Refining detection of drug-induced proarrhythmia: QT interval and TRIaD

QT interval prolongation is so frequently associated with torsades de pointes (TdP) that it has come to be recognized as a surrogate marker of this unique tachyarrhythmia. However, not only does TdP not always follow QT interval prolongation, but TdP can occur even in the absence of a prolonged QT interval. Worse still, even shortening of the QT interval may be associated with serious arrhythmias (particularly ventricular tachycardia [VT] and ventricular fibrillation [VF]). It appears increasingly probable that the distinction between various ventricular tachyarrhythmias may be arbitrary, and drug-induced TdP, polymorphic VT, VT, catecholaminergic polymorphic VT, and VF may represent discrete entities within a spectrum of drug-induced proarrhythmia. Although they are differentiated by the coupling interval and the duration of QT interval, they appear to share a common substrate: a set of disturbances of repolarization characterized by Triangulation, Reverse use dependency, electrical Instability of the action potential, and Dispersion (TRIaD). It is becoming increasingly evident that augmentation of TRIaD, rather than changes in the duration of QT interval, provides the proarrhythmic substrate. In contrast, when not associated with an increase of TRIaD, QT interval prolongation can be an antiarrhythmic property. Electrophysiologically, augmentation of TRIaD can be explained by inhibition of hERG (human ether-a-go-go related gene) channel. Because drug-induced disturbances in repolarization commonly result from inhibition of hERG channels or I(Kr), hERG blockade and the resulting prolongation of QT interval are important properties of a drug to be studied. However, these need only be a concern if associated with TRIaD. More significantly, TRIaD so often precedes prolongation of action potential duration or QT interval and ventricular tachyarrhythmias that it should be considered a marker of proarrhythmia until proven otherwise, even in the absence of QT interval prolongation. Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT interval prolongation alone.     

Fast and slow torsade de pointes--electrocardiographic characteristics

BACKGROUND: Clinical value of electrocardiographic features of torsade de pointes (TdP) has not yet been well established. AIM: To compare the mode of onset and ECG characteristics of slow (s-TdP) and fast (f-TdP) episodes of TdP. METHODS: 54 episodes of TdP recorded in 6 patients (5 females, one male, mean age 64.4 years) with acquired long QT syndrome were analysed. Baseline rate of TdP (V-V), ventricular rate variability (VRV), coupling interval (CI) at the onset of TdP, prematurity index (PI) and the first cycle length (FCL) were compared between 31 s-TdP (<200 beats/min) and 23 f-TdP (> or =220) episodes of TdP. RESULTS: Episodes of f-TdP were preceded by a significantly faster basal rhythm than s-TdP (R-R interval: 922 ms vs 1062 ms, p=0.03). QT interval was almost identical in both groups (517 ms vs 515 ms, NS, respectively). No significant differences were noted in the CI of the initiating beat (488 ms vs 472 ms, NS) nor in the PI (0.53 vs 0.47, NS). TdP was most frequently spontaneously terminated by a gradual slowing of the tachycardia rate; 58% of s-TdP and 39% of f-TdP episodes stopped in this way. An acceleration of ventricular rate before termination of TdP was noted in 32% of s-TdP and in 26% of f-TdP episodes. Episodes of f-TdP were longer than s-TdP episodes (mean of 19.7 vs 6.7 ventricular complexes per one episode, p=0.0003).There were significant differences in the VRV parameter (p=0.0005) and FCL (p=0.004) between both types of TdP. Faster TdP were characterised by lower ventricular rate variability (VRV - 19.5 msec) than s-TdP (VRV - 39.4 msec). Of 54 episodes of TdP, 9 (16.6%) degenerated into VF and required DC shock. Of 31 s-TdP episodes, one (3.2%) degenerated into VF compared with 8 (34.7%) episodes of f-TdP (p<0.04). CONCLUSIONS: Episodes of fast TdP were characterised by a longer duration, shorter first cycle of the arrhythmia and lower ventricular rate variability than episodes of slow TdP. Fast episodes of TdP were preceded by faster baseline rhythm before TdP. Faster TdP more frequently degenerated into VF than slower episodes.     

