Phase 2 Early Afterdepolarization as a Trigger of Polymorphic Ventricular Tachycardia in Acquired Long-QT Syndrome

Yan, Gan‐Xin; Wu, Ying; Liu, Tengxian; Wang, Jixin; Marinchak, Roger A.; Kowey, Peter R.

doi:10.1161/01.cir.103.23.2851

Cited by 255 publications

(229 citation statements)

References 14 publications

Supporting

Mentioning

212

Contrasting

Unclassified

Order By: Relevance

“…This accuracy of repolarization time measurement is important in the study of arrhythmogenic mechanisms because it is the heterogeneity of instantaneous local repolarization that underlies phase 2 reentry and initiation of ventricular arrhythmias. 3,18 In agreement with Chen et al, 12 the Wyatt method considerably underestimates ARI for the positive T wave in our report, despite a good correlation with MAP90% (rϭ0.86). With this method, the error between MAP90% and ARI for the positive T wave was Ϫ47Ϯ12 ms.…”

Section: Discussionsupporting

confidence: 92%

Determination of Human Ventricular Repolarization by Noncontact Mapping

et al. 2004

View full text Add to dashboard Cite

Background-Noncontact mapping (NCM) has not been validated as a clinical technique to measure ventricular repolarization. We used NCM to determine repolarization characteristics by analysis of reconstructed unipolar electrograms (UEs) at the same sites as monophasic action potential (MAP) recordings in the human ventricle. Methods and Results-MAPs were recorded from a total of 355 beats at 46 sites in the left or right ventricle of 9 patients undergoing ablation of ventricular tachycardia guided by NCM (EnSite system). Measurements were made during sinus rhythm, constant right ventricular pacing, and ventricular extrastimuli during restitution-curve construction. The EnGuide locator signal was used to document MAP catheter locations on the endocardial geometry. UE-determined activation-recovery interval (ARI) measured at the maximum derivative of the T wave (Wyatt method) and the minimum derivative of the positive T wave (alternative method) was correlated with MAP measured at 90% repolarization (MAP90%) at the same sites. ARI correlated with MAP90% during steady state by the Wyatt method (rϭ0.83, PϽ0.001) and the alternative method (rϭ0.94, PϽ0.001). Restitution curves constructed from MAP and UE data exhibited the same characteristics, with a mean correlation coefficient of 0.95 (range, 0.90 to 0.99, PϽ0.001). The error between ARI and MAP90% was greater over a shorter diastolic coupling interval but was not influenced by distance of the sampling site from the multielectrode array. Conclusions-NCM accurately determines steady-state and dynamic endocardial repolarization in humans. Global, high-density, NCM data could be used to characterize abnormalities of human ventricular repolarization. (Circulation.

show abstract

Section: Discussionsupporting

confidence: 92%

Determination of Human Ventricular Repolarization by Noncontact Mapping

et al. 2004

View full text Add to dashboard Cite

show abstract

“…This characteristic of the rabbit ventricle, particularly in female gender, renders it exceptionally sensitive even to weak QT prolonging agents. 2,7,8,27 In the present study, a positive signal for QT prolongation was observed for all drugs with a known TdP risk, even for drugs that tested negative in other preclinical models. For example, terfenadine, a non-cardiac drug with a TdP risk in humans, caused little QT or action potential prolongation in conscious dogs, 28 or in isolated canine Purkinje fibers, 29 porcine myocardium or Purkinje fibers, 30 but prolonged QT interval by more than 20% in the rabbit left ventricular wedge preparation and increased dispersion of repolarization by nearly 50%.…”

Section: Discussionsupporting

confidence: 48%

“…6 From a mechanistic point of view, other factors, such as dispersion of repolarization, have been shown to contribute to the development of TdP. 5,[7][8][9] There are a number of in vitro and in vivo experimental models available for the preclinical assessment of the TdP potential of new agents. However, few have been validated in a blinded fashion for their positive and negative predictive value.…”

Section: Introductionmentioning

confidence: 99%

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

Liu¹,

Brown²,

Wu³

et al. 2006

Heart Rhythm

Self Cite

116

117

View full text Add to dashboard Cite

BACKGROUND-The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP.

