Increased Propensity of Women to Develop Torsades de Pointes During Complete Heart Block

TdP and Complete Heart Block. Introduction : To determine whether an increased female gender susceptibility to torsades de pointes (TdP) may exist in a clinical model of bradycardia- induced long QT syndrome, we investigated reported cases of TdP associated with acquired complete heart block.
Methods and Results : Seventy-two cases reported in the medical literature dating from 1941 through 1993 were identified, all describing TdP or "transient ventricular tachycardia/fibrillation" (to include those cases reported prior to the use of TdP terminology) in the setting of acquired complete heart block unassociated with QT prolonging drugs. Expected female prevalence in complete heart block was estimated at 52%, based on projections derived from 206,016 hospital discharges in the National Inpatient Profile (Commission on Professional and Hospital Activities, Ann Arbor, MI), over the years 1985 through 1992. During complete heart block, mean heart rate was 37 beats/min in both sexes (combined n = 43), and absolute QT interval ranged from 0.52 to 0.88 seconds, with a mean of 0.68 seconds (n = 25). Female prevalence among patients with TdP during complete heart block was greater than expected: 72% for all studied cases (P < 0.001); 70% (P < 0.04) and 74% (P < 0.02) among those reported prior to (n = 35) and during or alter (n = 37) 1980, respectively; 73% (P < 0.03) among those with documented normokalemia (n = 26); and 68% (P = 0.2) among those with a prolonged QT interval and known polymorphic VT (i.e., unequivocal TdP; n = 25).
Conclusion : Despite inherent limitations of this retrospective study, the data are consistent in suggesting a greater than expected female prevalence among patients with TdP related to complete heart block. This finding lends support to a broadening concept of increased susceptibility of women to the development of TdP in various settings of QT prolongation.     

Proarrhythmia with Class III Antiarrhythmic Drugs: Definition, Electrophysiologic Mechanisms, Incidence, Predisposing Factors, and Clinical Implications

Proarrhythmia with Class III Antiarrhythmic Agents. Antiarrhythmic drugs can and do induce unexpected and sometimes fatal reactions by either producing new symptomatic arrhythmias or by aggravating existing arrhythmias. The definition of proarrhythmia has changed since controlled clinical studies showed a dichotomy between arrhythmia suppression and mortality. The nature of proarrhythmia reactions is linked to the electrophysiologic effects of various antiarrhythmic drugs. Whereas Class I agents without accompanying effects on repolarization generally produce ventricular tachycardia (often incessant) or fibrillation. Class III agents typically produce torsades de pointes that may deteriorate into ventricular fibrillation. The precise mechanism of torsades de pointes is not fully elucidated, although early afterdepolarization and increases in spatial or temporal dispersion of repolarization are likely possibilities. Proarrhythmic risk is lowest for amiodarone and is probably related to the drug's complex electrophysiologic profile. The incidence of torsades with sotalol increases with dose and the baseline values of the QT interval; the incidence with d-sotalol and other pure Class III agents remains unclear. Prospective, randomized, placebo-controlled studies to evaluate this are under way. The fact that d-sotalol increases mortality in postinfarction patients suggests that it may possibly be a common property of most, if not all, pure Class III compounds. The ongoing clinical trials with various Class III agents are likely to provide the critical information on this important therapeutic issue.     

The Role of Late INa and Antiarrhythmic Drugs in EAD Formation and Termination in Purkinje Fibers

Multiple components of cardiac Na current play a role in determining electrical excitation in the heart. Recently, the role of nonequilibrium components in controlling cardiac action potential plateau duration, and their importance in regulating the occurrence of afterdepolarizations and arrhythmias have garnered more attention. In particular, late Na current (late I _Na) has been shown to be important in LQT2 and LQT3 arrhythmias. Class III agents like dofetilide, clofilium, and sotalol, which can all cause a drug-induced form of LQT2, significantly lengthen action potential duration at 50% and 90% repolarization in isolated rabbit Purkinje fibers, and can initiate the formation of early afterdepolarizations, and extra beats. These actions can lead to the development of a serious ventricular tachycardia, torsades de pointes, in animal models and patients. However, pretreatment with agents that block late I _Na, like lidocaine, mexiletine, and RSD1235, a novel mixed ion channel blocker for the rapid pharmacologic conversion of atrial fibrillation, significantly attenuates the prolonging effects of Class III agents or those induced by ATX-II, a specific toxin that delays Na channel inactivation and amplifies late I _Na greatly, mimicking LQT3. The Na channel block caused by lidocaine and RSD1235 can be through the open or inactivated states of the channel, but both equivalently inhibit a late component of Na current ( I _Na), recorded at 22°C using whole-cell patch clamp of Nav1.5 expressed in HEK cells. These protective actions of lidocaine, mexiletine, and RSD1235 may result, at least in part, from their ability to inhibit late I _Na during action potential repolarization, and inhibition of the inward currents contributing to EAD and arrhythmia formation.     

