Mechanism Of Torsade De Pointes Research Articles

A model of cardiac ryanodine receptor gating predicts experimental Ca2+-dynamics and Ca2+-triggered arrhythmia in the long QT syndrome

Abnormal Ca2+ handling is well-established as the trigger of cardiac arrhythmia in catecholaminergic polymorphic ventricular tachycardia and digoxin toxicity, but its role remains controversial in Torsade de Pointes (TdP), the arrhythmia associated with the long QT syndrome (LQTS). Recent experimental results show that early afterdepolarizations (EADs) that initiate TdP are caused by spontaneous (non-voltage-triggered) Ca2+ release from Ca2+-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca2+-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca2+ elevation increases gradually in amplitude, occurs before overt voltage instability, and then precedes the rise of EADs. Here, we used a modified Shannon-Puglisi-Bers model of rabbit ventricular myocytes to reproduce experimental Ca2+ dynamics in bradycardia and LQT2. Abnormal systolic Ca2+-oscillations and EADs caused by SR Ca2+-release are reproduced in a modified 0-dimensional model, where 3 gates in series control the ryanodine receptor (RyR2) conductance. Two gates control RyR2 activation and inactivation and sense cytosolic Ca2+ while a third gate senses luminal junctional SR Ca2+. The model predicts EADs in bradycardia and low extracellular [K+] and cessation of SR Ca2+-release terminate salvos of EADs. Ca2+-waves, systolic cell-synchronous Ca2+-release, and multifocal diastolic Ca2+ release seen in subcellular Ca2+-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca2+-overload, abnormal SR Ca2+-release, and the subsequent activation of the electrogenic Na+/Ca2+-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.

Perpetuation of torsade de pointes in heterogeneous hearts: competing foci or re‐entry?

The underlying mechanism of torsade de pointes (TdP) remains of debate: perpetuation may be due to (1) focal activity or (2) re-entrant activity. The onset of TdP correlates with action potential heterogeneities in different regions of the heart. We studied the mechanism of perpetuation of TdP in silico using a 2D model of human cardiac tissue and an anatomically accurate model of the ventricles of the human heart. We found that the mechanism of perpetuation TdP depends on the degree of heterogeneity. If the degree of heterogeneity is large, focal activity alone can sustain a TdP, otherwise re-entrant activity emerges. This result can help to understand the relationship between the mechanisms of TdP and tissue properties and may help in developing new drugs against it. Torsade de pointes (TdP) can be the consequence of cardiac remodelling, drug effects or a combination of both. The mechanism underlying TdP is unclear, and may involve triggered focal activity or re-entry. Recent work by our group has indicated that both cases may exist, i.e. TdPs induced in the chronic atrioventricular block (CAVB) dog model may have a focal origin or are due to re-entry. Also it was found that heterogeneities might play an important role. In the current study we have used computational modelling to further investigate the mechanisms involved in TdP initiation and perpetuation, especially in the CAVB dog model, by the addition of heterogeneities with reduced repolarization reserve in comparison with the surrounding tissue. For this, the TNNP computer model was used for computations. We demonstrated in 2D and 3D simulations that ECGs with the typical TdP morphology can be caused by both multiple competing foci and re-entry circuits as a result of introduction of heterogeneities, depending on whether the heterogeneities have a large or a smaller reduced repolarization reserve in comparison with the surrounding tissue. Large heterogeneities can produce ectopic TdP, while smaller heterogeneities will produce re-entry-type TdP.