Heterogeneous regional endocardial repolarization is associated with increased risk for ischemia-dependent ventricular fibrillation after myocardial infarction

Repolarization Heterogeneity and Sudden Death Risk. INTRODUCTION: The aim of this study was to investigate whether the characteristics of endocardial ventricular repolarization are associated with differential risk for sudden death. Prolonged surface QT interval is associated with increased arrhythmic risk after myocardial infarction (MI), but the underlying mechanism of QT prolongation and its relation to lethal arrhythmias are unclear. METHODS AND RESULTS: Ventricular fibrillation (VF) risk was assessed in 12 dogs 1 month after anterior MI during an exercise test coupled with brief circumflex coronary occlusion. Susceptible dogs (n = 5) developed VF during the brief ischemic episode, whereas resistant dogs did not (n = 7). Surface QT interval was measured at rest. Endocardial electroanatomic catheter maps of left ventricular repolarization were obtained in four unique regions identified by echocardiography and compared between groups. Compared to resistant dogs, susceptible dogs were characterized by prolonged surface QT intervals (240 +/- 10 msec vs 222 +/- 7 msec, P = 0.04). In addition, they had lower baroreflex sensitivity (9.7 +/- 1.5 msec/mmHg vs 28 +/- 9.8 msec/mmHg, P < 0.01) and a tachycardic response to acute ischemia suggesting higher propensity for stronger sympathetic reflexes. Surface QT interval prolongation in susceptible dogs was due to a marked heterogeneity of endocardial left ventricular repolarization (239 +/- 42 msec, basal anterior wall vs 197 +/- 35, lateral wall; P < 0.001). Resistant animals had no regional differences in endocardial repolarization. CONCLUSION: Sympathetic activation following MI not only produces adverse structural remodeling but also contributes to adverse electrophysiologic remodeling resulting in heterogeneous ventricular repolarization and in a myocardial substrate conducive to lethal reentrant arrhythmias.     

Predictive factors of ventricular fibrillation triggered by pause-dependent torsades de pointes associated with acquired long QT interval: role of QT dispersion and left ventricular function

INTRODUCTION: Death due to acquired torsades de pointes usually is caused by ventricular fibrillation (VF), but the contributing factors to VF triggered by pause-dependent torsades de pointes are not understood. METHODS AND RESULTS: We evaluated 91 patients who fulfilled four criteria: (1) pause-dependent torsades de pointes; (2) prolonged QT interval and/or corrected QT (QTc) (>0.44 sec); (3) long-short initiation sequence; and (4) conditions known to induce pause-dependent torsades de pointes. There were 38 patients with a documented VF (group I) and 53 without VF (group II). Absolute and relative dispersions of QT and QTc were calculated based on the 12-lead standard ECG. Group I differed from group II with regard to myocardial infarction history (32% vs 13%; P = 0.035), left ventricular ejection fraction (44% +/- 14% vs 65% +/- 9%; P < 0.0001), presence of structural heart disease (100% vs 20.8%; P < 0.0001), QT mean (591 +/- 73 msec vs 514 +/- 78 msec; P < 0.0001), QTc mean (563 +/- 76 msec vs 508 +/- 90 msec; P = 0.002), absolute QT dispersion (166 +/- 56 msec vs 84 +/- 49 msec; P < 0.0001), relative QT dispersion (9.9% +/- 3.5% vs 6.3% +/- 3.2%; P < 0.0001), absolute QTc dispersion (158 +/- 57 msec vs 81 +/- 44 msec; P < 0.0001), and relative QTc dispersion (9.9% +/- 3.6% vs 6.2% +/- 3%; P < 0.0001). Multiple regression analysis showed that ejection fraction (P = 0.0001), presence of structural heart disease (P < 0.0001), and relative QTc dispersion (P = 0.038) were the only independent predictors of VF. CONCLUSION: Left ventricular function, presence of structural heart disease, and QTc relative dispersion should be evaluated carefully in patients with conditions susceptible to inducing torsades de pointes.     

Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs

Drug-induced QT prolongation has such a strong correlation with torsade de pointes (TdP) that it comes to serve as a surrogate for TdP. As a result, drugs that prolong QT by as little as a few ms, even without any evidence of TdP, may get dropped from development or blocked from approval. However, measurement of QT with ms accuracy may be impossible to achieve. Worse, some drugs that lengthen the QT interval are not only not proarrhythmic, they may even be antiarrhythmic; while some that shorten the QT can be strongly proarrhythmic. Indeed, proarrhythmia related to repolarization disturbances is caused by triangulation, reverse use dependence, instability, and dispersion (TRIaD). When TRIaD is present with QT prolongation it commonly yields TdP, but when TRIaD is combined with QT shortening it preferentially leads to VF instead. While TdP is lethal in less than 20% of instances, VF is much more morbid. Worse, available evidence suggests that there is more death from drug-induced fibrillation than TdP. Thus, QT prolongation alone is not very useful. Instead, the T-wave should be used in alternate ways: extraction of TRIaD.     

Unique ECG presentations and clinical management of a symptomatic LQT2 female carrying a novel de novo KCNH2 mutation

A 26-year-old woman, 12 days in postpartum, developed recurrent syncope and cardiac arrest. Her ECG revealed QT-prolongation associated with LQT2-specific T-U wave patterns, T wave alternans, long QT-dependent torsade de pointes (TdP) and ventricular fibrillation (VF). She also had intermittent LBBB (80 bpm) on alternate beats and RBBB at sinus tachycardia (113 bpm). Family genotyping revealed a novel de novo missense mutation G604C of KCNH2. Propranolol slowed heart rate and further prolonged QT interval (610 ms) that caused TdP recurrence. Mexiletine combined with magnesium and potassium supplements prevented TdP/VF recurrence. This patient has remained event-free after 9-month follow-up.     

完全性房室传导阻滞患者发生尖端扭转型室性心动过速的危险因素分析

目的　分析完全性房室传导阻滞患者发生尖端扭转型室性心动过速 (Td P)的危险因素。方法　用 logistic回归法分析 116例完全性房室传导阻滞住院患者 Td P的发生率与年龄、性别、治疗前血钾浓度、QT间期、校正的 QT间期 (QTc)、心率 (HR)的相关性。结果　 12例患者 (10 .3% )发生 Td P,其中女性 9例。Td P组血钾浓度为 (3.5 4±0 .5 5 ) m mol/ L ,明显低于未发生 Td P组血钾浓度 (4 .0 1± 0 .5 7) mm ol/ L (P<0 .0 1)。 Td P组 QT间期为 (0 .5 7±0 .0 75 ) s,明显大于未发生 Td P组 QT间期 (0 .4 6 5± 0 .0 93) s,(P<0 .0 1)。 Td P组年龄、HR、QTc与未发生 Td P组无显著差异。女性、血钾浓度和 QT的风险比值 (OR)分别为 5 .6 39、6 .773和 5 .90 5 ;而年龄、HR、QTc的 OR分别为 1.0 12、0 .92 5、1.0 30。结论　完全性房室传导阻滞患者发生 Td P的独立危险因素是低血钾浓度、长 QT间期和女性。对女性完全性房室传导阻滞患者应给予更积极的治疗 ,以免发生 Td P。     

Suppression of amiodarone-induced torsade de pointes by landiolol in a patient with atrial fibrillation-mediated cardiomyopathy

An elderly Japanese woman developed acute decompensated heart failure caused by persistent atrial fibrillation (AF) and left ventricular systolic dysfunction. Approximately 6 days after starting intravenous administration of amiodarone (600 mg/day) for maintaining sinus rhythm after cardioversion of AF, electrocardiograms revealed a prolonged QT interval associated with torsade de pointes (TdP). The amiodarone-induced TdP disappeared after intravenous administration of landiolol plus magnesium and potassium, without discontinuation of amiodarone or overdrive cardiac pacing, although the prolonged QT interval persisted. To the best of our knowledge, this is the first report that landiolol could be effective for amiodarone-induced TdP.     