Torsades de Pointes as a Cause of Sudden Death in a Patient with Aortic Stenosis and Atrial Fibrillation

The occurrence of sudden cardiac death during Holter monitoring in patients with aortic stenosis has been reported previously. In the majority of the reported cases, the cause of death was a malignant ventricular tachyarrhythmia. The presence of a strong association between frequency and complexity of ventricular arrhythmias and sudden death in patients with aortic stenosis has been proposed. We report the case of a 77‐year‐old woman with aortic stenosis and atrial fibrillation who had an episode of torsades de pointes that degenerated into ventricular fibrillation during Holter monitoring. A short–long–short sequence, but not increased ventricular ectopics, precipitated torsades de pointes and sudden death in this case which is strongly indicative of triggered activity as the underlying mechanism of the lethal arrhythmia.     

Ibutilide-Induced Changes in the Temporal Lability of Ventricular Repolarization in Patients with and without Structural Heart Disease

Introduction: Ibutilide has been shown to prolong repolarization times and increase the risk of ventricular tachyarrhythmias particularly in patients with structural heart disease. The mechanisms underlying its proarrhythmic effects remain incompletely understood. We sought to define the effects of ibutilide on the temporal lability of ventricular repolarization in patients with and without structural heart disease.
Methods: Twenty-four patients referred for electrophysiology study underwent monophasic action potential (MAP) recordings in the right ventricle during sinus rhythm and random interval right atrial pacing (RIAP). Ibutilide was subsequently administered and the recordings repeated both in sinus rhythm and with RIAP. Digitized recordings were analyzed offline for calculation of the QT variability index (QTVI) based on surface ECG, and the MAP duration variability index (MAPDVI) based on the intracardiac MAP signal.
Results: Of 24 patients enrolled, analyses were performed in 21 patients (mean age 59 ± 15 years, 38% women). In three patients, the data were not analyzed due to frequent premature ventricular complexes. Ibutilide resulted in significant changes in heart rate (mean difference: −7.4 ± 0.91 bpm, P < 0.0001) and the surface QT interval (mean difference: 59.6 ± 12.2 ms, P = 0.0001) during sinus rhythm. After ibutilide, QTVI remained unchanged from baseline during sinus rhythm but was significantly different in the setting of RIAP (mean difference: 0.345 ± 0.098, P = 0.0022). With subgroup analyses, these differences remained significant regardless of the presence or absence of heart disease.
Conclusion: Ibutilide results in overall prolongation of ventricular repolarization and reductions in baseline sinus rates. Ibutilide increases temporal lability of repolarization only with enriched fluctuations in heart rate.     

QT and JT Dispersion in Children with Long QT Syndrome

QT and JT Dispersion in Long QT Syndrome. Introduction: Abnormalities of ventricular repolarization leading to ventricular arrhythmias place children with long QT syndrome at high risk for sudden death. Dispersion of the QT (QTd) and JT (JTd) intervals, as markers of cardiac electrical heterogeneity, may be helpful in evaluating children with long QT syndrome and identifying a subset of patients at high risk for development of critical ventricular arrhythmias (ventricular tachycardia, torsades de pointes, and/or cardiac arrest). Methods and Results: The QTd and JTd intervals in 39 children with long QT syndrome were compared to those of 50 normal age-matched children. In the long QT syndrome group, QTd measured 81 ± 70 msec compared to 28 ± 14 msec in the control group (P < 0.05), and JTd in the long QT syndrome group was 80 ± 69 msec compared to 25 ± 15 msec in the control group (P < 0.05). Conclusion: Children with long QT syndrome have an increased QTd and JTd when compared to normal controls. A QTd or JTd ≥ 55 msec correlates with the presence of critical ventricular arrhythmias. These ECG measures of dispersion can be useful in stratifying children with the long QT syndrome who are at higher risk for developing critical ventricular arrhythmias.     