Biexcitability and Early Afterdepolarization-Mediated Cardiac Arrhythmias

Under normal conditions in ventricular tissue, both planar wave propagation and spiral wave reentry are mediated by Na current (INa)-mediated depolarization. Under diseased conditions in which repolarization reserve is reduced, however, secondary depolarizations can occur in the plateau or repolarizing phase of the action potential (AP) due to reactivation of the L-type calcium current (ICa,L), known as early afterdepolarizations (EADs). Under these conditions, we observed a novel behavior in which both INa-mediated spiral wave reentry and ICa,L-mediated spiral wave reentry coexisted in the same homogeneous tissue. INa-mediated spiral waves were similar to those observed under normal condition, with high rotation frequency (∼10 Hz) and nearly full repolarization between beats. ICa,L-mediated spiral waves, however, rotated much slower (2-3 Hz) with membrane voltage remaining above −40 mV, at which INa is inactivated. We call this novel property of an excitable medium biexcitability. In heterogeneous tissue with transmural AP gradients, pause-induced EADs initiated ICa,L-mediated rotors from the M-cell region. The resulting arrhythmia was characterized by co-existing ICa,L- and INa-mediated wavefronts, with a frequency and electrocardiographic appearance resembling Torsades de Pointes. The arrhythmia either terminated spontaneously or degenerated to ventricular fibrillation. We propose biexcitability as a novel mechanism of Torsades de Pointes in long QT syndromes.

Torsade de pointes.

Torsade de pointes ventricular tachyarrhythmia in the long QT syndrome is a prime example of how molecular biology, ion channel, and cellular and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and the acquired long QT syndrome are caused by abnormalities (intrinsic, acquired, or both) of the ionic currents underlying ventricular repolarization. In this review, the continually unraveling molecular biology of congenital long QT syndrome is discussed. The various pharmacologic agents associated with the acquired long QT syndrome are listed. Although it is difficult to predict which patients are at risk for torsade de pointes, careful assessment of the risk to benefit ratio is important before prescribing drugs known to cause QT prolongation. The in vivo electrophysiologic mechanism of torsade de pointes in the long QT syndrome is described, using as a paradigm the anthopleurin-A canine model, a surrogate for LQT3. The characteristic association of torsade de pointes with T-wave alternans and short-long cardiac sequences is discussed, with emphasis on electrophysiologic mechanisms. Finally, the expanding knowledge of genetic mutations other than long QT syndrome associated with polymorphic ventricular tachyarrhythmia is emphasized.

Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome.

Specific ion channel mutations underlie the congenital long-QT syndrome (LQTS). However, the mechanisms by which dysfunction at the molecular level translates into functional electrical instability leading to torsade de pointes (TdP) in LQTS are poorly understood. The cellular basis of TdP was investigated using a novel approach of transmural optical imaging in the canine wedge preparation (n=14). The spatial organization of repolarization and arrhythmogenesis were determined in a surrogate model of LQT2. Action potentials were recorded simultaneously from 128 sites spanning the transmural wall of the left ventricle. In LQT2, QT interval prolongation was paralleled by an abrupt rise in transmural dispersion of repolarization (DOR) from 2.7 plus/minus 0.9 ms/mm (controls) to 12.2 plus/minus 2.1 ms/mm (LQT2). Islands of midmyocardial (M) cells formed zones of increased refractoriness in LQT2, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits underlying TdP. These data provide direct evidence supporting the functional expression of M cells in intact myocardium and a central role for M cells in the development of reentrant TdP arrhythmias in LQTS.

Acquired QT Prolongation: Mechanisms and Implications.

QT interval prolongation can be caused by several drugs. Torsade de pointes (TdP) is a form of ventricular proarrhythmia associated with QT interval prolongation, and in some cases, the development of U waves. The mechanism of TdP is believed to be related to an abnormality of repolarization in the ventricular myocardium and the development of early afterdepolarizations. QT prolongation leading to TdP can be caused by antiarrhythmic drugs (primarily class IA and III drugs), as well as a variety of other drugs. These other classes of drugs include phenothiazines, tricyclic antidepressants, antihistamines, antibiotics, antifungal agents, and antianginals. The recognition of a patient profile at increased risk for the development of TdP can help the patient avoid this drug-related complication. Treatment of TdP depends on the correct identification of the problem and discontinuation of the agent causing TdP, as well as correction of metabolic abnormalities, increase in the resting heart rate, and infusion of magnesium. Prompt diagnosis and treatment of this condition are central to avoid poor outcome.

Electrophysiologic features of torsades de pointes: insights from a new isolated rabbit heart model.

