Analysis of the pattern of initiation of sustained ventricular arrhythmias in patients with implantable defibrillators

INTRODUCTION: The purpose of this study was to analyze the pattern of initiation of sustained ventricular arrhythmias in patients with varying types of underlying structural heart disease. METHODS AND RESULTS: The study group consisted of 90 patients with an implantable cardioverter defibrillator. Cardiovascular diagnoses included coronary artery disease in 64 patients (71%). The patients were divided into four groups based on the type and severity of structural heart disease. Two hundred sixty episodes of sustained ventricular arrhythmias were analyzed. The mean coupling interval of the initiating beat of all ventricular arrhythmias was 523 +/- 171 msec. The coupling interval of the initiating beat was longer in patients with impaired ventricular function, particularly those with nonischemic dilated cardiomyopathy. The prematurity index was similar regardless of the type of underlying structural heart disease. However, the prematurity index was shorter in patients with polymorphic ventricular tachycardia (VT) compared to those with monomorphic VT. A pause was observed more commonly before the onset of polymorphic VT/ventricular fibrillation than sustained monomorphic VT. Two hundred twenty-two (85%) of the arrhythmia episodes were initiated by a late-coupled premature beat, 33 (13%) were initiated by an early-coupled premature beat, and 5 episodes (2%) were initiated with a short-long-short sequence. The pattern of initiation of the ventricular arrhythmias was similar in all patient groups and for both monomorphic and polymorphic tachycardias. CONCLUSION: These findings demonstrate that sustained ventricular arrhythmias typically are initiated by late-coupled ventricular premature depolarizations, regardless of the type or severity of underlying structural heart disease or resultant arrhythmia.     

When an ICD is not the answer... hypothyroidism-induced cardiomyopathy and torsades de pointes

Introduction: An increasing number of patients with left ventricular (LV) dysfunction are referred for placement of an implantable cardioverter‐defibrillator (ICD). Case Report: A 78‐year‐old female with fatigue, palpitations, and presyncope was referred for consideration of an ICD because of a cardiomyopathy and nonsustained ventricular tachycardia (VT). Her evaluation revealed severe hypothyroidism, marked QT prolongation, and episodes of torsades de pointes. With levothyroxine therapy, her ventricular arrhythmias rapidly abated, with subsequent normalization of LV function and the QT interval. Conclusions: This report highlights the critical importance of detecting hypothyroidism as an unusual cause for reversible cardiomyopathy and ventricular arrhythmias.     

Terminology of torsades de pointes

Marked prolongation of the QT interval may be associated with life-threatening ventricular tachycardia. The ventricular tachycardia has a polymorphous appearance and is usually induced by antiarrhythmic drugs. This peculiar type of ventricular tachycardia was termed by Desserstenne torsades de pointes because of its twisting ORS axis. The main reason to give this entity a special name that differentiates it from other types of ventricular tachycardia is the unique therapeutic approach to its treatment. Torsades de pointes can be suppressed by interventions that shorten the QT interval by increasing the heart rate, such as ventricular or atrial pacing, isoproterenol infusion, or atropine. Recently intravenous magnesium was also shown to be extremely effective. If torsades de pointes is treated as a conventional ventricular tachycardia by drugs that may further prolong the QT interval, it may lead to fatal results. To draw the attention of physicians to this unusual form of ventricular tachycardia, we suggest that the term torsades de pointes be kept. This specific diagnosis will hopefully guide the treating physician in selecting the appropriate mode of therapy.     

Report of a life-threatening arrhythmia after hospital discharge in a liver transplant recipient with previously unknown congenital long QT syndrome

The long QT syndrome affects heart rhythm by prolonging ventricular repolarisation; it is potentially life-threatening since it can evolve into torsades de pointes (a polymorphic ventricular tachycardia) and/or ventricular fibrillation. The case is presented of a 55-year-old liver transplant recipient with a genetically determined long QT syndrome not detected by the standard preoperative cardiological evaluation. It was mild in the immediate post-operative period but developed into torsades de pointes after discharge, probably as a result of therapy. This case was particularly challenging because the first arrhythmic episodes were short and electocardiographically silent, and thus the related faints were thought to have a neurological basis. When the true cause emerged during a monitored episode of torsades de pointes, electric defibrillation was used to restore sinus rhythm and isoproterenol administered to increase heart rate and thus shorten the prolonged QT interval Long-term control was obtained by means of an implantable intracardiac defibrillator. In orthotopic liver transplant recipients with long QT syndrome, particular attention should be given to post-operative therapy as some routinely used drugs can trigger life-threatening ventricular arrhythmias.     

Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs

The cardiovascular effects of cisapride administered intravenously at escalating doses with and without pretreatment with erythromycin were evaluated in morphine/chloralose anesthetized dogs. Dogs were instrumented to permit simultaneous recording of ECGs, left ventricular (LVP) and aortic (AoP) pressures, as well as programmed electrical stimulation (PES). Escalating intravenous doses of cisapride from 2 to 8 mg/kg (four times the recommended therapeutic dose) increased the heart rate (HR) and prolonged the corrected QT interval (QTc) (p<0.05) compared to controls. Pretreatment with erythromycin failed to enhance the effect of cisapride on either HR or QTc. Cisapride with or without erythromycin pretreatment had no effect on AoP, but depressed indices of left ventricular contractility (dP/dt _max decreased while PEP/ET increased) compared to controls. No dogs developed spontaneous arrhythmias, and arrhythmias were not inducible by PES. Cisapride with or without erythromycin pretreatment altered the orientation of the T-wave vector (p<0.05) compared to controls, indicating a primary effect of cisapride on ventricular repolarization. The QTc and T wave changes observed were consistent with the known action of cisapride on canine l_Kr channels.     

Cardiac Pacing in the Long QT Syndrome:

Cardiac Pacing in the Long QT Syndrome. A review of published data on cardiac pacing in the long QT syndrome (LQTS) is presented, in the hope that optimization of patient selection and pacemaker programming will prevent arrhythmic death. LQT3 patients may derive particular benefit from pacing because the dispersion of repolarization worsens steeply during bradycardia in this genotype. However, concluding that other genotypes will not benefit from pacing is premature. Pacing may he especially beneficial for patients with "pause-dependent" arrhythmias. Programming should include a sufficiently fast lower rate limit. Features that allow heart rate slowing beyond the lower rate limit or that may trigger pauses must he programmed "off" because pauses are proarrhythmic in this population. Pause-prevention pacing algorithms may he beneficial.     

Effects of Three Fluoroquinolones on QT Analysis After Standard Treatment Courses

Background: Fluoroquinolone (FQ) agents have been speculated to influence the risk of Torsades de pointes (Tdp). Methods of evaluating this risk are varied and not systematic. QTc interval (QTc) prolongation is the most commonly used marker of Tdp, but has questionable utility. QT dispersion (QTd) may be a more selective marker of Tdp. No assessment of QTd for FQs has been reported. The current study evaluates the effects of three commonly prescribed FQs by comprehensive QT analysis. Methods: In an open‐label crossover study, 13 healthy participants received 3 treatments in random order: ciprofloxacin 500 mg twice daily, levofloxacin 500 mg once daily, and moxifloxacin 400 mg once daily. Each treatment was given for 7 days with a 1‐week washout period. Twelve‐lead electrocardiographic measurements were performed prior to the first dose, 2 hours after the first dose, and following the 7‐day medication course. QTc prolongation was determined by measurement of lead II, and QTd from the difference between the maximum and minimum QTc intervals among the 12 leads. The data were analyzed using Friedman ANOVA, with the Wilcoxon signed rank test post hoc analysis, with P < 0.05 significance. Results and Conclusions: No difference was seen in baseline QTc (P = 0.48) or QTd (P = 0.92). Following 7 days of moxifloxacin, the QTc was prolonged by 6 ms relative to baseline (408 ms, P = 0.022), and 11 ms from the 2‐hour measurement (403 ms, P = 0.003). Ciprofloxacin and levofloxacin had no effect on QTc, and no FQ changed the QTd. Within our study population, ciprofloxacin and levofloxacin did not display an increased risk for Tdp. Moxifloxacin, while showing QTc prolongation, did not affect QTd, and an increased Tdp risk is questionable.     

