Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts

Volders, Paul G.A.; Vos, Marc A.; Szabó, Béla; Sipido, Karin R.; Groot, S. H. De; Gorgels, Anton P.M.; Wellens, Hein J.J.; Lazzara, Ralph

doi:10.1016/s0008-6363(00)00022-5

Cited by 303 publications

(273 citation statements)

References 169 publications

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“…It seems that midmyocardial cells are more susceptible to EADs in failing hearts, as in response to cardioactive agents under nondiseased conditions (1). In multicellular preparations and intact hearts, EADs constitute an important cellular mechanism for triggered activity (1,47). It appears that downregulation of multiple K ϩ channel currents, i.e., I to1 , I K1 , and I Ks , is responsible for the delayed repolarization and favors the genesis of EADs in the three regions, which is consistent with earlier simulation studies (25,35).…”

Section: Discussionsupporting

confidence: 86%

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Lau

Ducharme

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

222

186

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action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283: H1031-H1041, 2002. First published May 30, 2002 10.1152/ ajpheart.00105.2002.-Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K ϩ current (IK1) was homogeneously reduced by ϳ41% (at Ϫ60 mV) in the three cell types. Transient outward K ϩ current (Ito1) was decreased by 43-45% at ϩ30 mV, and the slow component of the delayed rectifier K ϩ current (IKs) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K ϩ current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of IK1, Ito1, and IKs increases APD and favors occurrence of EADs. heterogeneity; early afterdepolarizations; congestive heart failure; arrhythmias

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Section: Discussionsupporting

confidence: 86%

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Lau

Ducharme

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

222

186

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“…EADs are secondary depolarisations occurring during the plateau (phase 2) and the final repolarisation (phase 3) of the action potential. 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).…”

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

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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.

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“…36 -38 Thus, spontaneous Ca 2+ oscillations are not due to transmembrane potential changes but, given the correct initiating conditions, cause traveling Ca 2+ waves, depolarizations, and nondriven action potentials. 4 , 8 , 37 , 39 Although several investigators have identified the nature of the sarcolemmal currents that may underlie these depolarizations, 40 to date no specific antiarrhythmic agents directed toward these underlying currents (e.g., I ti ) have been developed. Thus, we propose that, at least for Purkinje cells from infarcted heart, agents directed toward eliminating aberrant spontaneous Ca 2+ release, which leads to micro Ca 2+ transients, cell-wide waves, and action potentials, may be effective antiarrhythmic agents.…”

Section: Implications Of Findingsmentioning

confidence: 99%

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

Boyden

Dun²,

Barbhaiya³

et al. 2004

Heart Rhythm

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Objectives/Background-Studies from several laboratories have implicated intracellular Ca 2+ dynamics in the modulation of electrical activity. We have reported that abnormal Ca 2+ wave activity is the underlying cause of afterdepolarization-induced electrical activity in subendocardial Purkinje cells that survive in the 48-hour infarcted canine heart. These cells form the focus of arrhythmias at this time postcoronary artery occlusion.Methods-We studied the effects of agonists and antagonists on the abnormal Ca 2+ release activity of Purkinje cell aggregates dispersed from the subendocardium 48 hours postcoronary artery occlusion (IZPCs). Studies were completed using epifluorescent microscopy of Fluo-3 loaded Purkinje cells.Results-Similar to our previous report, highly frequent traveling micro Ca 2+ transients(μCaiTs) and cell-wide Ca 2+ waves were seen in IZPCs in the absence of any drug. Isoproterenol (ISO) increased μCaiTs and cell-wide Ca 2+ waves in Purkinje cells dispersed from the normal heart (NZPCs). In IZPCs, ISO increased cell-wide wave frequency but had no effect on the already highly frequent micro Ca 2+ wave transient activity, suggesting that ISO lowers the threshold of cell-wide generators responding to micro Ca 2+ transients. Drugs that block inward sodium or calcium currents (verapamil, tetrodotoxin) had no effect on Ca 2+ activity in Purkinje cells. Antagonists of intracellular Ca 2+ release channels [ryanodine, JTV519(K201)] greatly suppressed spontaneous Ca 2+ release events in IZPCs. 2APB, an agent that blocks IP 3 receptors, greatly reduced the frequency of Ca 2+ events in IZPCs.Conclusions-In arrhythmogenic Purkinje cells that survive in the infarcted heart, agents that block or inhibit intracellular Ca 2+ release channel activity reduced Ca 2+ waves and could be antiarrhythmic.

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Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts

Cited by 303 publications

References 169 publications

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

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

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

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