The exact electrophysiologic mechanism of torsades de pointes (TdP) is under intense investigation. No isolated animal heart model of this particular arrhythmia exists. In isolated rabbit hearts, TdP was induced by means of bradycardia in the presence of a high concentration of d-sotalol (10(-4) M) and shortly after lowering the concentration of potassium and magnesium in the perfusate. Multiple simultaneous epicardial and endocardial monophasic action potentials (MAPs) and volume-conducted 12-lead ECGs were recorded. d-Sotalol prolonged repolarization and increased dispersion of ventricular repolarization compared to baseline recordings. With the onset of low potassium and magnesium concentrations, repolarization was further prolonged and dispersion of repolarization was further increased followed by the occurrence of early afterdepolarizations (EADs) in the majority of MAP recordings, i.e., at both endocardial and epicardial locations of both ventricles. Upon increase of EAD amplitude, triggered arrhythmias with TdP of up to 42 beats ensued in 10 of 11 hearts studied. MAP duration at 90% repolarization (APD90), dispersion of APD90, and the incidence of EADs as well as dispersion of the QT interval and T wave area were significantly higher in beats triggering bigemini, couplets, or runs of TdP. TdP observed in this new isolated heart model was associated with markedly increased dispersion of ventricular repolarization and the occurrence of EADs in multiple locations of the heart. TdP is initiated when the amplitude of an EAD reaches threshold for initiation of the first beat of an episode.

Early afterdepolarizationlike activity in patients with class IA induced long QT syndrome and torsades de pointes.

Early afterdepolarizations (EADs) have been linked to the mechanism of torsades de pointes in long QT syndrome. The purpose of this study was to investigate the role of EADs in Class IA induced torsades de pointes. We studied nine patients with Class IA induced torsades de pointes at the time this arrhythmia was present (acute period, n = 7) and after Class IA therapy was discontinued (chronic period, n = 6). ECGs and monophasic action potentials were recorded in both periods. In the chronic period, electrophysiological studies were performed before and after disopyramide infusion. In the acute period, QTc interval was markedly prolonged (655 +/- 32 ms1/2), and EAD-like activity was recorded in all patients. QTc interval returned to normal (428 +/- 45 ms1/2) and EAD-like activity disappeared after discontinuation of IA drug. Although, in the chronic period, disopyramide infusion prolonged QTc interval from 428 +/- 48 ms1/2 to 479 +/- 31 ms1/2 and induced EAD in three of six patients, the degree was not as marked as observed in the acute period. EADs may play an important role in the genesis of long QT and torsades de pointes. Disopyramide infusion in the chronic period could not reproduce marked repolarization abnormalities and torsades de pointes.

Differential effects of antiarrhythmic agents on post-pause repolarization in cardiac Purkinje fibres.

1. Marked action potential duration (APD) prolongation with agents such quinidine is often a precursor of early after-depolarizations and triggered activity, thought to be underlying mechanism of torsade de pointes. Episodes of torsade de pointes commonly occur following a pause. 2. We recently demonstrated that quinidine, but not disopyramide, produced marked further prolongation of APD immediately following pauses of 2-10s interpolated into a basic drive train in canine Purkinje fibres. 3. We report here experiments aimed at further elucidating the mechanisms of this phenomenon. 4. We used standard microelectrode techniques to record action potentials from canine Purkinje fibres driven at a baseline interstimulus interval (ISI) of 1000 ms. 5. We were able to reproduce the phenomenon of post-pause prolongation of APD with amitriptyline, which blocks both sodium and potassium channels, as does quinidine. Furthermore, we showed that the kinetics of interaction of amitriptyline, with the sodium channel, are similar to those known to exist for quinidine (time constant of recovery from blockade 2.3 +/- 0.6s). 6. In contrast, we were unable to reproduce post-pause prolongation of APD with three pure class III antiarrhythmic agents, D-sotalol, clofilium and dofetilide. 7. We propose that quinidine and amitriptyline behave similarly, in that they both produce two separate, opposing effects on APD. During a pause, the sodium channel-blocking action of these compounds diminishes exponentially, allowing the potassium channel blocking effect to become manifest as post-pause prolongation of APD. None of D-sotalol, clofilium or dofetilide exhibits significant sodium channel blockade and, thus, these agents do not manifest post-pause prolongation of repolarization. Disopyramide does produce sodium channel blockade, but recovery from this effect is much slower than for quinidine or amitriptyline (time constant 12-50s). Thus, we propose insufficient recovery occurs during the intervals under study to uncover the action potential-prolonging effect of the unopposed potassium channel blockade for disopyramide.

