. pp. 500–514 October 1992)