Initiation Of Torsades De Pointes Research Articles

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome.

Ventricular remodelling can make the heart more susceptible to ventricular arrhythmias like torsades de pointes. Understanding the underlying mechanisms of initiation of ventricular arrhythmias and the determining factors for its severity has the potential to uncover new interventions. Beat-to-beat variation of repolarisation, quantified as short-term variability of repolarisation (STV), has been identified as an important factor contributing to arrhythmogenesis. This article provides an overview of experimental data about STV in relation to the initiation of torsades de pointes in a canine model of complete chronic atrioventricular block susceptible to torsades de pointes arrhythmias. Furthermore, it explores STV in relation to the severity of the arrhythmic outcome.

Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog.

The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle-LV was similar between inducible and non-inducible dogs at baseline (327 ± 30 vs. 345 ± 17 ms) and after dofetilide administration (525 ± 95 vs. 508 ± 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 ± 20 vs. 142 ± 34 ms) and cubic dispersion (272 ± 29 vs. 176 ± 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate TdP.

Jervell and Lange-Nielsen syndrome in a father and daughter from a large highly inbred family: a 16-year follow-up of 59 living members

To report the autosomal dominant inheritance of the Jervell and Lange-Nielsen syndrome in a highly inbred family, the initiation of Torsades de Pointes, and the natural history of the syndrome based on a 16-year follow-up of the kindred. A family tree was constructed that included 66 blood relatives from three successive generations. Electrocardiograms were obtained from 59 living members including the proband, four members from a nuclear family, and 54 from the extended family. Evoked response audiometry was recorded for the proband and the nuclear family. All 59 family members were followed up regularly for 16 years. A total of 24 living members were affected--QTc: 480-680 ms. The proband had long QTc, bilateral high-tone sensorineural deafness, recurrent syncope, and Torsades de Pointes. The asymptomatic father had long QTc and unilateral high-tone sensorineural deafness that involved specifically the left ear. One asymptomatic sibling of the proband had long QTc and normal hearing. The mother and another sibling were asymptomatic; QTc and hearing were normal in both. A total of 21 affected members from the extended family had only long QTc, and all were asymptomatic. There were three congenitally deaf first cousins who had recurrent syncope and adrenergic-triggered sudden death. In all, seven of 10 parents had consanguineous marriage to a first cousin. Each affected offspring had at least one affected parent. The severely symptomatic proband who received only β-blocker therapy and the 23 affected members without antiadrenergic therapy, all remained asymptomatic throughout the 16-year follow-up period. Jervell and Lange-Nielsen syndrome was inherited as autosomal dominant in this kindred. The majority of the affected members had a mild phenotype. The severity of auditory and cardiac phenotypes corresponded.

Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α(1) -adrenoceptor-stimulated, anaesthetized rabbits.

Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP. We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP-' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined. Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration. 'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.

Cardiac Arrest Due to Torsades De Pointes in a Patient with Complete Heart Block: The “R-On-T” Phenomenon

(2010). Cardiac Arrest Due to Torsades De Pointes in a Patient with Complete Heart Block: The “R-On-T” Phenomenon. Baylor University Medical Center Proceedings: Vol. 23, No. 4, pp. 361-362.

Giant T–U Waves Precede Torsades de Pointes in Long QT Syndrome: A Systematic Electrocardiographic Analysis in Patients With Acquired and Congenital QT Prolongation

This study sought to identify electrocardiographic (ECG) criteria that are associated with initiation of torsades de pointes (TdP) in patients with acquired (a-) and congenital (c-) long QT syndrome (LQTS). Electrocardiographic criteria used as risk predictors for TdP commonly rely on a prolonged QT interval but rarely consider abnormal T-U waves. We analyzed ECG recordings with TdP from 35 LQTS patients (15 c-LQTS and 20 a-LQTS) and compared them with premature ventricular complexes (PVCs) from 40 patients with normal QT intervals and with PVCs in 24 of the 35 LQTS patients not related to TdP. Abnormal T-U waves (6.2 +/- 0.9 mm) directly preceded TdP in 34 of 35 LQTS patients and were larger than T-wave amplitude (2.8 +/- 0.2 mm) in control patients and larger than the largest T-U-wave in LQTS without TdP (4.7 +/- 0.8 mm). The TdP-initiating beat emerged from a T-U-wave in 27 of 35 LQTS patients and in none of 40 control patients. The QRS duration of the first TdP beat (175 +/- 12 ms) was longer than in control PVCs (145 +/- 4 ms) and in PVCs in LQTS patients not related to TdP (138 +/- 22 ms). The QRS angle was less steep before TdP than in other PVCs (all p < 0.05). Abnormal, giant T-U waves separate TdP initiation in LQTS patients from PVCs in other heart disease and from other PVCs in LQTS patients. These ECG analyses suggest that early afterdepolarizations initiate TdP and, if present, may help to identify an imminent risk for TdP.