Mechanisms in simulated torsade de pointes.

A mechanism of torsade de pointes consisting of moving sites of reentrant excitation has been proposed on the basis of findings with a computer model. Substantial additions to that mechanism are now proposed based on further studies with the same model. The model simulated propagation, cycle length-dependent recovery of excitability, and slow propagation during incomplete recovery. Regions of relatively short and long recovery were assigned because of evidence of regional prolongation of recovery in long QT syndromes in which torsade de pointes is frequent. As previously reported, premature excitation in the short recovery region initially propagated independently, then entered the long recovery region and reentered the short recovery region distal to the site of origin. Reentrant excitation initiated a similar series of events, and serial reentry at systematically changing locations resulted in changing patterns of excitation compatible with the changing QRS waveform in torsade de pointes. Episodes terminated when reentrant excitation reached the end of unclosed short recovery paths, collided in closed paths, or encountered refractoriness in the presence of nonuniform short recovery. In this study, it was shown that excitation preceding reentry had important effects on the mechanism. These included reversal of the direction of serial reentry, bidirectional serial reentry, reentry at multiple sites from the same parent conditions, and occurrence of reentry without the requirement of slow propagation. Evidence for a Doppler shift of cycle lengths in regions from which serial reentry was receding or approaching was obtained. Sustained serial reentry was also demonstrated and is a possible mechanism for polymorphic ventricular tachycardia. Findings further define a possible mechanism of torsade de pointes.

Electrophysiologic Mechanisms for Ventricular Arrhythmias in Left Ventricular Dysfunction: Electrolytes, Catecholamines and Drugs

Cardiac arrhythmias are generated as the result of disorders of automaticity or of impulse conduction. Regardless of the mechanism, calcium is likely to be involved, although calcium antagonists are rarely useful antiarrhythmics in ventricular arrhythmias. Myocardial cells that do not ordinarily initiate action potentials may do so when they are partially depolarized, giving rise to an ectopic focus. Early afterdepolarizations (EADs) are also induced in cardiac cells by partial depolarization, whereas delayed afterdepolarizations (DADs) are induced by Ca++ overloading. EADs may be the initiating mechanism of torsade de pointes, a complication of QT prolongation associated with quinidine therapy. Both in the animal model and in humans, treatment with magnesium, isoproterenol, or pacing, all of which suppress EADs, will also suppress torsade de pointes. Ventricular tachycardia is a manifestation of ordered re-entry, and may be exacerbated by antiarrhythmics, especially class 1c drugs. In the individual patient, prediction of proarrhythmia is not possible. The risk of proarrhythmia is increased in patients with episodes of sustained ventricular tachycardia or with significant left ventricular dysfunction.

The Sympathetic Imbalance Hypothesis of QT Interval Prolongation

Sympathetic Imbalance. The demonstration of QT interval prolongation after left stellate ganglion stimulation led to the successful trial of left cervicothoracic sympathectomy for the control of arrhythmias in long QT syndromes. Based on those findings, sympathetic imbalance with excessive left‐sided effects became widely regarded as the mechanism of QT prolongation and arrhythmias in the syndromes. Prolongation of the interval was attributed to regional reduction of repolarization durations with exposure of previously cancelled electrocardiographic effects and arrhythmias to nonuniform recovery of excitability permitting reentrant excitation. Subsequent findings have not, however, supported this hypothesis. It has been shown that QT prolongation following left stellate ganglion stimulation is transient and unlikely to account for the sustained prolongation in the syndromes. It has also been shown that QT prolongation is not unique for left stellate stimulation and also occurs transiently after right stellate stimulation or bolus injections of catecholamines. It remains possible that sympathetic imbalance in the form of deficient right‐sided sympathetic effects on the heart that experimentally results in prolonged repolarization and sustained QT interval prolongation is a mechanism in long QT syndromes. ECG mapping suggests prolongation of repolarization in the region normally innervated by the right stellate ganglion and a plausible mechanism of torsade de pointes based on regionally disparate recovery has been proposed.