show abstract

“…EADs are thought to be generated by the recovery and reactivation of ICa L (window Ca 2+ current) and / or the late sodium current as a result of incomplete inactivation of sodium channels during the prolonged APD (Volders et al, 2000;Zeng et al, 1995). The combination of an increased dispersion of repolarisation creating a substrate for reentry and EADs triggering reactivation of non-refractory tissue may lead to functional reentry and Torsades de Pointes (TdP) (Antzelevitch et al, 2006;Yan et al, 2001). The term 'Torsades de Pointes', which in English means 'twisting of the points', was originally coined by Desertenne in 1966 as a description of the irregular change in polarity of the QRS complexes of the surface ECG during tachycardia (Desertenne, 1966).…”

Section: Mechanisms Of Class III Induced Proarrhythmiamentioning

confidence: 99%

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson

Andersson

Duker

et al. 2007

European Journal of Pharmacology

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most common tachyarrhythmia in the adult population and is a major cause of morbidity and mortality. AF can be terminated and sinus rhythm restored by prolonging the action potential duration (APD) and the refractory period. Unfortunately, antiarrhythmic agents that prolong the APD and increase the refractory period via selective inhibition of the rapid delayed rectifier potassium current (IK r ), i.e. class III antiarrhythmic drugs, are associated with an increased risk of the ventricular tachycardia Torsades de Pointes. AZD7009 is an antiarrhythmic agent with predominant actions on atrial electrophysiology that shows high antiarrhythmic efficacy and low proarrhythmic potential in animals and man. The aim of the current studies was to characterize the effect of AZD7009 on cardiac ion currents and APD in order to provide a mechanistic explanation for its predominant atrial effects and low proarrhythmic potential.The human cardiac ion channels hERG (IK r ), Kv1.5 (IK ur ), Kv4.3/KChIP2.2 (I to ), KvLQT1/minK (IK s ), Kir3.1/Kir3.4 (IK ACh ) and Nav1.5 (INa) were expressed in mammalian cells. Whole-cell currents were inhibited by AZD7009 with the following IC 50 values: hERG 0.6 μM, Nav1.5 8 μM, Kv4.3/KChIP2.2 24 μM, Kv1.5 27 μM, Kir3.1/Kir3.4 166 μM and KvLQT1/minK 193 μM. Whole-cell sodium and calcium currents were recorded in isolated rabbit atrial and ventricular myocytes using amphotericin B perforated patch. The late sodium current in rabbit atrial and ventricular myocytes was inhibited by AZD7009 in a concentration dependent way, with approximately 50% inhibition at 10 μM AZD7009. The L-type Ca 2+ current (ICa L ) in rabbit ventricular myocytes was inhibited with an IC 50 of 90 μM. Transmembrane action potentials were recorded in tissue pieces from rabbit atrium, ventricle and Purkinje fibre in control, during exposure to the selective IK r blocker E-4031 and to E-4031 in combination with AZD7009. In Purkinje fibres, but not in ventricular tissue, AZD7009 attenuated the E-4031-induced APD prolongation. In contrast, in atrial cells, AZD7009 further prolonged the APD. In addition, AZD7009 was able to suppress early afterdepolarisations (EADs) induced by E-4031 in Purkinje fibre preparations.In conclusion, AZD7009 delays repolarisation and increases refractoriness in atrial tissue through synergistic inhibition of IK r , I to , IK ur and INa, a mixed ion channel blockade that may underlie its high antiarrhythmic efficacy. Inhibition of the late sodium current, counteracting excessive APD prolongation and EADs in susceptible cells (midmyocardial and Purkinje cells), may explain the low proarrhythmic potential of AZD7009.

show abstract

Phase 2 Early Afterdepolarization as a Trigger of Polymorphic Ventricular Tachycardia in Acquired Long-QT Syndrome

Abstract: This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation.

Cited by 255 publications

References 14 publications

Determination of Human Ventricular Repolarization by Noncontact Mapping

Determination of Human Ventricular Repolarization by Noncontact Mapping

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Contact Info

Product

Resources

About