Early after depolarization

Early after-depolarizations are purported to be the mechanism giving rise to torsades de pointes. Conditions or drugs known to prolong the action potential, especially by interventions that decrease the outward potassium currents, facilitate development of torsades de pointes tachyarrhythmias. Early after-depolarizations may develop in association with hypokalemia, hypoxia, acidosis, and a wide range of pharmacological agents that interfere with outward currents or enhance inward currents. Antiarrhythmic agents, in particular sotalol. 

Early after-depolarizations and the associated ventricular arrhythmia can be prevented or suppressed by the appropriate adjustment of plasma potassium and/or magnesium concentrations. Lidocaine or procainamide may be effective for termination of the arrhythmia. 

It is always best to understand a biological problem before trying to find ways to avoid it. The reason that action potential duration is important is that repolarization is a fragile process. It can fail, and when it does so, the action potential is followed by one or many oscillations. These are called early after-depolarizations (EADs). We will also encounter late after-depolarizations (DADs) later in this chapter. 

Early after depolarization without mutation Re polarization failure with mutation ... 

The evaluation is based on the incidence of either an overt tachyarrhythmia or the appearance of early after depolarizations in the monophasic action potential. 

In studies by Carlsson (1990) the subsequent administration of clofilium (20.8 pmol/kg) lead to a prolongation of the QTU interval and the monophasic action potential with the appearance of early after depolarizations. This was followed by ventricular arrhythmias in all rabbits. Pretreatment with prazosin (1 mg/kg iv) was able to attenuate the arrhythmia. 

The evaluation involves determining incidence of arrhythmia or early after depolarizations after drug... 

Using an endocardial monophasic action potential recording, the incidence of early after depolarizations can be determined. The catheter (e.g. Franz combination catheter, EPT No. 1650) can be placed through the jugular vein or carotid artery under fluoroscopic guidance. 

An important predictor of arrhythmia is changes in the duration of the QT trace, the time for ventricular repolarization, displacement of the ST-segment, and changes in the pattern of T-waves that may sometimes be seen as a T and U wave (Roden, 2004, 2008). It can be linked to ventricular tachycardia, including TdP. Lengthened QT increases the time available for intracellular calcium accumulation, enabling early after-depolarization (BAD) in the Purkinje fibers, and activates calmodulin (CaM) and calmodulin kinase (CaMK). CaMK is believed to enhance after-... 

The main effect of adrenergic stimulation is to enhance the intracellular adenylyl cyclase activity. This in turn increases cyclic adenosine monophosphate levels. Protein kinase A is activated which modulates, i.e. phosphorylates, calcium and potassium channels. Phosphorylation of the calcium channel increases the inward current leading to early after-depolarization. 

An animal study of the mechanism of bupivacaine-induced dysrhythmias has shown that bupivacaine facilitates early after-depolarization in rabbit sinoatrial nodal cells by blocking the delayed rectifier potassium current (11). 

Matsuda T, Kurata Y. Effects of nicardipine and bupivacaine on early after depolarization in rabbit sinoatrial node cells a possible mechanism of bupivacaine-induced arrhythmias. Gen Pharmacol 1999 33(2) 115-25. 

Figure 3-3 Original current-clamp recording of a spontaneous beating cardiomyocyte derived from human embryonic stem cells. The cell was superfused with 100 nM E-4031, a potent hERG channel blocker, which lead after an action potential prolongation to early after depolarizations and chaotic electrical behavior at the cellular level (cellular arrhythmia).

Puisieux F, Adamantidis M, Dumotier B, et al. Cisapride-induced prolongation of cardiac action potential and early after depolarizations in rabbit Purkinje fibres. Br / Pharmacol. 1996,117,1377-1379. 

Triggered automaticity is also a possible mechanism for abnormal impulse generation. Briefly, triggered automaticity refers to transient membrane depolarizations that occur during repolarization (early after-depolarizations [EADs]) or after repolarization (delayed afterdepolarizations [DADs]) but prior to phase 4 of the action potential. After-depolarizations may be related to abnormal calcium and sodium influx during or just after full cellular repolarization. Experimentally, early after-depolarizations may be precipitated by hypokalemia, type la antiarrhythmic drugs, or slow stimulation rates— any factor that blocks the ion channels (e.g., potassium) responsible... 

AVID Antiarrhythmic drug Versus Internal Defibrillator trial CAST Cardiac Arrhythmia Suppression Trial DCC direct-current cardioversion EADs early after-depolarizations... 

Kaseda S, Gihnour RF Jr, Zipes DP (1989). Depressant effect of magnesium on early after depolarizations and triggered activity induced by cesium, quinidine, and 4-aminopyridine in canine cardiac Purkinje fibers. Am Heart J 118 458 66. 

Rozanski GJ, Witt RC (1991). Early after depolarizations and triggered activity in rabbit cardiac Purkinje fibers recovering from ischemic-hke conditions. Role of acidosis. Circulation 83 1352-1360. 

APD, action potential duration ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy CM, cardiomyocyte CPVT, catecholaminergic polymorphic ventricular tachycardia DAD, delayed after depolarizations DCM, dilated cardiomyopathy EAD, early after depolarization HCM, hypertrophic cardiomyopathy 1 rectifier potassium current 1, sodium current MEA, multielectrode array TNNT2, troponin T type 2. 

Since novel QT-shortening drugs have been shown to minimize or eliminate early after-depolarizations, beneficial antiarrhythmic effects in heart failure patients are possibly more likely. 

Administration of magnesium sulfate is currently recommended as immediate first-line treatment for torsades (Zipes et al. 2006). While the mechanism of action is uncertain, magnesium may reduce the amplitude of early after-depolarizations by inhibiting the late influx of calcium ions via L-type calcium channels that are associated with delayed ventricular repolarization. Consequently, early afterdepolarizations are less likely to reach threshold potential and provoke or sustain torsades (Kaye and O Sullivan 2002). 

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