Mode of Onset of Malignant Ventricular Arrhythmias in Idiopathic Ventricular Fibrillation

Mode of Onset of Idiopathic VF. Introduction : The mode of onset of malignant ventricular arrhythmias (ventricular tachycardia [VT] or ventricular fibrillation [VF] has been well described in patients with organic heart disease and in patients with the long QT syndromes. Less is known about the mode of onset of VF in patients with out-of-hospital VF who have no evidence of organic heart disease or identifiable etiology.
Methods and Results : We reviewed the ECGs of all our patients with Idiopathic VF. Documentation of the onset of spontaneous arrhythmias was available for 22 VK episodes in 9 patients (6 men and 3 women; age 41 ± 16 years). In all instances, spontaneous VF followed a rapid polymorphic VT, which was initiated by premature ventricular complexes (PVCs) with very short coupling intervals. The PVC initiating VF had a coupling interval of 302 ± 52 msec and a prematurity index of 0.4 ± 0.07. These PVCs occurred within 40 msec of the peak of the preceding T wave. Pause-dependent arrhythmias were never observed.
Concltision : Cardiac arrest among patients with idiopathic VF has a very distinctive mode of onset. Documentation of a polymorphic VT that is not pause dependent is of diagnostic value.     

Suppression of amiodarone‐induced torsade de pointes by landiolol in a patient with atrial fibrillation‐mediated cardiomyopathy

An elderly Japanese woman developed acute decompensated heart failure caused by persistent atrial fibrillation (AF) and left ventricular systolic dysfunction. Approximately 6 days after starting intravenous administration of amiodarone (600 mg/day) for maintaining sinus rhythm after cardioversion of AF, electrocardiograms revealed a prolonged QT interval associated with torsade de pointes (TdP). The amiodarone‐induced TdP disappeared after intravenous administration of landiolol plus magnesium and potassium, without discontinuation of amiodarone or overdrive cardiac pacing, although the prolonged QT interval persisted. To the best of our knowledge, this is the first report that landiolol could be effective for amiodarone‐induced TdP.     

克罗卡林对长QT间期扭转型室性心动过速的治疗作用及机制

记录家兔心外膜单相动作电位（ＭＡＰ），应用氯化铯（ＣｓＣｌ）建立多形性室性心动过速（简称室速）模型，模拟临床ＱＴ间期延长扭转型室速（ＴｄＰ），研究克罗卡林（Ｃｒｏｍａｋａｌｉｍ）对触发活动及ＴｄＰ的抑制作用。结果显示：（１）应用ＣｓＣｌ后，１６只家兔均出现早期后除极（ＥＡＤ）及室性心律失常（其中１０只为ＴｄＰ）。异位心室搏动的启动电位、耦联间期与ＥＡＤ的振幅及耦联间期高度相关（ｒ分别为０．９４，０．９７）；（２）与用药前相比，克罗卡林使ＥＡＤ发生率下降（１００％ＶＳ１８．８％，Ｐ＜０．０５），平均振幅降低（１１．５±２．６ｍＶＶＳ５．２±４．０ｍＶ，Ｐ＜０．０５）；（３）克罗卡林能纠正ＣｓＣｌ引起的各种室性心律失常。结果提示：（１）触发活动为长ＱＴ间期ＴｄＰ的重要发生机制；（２）克罗卡林通过抑制触发活动而对长ＱＴ间期ＴｄＰ产生治疗作用。     

Changing capacity of electrocardiographic ventricular repolarization in post-myocardial infarction patients with and without nonfatal cardiac arrest