腺垂体功能减退症伴长QT综合征发作尖端扭转性室速一例

患者男性63岁,因突发晕厥急诊入院,发病时在外院颅脑MRI示:空泡蝶鞍,ECG示:长QT伴尖端扭转型室速,给与胺碘酮静脉用药后终止室速,后转入笔者医院,期间无明显诱发因素再发两次.辅助检查:动态心电图示:QT570-640ms窦性心动过缓,交界区逸搏心律;腺垂体功能低下.有植入ICD的绝对适应征,因患者个人因素给予植入...     

Correction for Heart Rate Is Not Necessary for QT Dispersion in Individuals without Structural Heart Disease and Patients with Ventricular Tachycardia

Background: It remains controversial whether QT dispersion should be corrected for heart rate, especially when the limitations of rate correction formulae are considered. We investigated whether incremental atrial pacing affects QT dispersion and the rate‐corrected values according to Bazett's formula in individuals without structural heart disease and in patients with history of sustained ventricular tachycardia. Methods: We studied 32 individuals without structural heart disease (group A), and 16 patients with a history of sustained ventricular tachycardia (group B). QT dispersion and corrected for heart rate QT dispersion using Bazett's formula (QTc dispersion) were calculated in sinus rhythm, and during continuous right atrial pacing for one minute at 100 and 120 beats/min. Results: Interobserver variability was not significant (P ≧ 0.10). QT dispersion did not differ at rest between groups A and B and did not change significantly from baseline at any heart rate in both groups. However, QTc dispersion increased significantly with atrial pacing in a similar manner in group A and group B (42 ± 19 ms at rest vs 53 ± 23 ms at 120 beats/min, P < 0.001 for group A, 39 ± 16 ms at rest vs 60 ± 19 ms at 120 beats/min, P < 0.001 for group B). Conclusions: We conclude that QT dispersion remains unchanged during atrial pacing at heart rates up to 120 beats/min in both individuals without structural heart disease and in patients with a history of sustained ventricular tachycardia. Correction by Bazett's formula results in prolongation of QTc dispersion, yielding values which may be misleading. A.N.E. 2002;7(1):47–52     

尖端扭转型室性心动过速与TP—TE时间及Q—T间期比值关系的研究

目的探讨长Q—T间期患者T波峰末时间（TP-TE时间）、TP-TE／Q—T与尖端扭转型室性心动过速（TdP）发生的相关性。方法选择长Q—T间期患者29例,将其分为伴TdP组（发作期或稳定期）和不伴TdP组两组,通过常规心电图和动态心电图分析测量并比较Q—T间期、校正的Q—T间期（Q—Tc间期）、TP-TE时间和TP-TE／Q—Tc结果伴TdP组稳定期患者TP-TE时间、TP—TE／Q—T（14157±37．33ms、0．27±0．05）和发作期（154．29±42ms、0．29±0．06）均较不伴TdP组（97．60±5．51ms、0．19±0．13）延长或增大。差异均有统计学意义（均P〈0．05）;在预测TdP发生风险时,伴TdP组稳定期和发作期TP-TE时间、TP-TE／Q—T均较Q—T间期更敏感（Wald值分别为1247、15．77和5．77、6．23）,差异均有统计学意义（P〈O．05）。结论TP-TE时间TP-TE／Q—T比值有助于预测长Q—T间期患者发生TdP的风险。     

Long QT syndrome and torsade de pointes in transient left ventricular apical ballooning syndrome

A recently reported cardiac syndrome of reversible left ventricular apical ballooning, also called Takotsubo cardiomyopathy or ampulla cardiomyopathy, clinically resembles acute myocardial infarction and presents with chest pain, anterior electrocardiographic changes and minimal elevation of cardiac enzymes in absence of myocardial ischemia or injury. Left ventricular function recovers completely in days to weeks. This syndrome is likely a non-ischemic, metabolic-dependent syndrome caused by stress-induced activation of the cardiac adrenoceptors, and results in markedly abnormal ventricular repolarization. Reported here is a case of left ventricular apical ballooning syndrome with QT interval prolongation in a young man who developed torsade de pointes and experienced aborted sudden cardiac death. Patient had a complete recovery of cardiac function and normalization of QT interval in a few days. The syndrome of transient left ventricular apical ballooning could be considered among the causes of long QT syndrome and torsade de pointes.     