QT Dispersion: Problems of Methodology and Clinical Significance

QT Dispersion. QT dispersion is defined as the difference in QT interval between the different leads of the surface 12-lead ECG. This may provide an indirect measure of the underlying inhomogeneity of myocardial repolarization, which is believed to be important in arrhylhmogenesis. Methodology for determining QT dispersion varies significantly between studies, and the results of these studies need to be interpreted in light of the methodology used. Although QT dispersion is developing into an important research tool, as yet it has no established role in clinical practice. Once standardization of methodology is achieved a clinical role may emerge, particularly in the assessment of patients before and after intervention aimed at reduction of arrhythmia risk.     

Torsades de pointes: Arrhythmia,syndrome, or chimera? A perspective in the light of the Lambeth Conventions

What is torsades de pointes? Is it an arrhythmia or a syndrome? The distinction is critical. In this article I have attempted to explain why this is so. Both from the clinical and nonclinical standpoint, it is of overriding importance that torsades de pointes be amenable to measurement and quantification. This is the fundamental prerequisite for any variable to be of value as an endpoint in an investigation. Measurement and quantification require that a variable has an objective definition that is both inclusive and exclusive. In his seminal work, Dessertenne coined the term torsades de pointes to describe an arrhythmia with unusual features. However, torsades de pointes has been reinterpreted and redefined by Dessertenne's successors. It was originally described as occurring in certain settings (e.g., hypokalemia). However, this has been reinterpreted to mean that a specific set of antecedent conditions (such as hypokalemia) are part of the definition of torsades de pointes. If this is the case, then torsades de pointes is a syndrome, not an arrhythmia. For those more concerned with arrhythmias than with syndromes, the key issue to be determined is what to call the arrhythmia that is part of the syndrome. I have put forward some suggestions with the objective of answering this question, using the Lambeth Conventions as a guide. I believe that there is strong case for ventricular tachyarrhythmias to be classified simply as tachycardia or fibrillation, with the optional use of the term delayed repolarization syndrome in cases where a long QT interval is present. The latter term should be used as one might use the term acute myocardial ischemia, i.e., to denote an underlying condition; it should not be used to define the arrhythmia itself. Twenty-four years after its introduction, the term torsades de pointes has now become a chimera and is best abandoned.     

Arrhythmogenesis of T wave alternans associated with surface QRS complex alternans and the role of ventricular prematurity: observations from a canine model of LQT3 syndrome

INTRODUCTION: T wave alternans (TWA) is characterized by cycle-to-cycle changes in the QT interval and/or T wave morphology. It is believed to amplify the underlying dispersion of ventricular repolarization. The aim of this study was to examine the mechanisms and arrhythmogenesis of TWA accompanied by QRS complex and/or blood pressure (BP) waveform alternans, using transmural ventricular electrogram recordings in an anthopleurin-A model of long QT syndrome. METHODS AND RESULTS: The cardiac cycle length was gradually shortened by interruption of vagal stimulation, and TWA was induced in six canine hearts. Transmural unipolar electrograms were recorded with plunge needle electrodes from endocardial (Endo), mid-myocardial (Mid), and epicardial (Epi) sites, along with the surface ECG and BP. The activation-recovery interval (ARI) was measured to estimate local refractoriness. During TWA, ARI alternans was greater at the Mid than the Epi/Endo sites, and it was associated with the development of marked spatial dispersion of ventricular repolarization. As TWA increased, ventricular activation of the cycles associated with shorter QT intervals displayed delayed conduction at the Mid sites as a result of a critically longer ARI of the preceding cycle and longer QT interval, while normal conduction was preserved at the Epi site. Delayed conduction at the Mid sites manifested as surface ECG QRS and BP waveform alternans, and spontaneous ventricular tachyarrhythmias developed in absence of ventricular prematurity. In other instances, in absence of delayed conduction during TWA, ventricular premature complexes infringed on a prominent spatial dispersion of ventricular repolarization of cycles with long QT intervals and initiated ventricular tachyarrhythmia. CONCLUSION: TWA accompanied by QRS alternans may signal a greater ventricular electrical instability, since it is associated with intramural delayed conduction, which can initiate ventricular tachyarrhythmia without ventricular premature complexes.     