Prolonged and labile ventricular repolarization and decreased heart rate variability may be associated with susceptibility to ventricular fibrillation (VF) after myocardial infarction (MI). The response of ventricular repolarization related to abrupt heart rate changes may also be associated with arrhythmia vulnerability. We investigated whether diurnal maximal values or changing capacities of QT and T-wave peak to T-wave end (TPE) intervals are different in patients after MI with and without a history of VF. With an automated computerized program, Holter recordings from 29 patients after MI resuscitated from VF not associated with new MI (VF group) and 27 patients after MI without clinical ventricular arrhythmias (control group) were analyzed. Maximal QT and maximal TPE intervals were shorter in the VF group than in the control group. Patients with VF exhibited smaller capacity to change QT and TPE intervals, with differences between study groups being greatest at heart rates from 60 to 75 beats/min (p = 0.002 and 0.01, respectively). Capacity to change QT and TPE intervals correlated with vagally mediated measurements of heart rate variability (r from 0.35 to 0.46, p from 0.01 to <0.001, respectively). In conclusion, long maximal QT interval may not be the key factor exposing patients after MI to VF. Impaired capacity to change QT and TPE intervals seems to be associated with risk of VF after MI.     

QT and TdP. QT: an unreliable predictor of proarrhythmia

When triangulation, reverse use dependence, instability and dispersion (TRIaD) of the action potential are associated with drug-induced prolongation of the QT interval, then proarrhythmia in the form of torsade de pointes is most likely. However, as the QT interval is shortened, TRIaD increasingly leads to ventricular fibrillation (VF). Thus, use of QT prolongation by itself may not recognize drug-induced VF (false negatives) and in the absence of TRIaD may erroneously incriminate valuable and safe agents (false positives). In patients,TRIaD equivalents in the ECG may likewise be more important than QT interval.     

Electrophysiologic testing in patients with the long QT syndrome

Electrophysiologic studies were performed in 15 patients with syncope and/or cardiac arrest who had the long QT syndrome and 11 control subjects who had normal QT intervals. The syndrome was familial in five patients and idiopathic in 10. All patients had a prolonged QT (546 +/- 68 msec, mean +/- SD) and corrected QT (550 +/- 51 msec). Incremental atrial pacing at cycle lengths of 600 to 400 msec resulted in shortening of the QT interval, but there was no significant difference in the magnitude or percent of shortening of the QT interval between patients with the long QT syndrome and control subjects. Intravenous propranolol did not influence the QT interval measured at fixed atrial-paced cycle lengths in patients with either the familial or idiopathic form of the syndrome. Programmed right and left ventricular stimulation with up to three extrastimuli before and during isoproterenol infusion did not induce sustained ventricular tachycardia or ventricular fibrillation in any of the patients. However, rapid polymorphic nonsustained ventricular tachycardia was induced in six of the 15 patients (40%). Neither the inducibility of nonsustained ventricular tachycardia nor the results of electropharmacologic testing with beta-blockers proved to be of any prognostic value during the mean follow-up period of 28 +/- 17 months. Electrophysiologic studies are of limited value in the diagnosis and treatment of patients with the long QT syndrome.     

Treatment of torsade de pointes with magnesium sulfate

Twelve consecutive patients who developed torsade de pointes (polymorphous ventricular tachycardia with marked QT prolongation, TdP) over a 4 year period were treated with intravenous injections of magnesium sulfate. In nine of the patients a single bolus of 2 g completely abolished the TdP within 1 to 5 min, and in three others complete abolition of the TdP was achieved after a second bolus was given 5 to 15 min later. Nine of the patients also received continuous infusion of MgSO4 (3 to 20 mg/min) for 7 to 48 hr until the QT interval was below 0.50 sec. In nine of the 12 patients the TdP was induced by antiarrhythmic agents. The QT interval preceding TdP ranged from 0.54 to 0.72 sec. After the MgSO4 bolus, which prevented the recurrence of TdP, no significant changes were observed in the QT interval. There were no side effects of this treatment. In eight of the 12 patients potassium levels before the TdP were below 3.5 meq/liter; magnesium levels were available in eight patients before TdP, and were normal in all. Five additional patients with polymorphous ventricular tachycardia but normal QT intervals (non-TdP patients) received two to three boluses of MgSO4. This treatment was ineffective in all, but they responded to conventional antiarrhythmic therapy. Thus, MgSO4 is a very effective and safe treatment for TdP, and its application is rapid and simple. Its use is therefore recommended as the first line of therapy for TdP.     