Role of Dofetilide in Patients with Atrial Fibrillation. Insights from the Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) Study

Dofetilide is a class III antiarrhythmic drug (potassium channel blocker) that has been approved by the regulatory agencies in the United States and throughout the world to convert atrial fibrillation and maintain sinus rhythm. Therapy is initiated in-hospital during heart rhythm monitoring. Doses are selected according to the QT interval and estimated creatinine clearance.In patients with heart failure and prior myocardial infarction, dofetilide was very effective in converting atrial fibrillation and maintaining normal sinus rhythm. In patients with persistent atrial fibrillation, dofetilide compared to placebo was significantly better in converting atrial fibrillation and maintaining sinus rhythm. This was especially true for the highest dose of 500 microg twice-a-day. Caution must be used when initiating dofetilide therapy to avoid torsade de pointes ventricular tachycardia, especially in patients with heart failure, hypertrophy, bradycardia and female gender.     

Non-sustained microvolt level T-wave alternans in congenital long QT syndrome types 1 and 2

Background

Patients with long QT syndrome (LQTS) are predisposed to polymorphic ventricular tachycardia (VT) during adrenergic stimulation. Microvolt T-wave alternans (MTWA) is linked to vulnerability to VT in structural heart disease. The prevalence of non-sustained MTWA (NS-MTWA) in LQTS is unknown.

Congenital long QT syndrome: Severe Torsades de pointes provoked by epinephrine in a digenic mutation carrier

Congenital Long QT Syndrome (LQTS) is a potentially lethal cardiac channelopathy characterized by prolongation of the corrected QT (QTc) interval on the surface electrocardiogram. The hallmark phenotypic features are syncope, seizure or sudden death, however most of the mutation carriers are asymptomatic and their risk for arrhythmias such as Torsade de pointes (TdP) are low. We report a case of Long QT syndrome with a corrected QT of 520 ms. For symptom – arrhythmia correlation a loop recorder was implanted with no documented arrhythmias. Epinephrine testing was performed for clinical risk stratification leading to Torsades de pointes during recovery phase which required defibrillation. Genetic testing discovered two pathogenic heterozygous mutations in two different LQT genes (SCN5A and KCNQ1). We propose a calcium homeostasis mechanism for the interaction of both mutations that exaggerated the phenotype, while each mutation by itself is causing a relatively modest phenotype.     

Risk Stratification for Serious Arrhythmic Events Using Nonsustained Ventricular Tachycardia and Heart Rate Turbulence Detected by 24‐Hour Holter Electrocardiograms in Patients with Left Ventricular Dysfunction

Background: Previous studies have described the clinical usefulness of the presence of nonsustained ventricular tachycardia (NSVT) and defined heart rate turbulence (HRT) in stratifying patients at risk. We prospectively assessed whether HRT can facilitate the predictive accuracy of NSVT for identifying patients at risk for serious arrhythmic events in patients with left ventricular (LV) dysfunction. Methods: We enrolled 299 consecutive patients with LV dysfunction (ejection fraction ≤ 40%) including ischemic (n = 184) and nonischemic causes (n = 115). The presence of NSVT was assessed on Holter electrocardiograms (ECGs). HRT was simultaneously measured from Holter ECGs, assessing two parameters: turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO and TS were abnormal. The end point was defined as of sudden cardiac death (SCD) and sustained ventricular tachyarrhythmias (VTs). Results: NSVT was documented in 93 patients (32.7%). For HRT assessment, 17 patients (5.6%) were not utilized. Of 282 patients, 68 (24.1%) were HRT positive. During follow‐up of 960 ± 444 days, 14 patients (5.0%) reached the end point. NSVT, HRT, and diabetes were significantly associated with the end point. On multivariate analysis, NSVT had the strongest value for the end point, with an HR of 4.4 (95%CI, 1.4–14.3; P = 0.0138). When NSVT combined with HRT, the predictive accuracy is more increased, with an HR of 8.2 (95%CI, 2.9–23.3; P < 0.0001). The predictive values of the combination were higher than single use of NSVT or HRT. Conclusions: HRT can facilitate the predictive accuracy of NSVT for identifying patients at risk for serious arrhythmic events in patients with LV dysfunction.