Differences in Corrected QT Intervals at Minimal and Maximal Heart Rate May Identify Patients at Risk for Torsades de Pointes During Treatment with Antiarrhythmic Drugs

Change in QT Interval with HR May Predict Torsades. The mechanism of torsades de pointes as a proarrhythmic response to antiarrhythmic drugs is not clear. We hypothesized that the difference in the corrected QT interval (QT_c, Bazett's formula) with varying autonomic tone and heart rate during 24-hour ambulatory ECG would help identify patients at risk. Ten patients with antiarrhythmic drug-induced torsades de pointes were compared with 28 controls. The QT_c. at maximal and minimal heart rate during antiarrhythmic drug-free ambulatory ECGs were measured. The mean QT_c, at minimal heart rates for patients was 0.413 ± (KI02 seconds and 0.420 ± 0.072 seconds for controls (P = 0.715). The mean QT_c, at maximal heart rates for patients was 0.555 ± 0.022 seconds and for controls was 0.439 ± 0.011 seconds (P = 0.00l). Mean QT_c, between minimal and maximal heart rates were significantly different for patients (P = 0.015) but were not for controls (P = 0.151). Using an arbitrary QT, difference cutoff of 0.075 seconds, this approach identified patients at risk for antiarrhythmic drug-induced torsades de pointes with a sensitivity of 70% (7 of 10) and a specificity of 89% (P < 0.003 by Chi-square analysis with Vales' correction). In conclusion, patients with antiarrhythmic drug-induced torsades de pointes had a greater rise in QT_c, from minimal to maximal heart rate during ambulatory ECG than controls. Further larger prospective trials will be required to establish the value of this approach to identify patients at risk for this type of proarrhythmia.     

Bradycardia-Mediated Ventricular Electrical Remodeling

Bradycardic states are associated with myocardial electrical remodeling predisposing to potentially lethal ventricular tachydysrhythmias. We used a novel model of complete heart block (CHB) in the rabbit to test the hypothesis that ventricular activation rate is the primary determinant of early bradycardic electrical remodeling. Chronic endocardial right ventricular demand (VVI) pacing was applied at either the near-physiologic rate of 280 beats/min or at the bradycardic rate of 140 beats/min, beginning immediately after transcatheter radiofrequency AV node ablation. A third group of animals underwent sham ablation and served as non-paced, normal sinus rhythm controls. The major finding of this study was that electrical remodeling was established within 8 days of CHB induction in the bradycardic animals, but was not observed in either of the other 2 groups. Bradycardic animals had significant QT interval prolongation and biventricular downregulation of the delayed rectifier K+ currents, IKr and IKs. The Ca2+-independent transient outward K+ current, I_to, and the inwardly rectifying K+ current, I_K1, were unaffected. This paper highlights these findings in the context of a literature-based review of heart rate-dependent remodeling of the mammalian myocardium, summarizing the current state of knowledge and describing future challenges.     

Mechanism-Specific Antiarrhythmic Effects of the Potassium Channel Activator Levcromakalim Against Repolarization-Dependent Tachycardias

Mechanism-Specific Action of Levcromakalim. Introduction: The hypothesis that levcromakalim. a potassium channel (I_K-ATP.) activator with antihypertensive properties, has a mechanism-specific antiarrhythmic action against repolarization-dependent ventricular tachycardias (VTs) was tested in dogs. Methods and Results: A low dose of leveromakalim (0.01 mg/kg) was selected, which decreased blood pressure by 25% but had almost no electrophysiologic effect on AV nodal or ventricular conduction or effective refractory period. In dogs with chronic AV block, the antiarrhythmic action of this dose of levcromakalim was evaluated in three models of abnormal impulse formation: (I) dsotalol (2 mg/kg) induced torsades de pointes VT, initiated by early afterdepolarizations (EADs). (2) sustained ouabain-induced VTs, which are dependent on delayed after depolarizations (DADs), and (3) VT occurring 24 hours after left anterior descending coronary artery occlusion, which are likely based on abnormal automaticity. Levcromakalim abolished d-sotalol induced U waves, ventricular ectopic beats, and self-terminating bouts of torsades de pointes. Induction of torsades de pointes by pacing was also completely prevented. The cycle length of the idioventricular rhythm, which was lengthened after d-sotalol from 1490 ± 515 to 1700 ± 610 msec (P < 0.05), remained similar after levcromakalim (1655 ± 580 msec). The QT(U) duration, which was increased after d-sotalol from 410 ± 55 to 550 ± 40 msec (P < 0.05), normalized to 405 ± 70 msec (P < 0.05). Lcvcromakulim did not suppress but rather enhanced ouabain-induced VT by decreasing the cycle length slightly from 315 ± 35 to 290 ± 35 msec (P < 0.05). Pretreatment with a beta Mocker prevented this acceleration in rate. Finally, levcromakalim had no effect on VT 24 hours after infarction. Conclusion: A low dose of levcromakalim has specific antiarrhythmic properties against repolarization-dependent arrhythmias, but it does not affect VTs based on other mechanisms of abnormal impulse formation.     