Classification and mechanism of initiation in patients with congenital long QT syndrome

To examine the initiating mode of Torsade de Pointes (TdP) in patients with congenital long QT syndrome (LQTS). We evaluated 111 episodes of TdP recorded on the electrocardiograms of 24 patients with congenital LQTS, and clarified the initiating mode, the three consecutive preceding RR intervals defined as C(2), C(1), and C(0), the timing of initiating premature ventricular contraction (PVC) and the cycle length (CL) of TdP. Three different initiating patterns were observed: (1) a "short-long-short" sequence (SLS) pattern (23 patients, 72 TdP, 65%) defined as one or more short-long cardiac cycles followed by an initiating short-coupled PVC (C(1)>C(2) and C(0)), (2) an "increased sinus rate" (ISR) pattern (8 patients, 28 TdP, 25%) defined as a gradual increase in sinus rate with or without T-wave alternans (C(2)>/=C(1)>/=C(0)), and (3) a "changed depolarization" (CD) pattern (5 patients, 11 TdP, 10%) defined as a sudden long-coupled PVC or fusion beat followed by short-coupled PVC. The C(0) was shorter in ISR than SLS and CD (mean C(0): 488 vs. 587 and 603 ms, respectively; P<0.05). Therefore, the initiating PVC appeared near the T-wave peak of the last beat before onset in ISR, while it occurred after the T-wave peak in SLS and CD. The CL of TdP was shorter in ISR than in SLS (256 vs. 295 ms, P<0.05). Our data show the existence of three predominant initiating modes of TdP in patients with congenital LQTS and suggests a differential mechanism of initiation of TdP for each mode.

Initiation of Torsades de pointes by head-up tilt test in congenital long QT syndrome patient

Long QT syndrome is a cardiac disorder of repolarization which is characterized by electrocardiographic abn- ormalities including prolonged QT interval, T-wave abnormalities and polymorphic ventricular tachycardia known as Torsades de Pointes. Its clinical manifestations are recurrent syncope, seizure, and sudden death. Recently, we experienced Torsades de Pointes (TdP by head-up tilt test in 24 year-old female patient present- ing recurrent syncope and long QT interval. Beta-blocker and left cervicothoracic sympathetic ganglionectomy were not effective, then we tried mexiletine. After mexiletine medication, the QT interval was significantly shortened and there was no more syncope. ( ( ( (Korean Circulation J 2000;30( ( ( (8 :1040-1044

Time- and Rate-Dependent Alterations of the QT Interval Precede the Onset of Torsade de Pointes in Patients With Acquired QT Prolongation

Objectives. The purpose of this study was to determine whether the QT interval dynamics that precede torsade de pointes are consistent with the initiation of this arrhythmia by early afterdepolarization-induced triggered activity.Background. Early afterdepolarization-induced triggered activity has been suggested as an electrophysiologic mechanism for torsade de pointes. Consequently, the initiation of torsade de pointes should involve time- and rate-dependent alterations of ventricular repolarization similar to those known to modulate the development of early afterdepolarizations.Methods. RR and QT intervals were measured in digitized 24-h ambulatory electrocardiographic recordings obtained from seven patients with acquired prolongation of ventricular repolarization. Each patient had one or more episodes of torsade de pointes. The relation between RR and QT intervals was determined before, during and after multiple episodes of torsade de pointes.Results. In patients with multiple episodes of ventricular arrhythmias, the onset of the arrhythmias was associated with a critical prolongation of the QT interval. In some episodes, prolongation of the QT interval was associated with sudden prolongation of the sinus cycle length, whereas in other episodes, the QT interval prolonged progressively at a constant cycle length.Conclusions. The association between a critically prolonged QT interval and the onset of ventricular arrhythmias suggests that the initial complex of torsade de pointes is an early afterdepolarization-induced triggered response. However, prolongation of the QT interval itself was not sufficient to account for the initiation of torsade de pointes, suggesting that other, as yet unidentified factors are required.(J Am Coll Cardiol 1997;30:209–17)

Electrophysiological Remodeling of the Heart Owing to Rate

Although damage to the heart from inflammation and infarction are well-established stimuli that trigger major cardiac remodeling, it has been known since 1954 that a persistent supraventricular tachycardia also can alter cardiac structure and function.1 This clinical observation was exploited 8 years later when it was demonstrated that rapid stimulation of the normal heart could produce reversible congestive heart failure.2 Since then, rapid pacing has been used frequently to create an investigational animal model of heart failure. The effects of prolonged pacing-induced tachycardia, in the range of 250 bpm for 3 or 4 weeks, has been studied in depth in several animal species and has been shown to cause extensive myocardial remodeling. Biventricular enlargement with reduced wall thickness and no increase in muscle mass, reduced cross-sectional myocyte area and increased length, disarray of myofibril alignment and cytoarchitecture, increases in contractile protein degradation, and destruction of the supporting myocardial collagen matrix represent some of the structural changes contributing to reduced ventricular function.3 Diminished responsiveness to β-adrenoceptor stimulation caused by a reduction in β-receptor density and a variety of alterations in the adrenergic signaling processes also occur.4 Replacement fibrosis, loss of cells, and reactive hypertrophy of the remaining cells have been noted recently.5 mRNA levels for specific cytoskeletal proteins increase, along with alterations in cytoskeletal architecture6 and abnormalities in phospholamban.7 In pigs subjected to 3 weeks of a tachycardia-induced cardiomyopathy, myocyte action potential showed reduced membrane resting potential, reduced amplitude and upstroke velocity, and prolonged duration at 90% repolarization. Peak L-type Ca2+ current density was reduced because of an absolute reduction in L-type Ca2+ current flow into the myocyte possibly caused by reduced open probability of the channel.8 However, in dogs that had rapid ventricular pacing for 3 to 4 weeks, action …