Successful catheter ablation in a patient with polymorphic ventricular tachycardia

We describe a patient with polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF) without organic heart disease who was cured by radiofrequency catheter ablation. The patient was a 65-year-old woman with a 10-year history of recurrent syncope. There was no evidence of organic heart disease, and the QT interval during sinus rhythm was borderline normal (corrected QT interval = 0.45 sec1/2). ECG recording during syncope showed PVT. On one occasion, PVT degenerated into VF. This PVT was always induced by a premature ventricular complex (PVC) originating from the right ventricular (RV) outflow tract. Rapid pacing (220 beats/min) at the site of PVC origin reproduced polymorphic change of the QRS wave on surface ECG that was similar to PVT. This suggests that the PVT originated from a single focus in the RV outflow tract. Catheter ablation was performed at the site of PVC origin. During 18-month follow-up, PVT/VF was not documented.     

体表心电图及心外膜标测电恢复性质在诱发猪心室颤动中的作用

目的评价体表心电图及心外膜标测部位电恢复性质在诱发猪心室颤动（室颤）中的作用。方法雄性长白猪7、大，记录心电图的同时用10极单极电极记录心外膜动作电位，构建激动恢复间期（ARI）和QT间期恢复曲线。评价心外膜局部ARI和体表心电图电恢复性质同室颤阈值间的父系。结果局部ARI恢复曲线坡度与QT间期恢复曲线坡度有相关性，差异有统计学意义（r=0．725，P=0．018）。窀颤阈值同右心室心尖部ARI恢复曲线坡度呈正相关（r=0．752，P=0．019），窜颤阈值同体表心电图Ⅱ导联QT间期恢复曲线坡度呈正相关（r＝0．802，P＝0．005）。结论局部ARI及QT间期电恢复性质有明显相关性，两者同室颤诱发相关。     

QT and JT dispersion in patients with monomorphic or polymorphic ventricular tachycardia/ventricular fibrillation

The present study evaluates the repolarization abnormalities in patients with monomorphic sustained ventricular tachycardia (MVT) and polymorphic ventricular tachycardia/ventricular fibrillation (PMVT/VF) by measuring QT and JT dispersion on the surface electrocardiogram (ECG). QT dispersion is a predictor of ventricular arrhythmias in several clinical settings. However, the value of QT and JT dispersion in identifying patients at risk for PMVT/VF is controversial. Maximum QT (JT) interval duration and QT (JT) dispersion were compared between 20 healthy individuals, 12 patients with inducible MVT during programmed electrical stimulation and seven patients with PMVT/VF recorded during 24-hour ambulatory ECG or induced by programmed electrical stimulation. QT dispersion was 40 +/- 9 ms in the control group, 63 +/- 21 ms in the MVT group, and 79 +/- 31 ms in the PMVT/VF group. QT dispersion in both the MVT and PMVT/VF groups were significantly greater than in the control group (P <.001 and P <.0001, respectively); however, there was no significant difference between the MVT and PMVT/VF groups. JT dispersion was 41 +/- 14 ms in the control group, 69 +/- 14 ms in the MVT group and 103 +/- 37 ms in the PMVT/VF group. JT dispersion differed significantly between the study groups and was significantly increased in PMVT/VF group than in the control group or MVT groups (P <.0001 vs. the control group, P <.005 vs. the MVT group). Patients with PMVT/VF have a greater dispersion of ventricular repolarization time. Repolarization abnormalities are important for ventricular arrhythmogenesis and detectable on the surface ECG.     

Role of QT prolongation secondary to a postextrasystolic pause as a possible mechanism for the induction of ventricular fibrillation. Report of two cases

Two patients developed ventricular fibrillation (VF) while undergoingcontinuous electrocardiographic monitoring. Analysis showedthat VF appeared only when a particular combination of circumstancesoccurred: a postextrasystolic pause. QT prolongation of thesubsequent beat and a premature ventricular beat that did nothave a short coupling interval. The relevance of this sequenceas a trigger mechanism of VF is discussed.