Early Afterdepolarizations Produced by d,1-Sotalol and Clofilium

EAD Formation by Class III Drugs. Introduction: The roles for L-type calcium current and Na-Ca exchange in early afterdepolarizations (EADs) attending d, l-sotalol and clofilium were examined in canine Purkinje fibers and in enzymatically dispersed myocytes from canine subepicardium. Methods and Results: Spontaneous EADs were compared to EAD formation potentiated by stimulation of Na-Ca exchange and facilitation of I_Ca-L (Bay K8644). Bay K8644 (10^-8 M) and stimulation of Na-Ca exchange potentiated bradycardia-dependent EADs. Stimulation of Na-Ca exchange in Pnrkinje fibers pretreated with d, l-sotalol (10^-5 M) and clofilium (10^-7 M) induced EADs at takeoff potentials negative (-63 ± 4 and -62 ± 4 mV, respectively) to EADs potentiated by Bay K8644 (10^-8 M) (-33 ± 2 and -34 ± 2 mV, respectively, P < 0.05), or EADs induced by Bay K8644 alone (10^-6 M) (-31 ± 5 mV). In myocytes, Bay K8644 (10^-8 M) potentiated EADs in d, l-sotalol- (10^-6 to 10^-4M) or clofilium-treated (10^-9 to 10^-7 M) cells at reduced potentials (-10 ± 3 and -10 ± 4 mV, respectively) compared to EADs elicited by clofilium or d, l-sotalol alone (-25 ± 3 and -24 ± 3 mV, respectively), or stimulation of Na-Ca exchange in the presence of d, l-sotalol or clofilium (-26 ± 4 and -26 ± 4 mV, respectively). Spontaneous EADs or EADs elicited by stimulation of Na-Ca exchange coincident with drug treatment were suppressed by increasing Ca_o²⁺ but were not suppressed by nifedipine (10^-7 M). Conclusion: EADs elicited by d, l-sotalol and clolllium in canine Purkinje tissue and epicardial myocytes are dependent upon Na-Ca excbange rather than I_Ca-L“window current.”     

Transient QT prolongation with torsades de pointes tachycardia after ablation of permanent junctional reciprocating tachycardia

INTRODUCTION: Catheter ablation with radiofrequency energy is a curative therapy in patients with permanent junctional reciprocating tachycardia (PJRT). METHODS AND RESULTS: For the first time, we report a case of transient QT prolongation with torsades de pointes tachycardia 18 hours after successful radiofrequency energy ablation of PJRT in a 25-year-old woman with tachycardia-induced cardiomyopathy. Of note, the torsades de pointes occurred in the absence of bradycardia, electrolyte disturbances, or QT-prolonging drugs. This patient initially was thought to have a hereditary long QT syndrome that was unmasked by PJRT ablation. Therefore, the patient received an implantable defibrillator in addition to beta-blocker therapy, which was discontinued 6 months later. Surprisingly, the QT interval completely normalized within 1 week after PJRT ablation, and the patient remained free of arrhythmias during a follow-up period of 4.5 years. CONCLUSION: Patients with incessant tachyarrhythmias should undergo ECG monitoring for at least 24 hours following successful radiofrequency catheter ablation because transient QT prolongation with torsades de pointes may occur even in the absence of bradycardia, QT-prolonging drugs, or electrolyte disturbances.