The Mechanism of Simulated Torsade de Pointes in a Computer Model of Propagated Excitation

Mechanism of Torsade de Pointes. A computer model that simulated propagation, nonuniform cycle length dependent recovery of excitability, and slow propagation during incomplete recovery in cardiac muscle has been shown to exhibit behavior similar to torsade de pointes. The conditions required in the model resembled those in long QT syndromes with regionally prolonged ventricular repolarization. In the model, premature excitation of a path with relatively short refractory periods resulted in sequential reentry of that path from a region with longer refractory periods. Sites of reentry become progressively more distal to the site of initiation. The episodes terminated spontaneously when reentrant excitation reached the end of unclosed paths or collided in closed paths. Each reentry site moved away from its initial position in the short recovery path because the distance traversed by propagation in that path exceeded the distance at which reentry occurred via the longer recovery region. The migrating sites of reentry resulted in changing QRS waveform in calculated electrocardiograms including changing QRS polarity when calculated from appropriate sites. Variations of the basic behavior occurred with nonuniform distribution of refractory periods within relatively short and long refractory period regions and included unidirectional progression of reentry sites and multiple circuits of reentry in closed paths. Termination of serial reentry at times other than those when activation reached the end of unclosed paths or collided in closed paths also occurred with nonuniform distribution of refractory periods. Findings provide a plausible explanation for the changing QRS waveform, spontaneous termination, and association of torsade de pointes with long QT syndromes but do not elucidate the mechanism of initiation of the tachyarrhythmia.

Effect of procainamide on dispersion of ventricular refractoriness

Ventricular arrhythmias after Q-T prolongation by drugs could result from a nonhomogeneous increase in refractoriness (dispersion). Dispersion of effective refractory periods (ERP) was measured before and after infusion of 1 g of procainamide using twice-threshold extrastimuli applied in sinus rhythm and with 500 ms ventricular drive cycle length at 3 right ventricular sites (2 patients) or 2 right and 1 left ventricular site (10 patients). Procainamide prolonged ERP. In drive, average ERP was 247 ± 5 ms (standard error of the mean) before and 277 ± 7 ms after procainamide (p < 0.001). The Q-T interval was prolonged by 50 ms in drive (p < 0.001), but Q-T prolongation did not reflect the increased ERP (r = −0.05). However, procainamide did not alter measured dispersion (54 ± 16 to 44 ± 14 ms in sinus, 48 ± 14 to 47 ± 13 ms in drive). Polymorphic ventricular tachycardia (VT) was induced in 6 patients in whom drive itself generally failed to reduce dispersion, and failure to induce tachycardia or shorter runs after procainamide was associated with narrowed dispersion. Polymorphic VT was not induced after procainamide in 2 patients with clinical episodes of torsades de pointes caused by type I agents. The mechanism of torsades de pointes was not explained by dispersion of refractoriness or by polymorphic VT initiated by premature beats after a type I drug.

A mechanism of torsades de pointes in a canine model.

A dog model of torsades de pointes (TdP) was developed. Twenty 18-30-kg dogs had cardiopulmonary bypass instituted to maintain stable temperature, perfusion pressure and oxygenation. Quinidine, 30 mg/kg, was then administered and burst ventricular pacing was used to induce arrhythmias. The left anterior descending coronary artery was occluded for 15 minutes and repeat pacing studies were performed. Maps of epicardial activation were made from 27 simultaneously recorded electrograms obtained from 1-mm bipolar electrodes secured to the epicardium with a nylon mesh sock. Arrhythmias in five dogs met criteria for the diagnosis of TdP: All had the characteristic undulating QRS morphology typically associated with TdP, all occurred in the setting of QT prolongation and all ended spontaneously. The epicardial maps demonstrated that each change in QRS morphology was associated with a change in the site of epicardial breakthrough. Those QRS complexes during the transition from one morphology to the next were associated with fusion cycles in which both the old and new sites of epicardial breakthrough were present. In essence, two or more competing activation sequences were vying for control of epicardial depolarization. This conclusion was strengthened by our ability to simulate TdP in the surface ECG and in epicardial maps by simultaneously pacing from two widely separated ventricular sites at slightly different, varying rates.