Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation

Abstract

Early (EAD) and delayed (DAD) afterdepolarizations-induced triggered activity is capable of initiating and maintaining cardiac arrhythmias. EAD-induced triggered responses are traditionally thought to be involved in the generation of ventricular arrhythmias under long QT conditions and are precipitated by bradycardia or long pauses. In contrast, DAD-induced triggered activity commonly underlies arrhythmias precipitated by tachycardia. Spontaneous release of calcium from the sarcoplasmic reticulum (SR) secondary to cellular calcium overload induces DADs and some forms of EADs. Recent studies from our laboratory have uncovered a novel mechanism giving rise to triggered activity, termed "late-phase 3 EAD," which combines properties of both EAD and DAD, but has its own unique character. Late-phase 3 EAD-induced triggered extrasystoles represent a new concept of arrhythmogenesis in which abbreviated repolarization permits "normal SR calcium release" to induce an EAD-mediated closely coupled triggered response, particularly under conditions permitting intracellular calcium loading. This review briefly describes the mechanisms and properties of late-phase 3 EADs, how they differ from conventional EADs and DADs, as well as their role in the initiation of cardiac arrhythmias, such as atrial fibrillation.

Figure 1

Early (EAD) and delayed (DAD) afterdepolarizations and EAD- and DAD-induced triggered action potentials (AP). (A) Phase 2 EAD and phase 3 EAD-induced APs in canine isolated Purkinje fiber preparation treated with d-sotalol (I _Kr block). The conditional phase of EAD is defined as the time interval spanning from the moment when membrane potential starts to deviate from normal course to the moment that immediately precedes the EAD upstroke or downstroke. (B) DAD and DAD-induced triggered activity in canine ventricular preparation induced by rapid pacing in the presence of isoproterenol (β-adrenergic agonist, augmenting intracellular calcium activity).

Figure 2

An example of spontaneous termination of acetylcholine-mediated AF and its immediate reinitiation in a canine isolated coronary-perfused right atrial preparation. Note the significant transient augmentation of phasic tension (which approximates the amount of sarcoplasmic reticulum calcium release) following the termination of AF and its association with the immediate AF recurrence. (Reproduced with permission from Ref. .)

Figure 3

Late-phase 3 EAD-induced extrasystole arising following termination of rapid pacing initiates AF. Tension, ECG, and transmembrane action potential (AP) recordings recorded as the pacing CL was increased from 150 to 700 ms (A) or from 100 to 700 ms (B) are shown. (A) With rapid pacing at a CL of 150 ms, only a modest increase in tension and a prolongation of late repolarization are observed in the first AP recorded after termination of rapid pacing. (B) With rapid pacing at a CL of 100 ms, a more dramatic increase in phasic tension is associated with the development of a late-phase 3 EAD-induced triggered beat, which initiates a run of AF. (Reproduced with permission from Ref. .)

Figure 4

Proposed mechanism for the development of late-phase 3 EADs. Superimposed action potential (AP) and phasic tension recordings obtained under steady-state conditions and during the first regular postrapid pacing beat in control and in the presence of acetylcholine are shown. See text for further discussion. (Re-produced with permission from Ref. .)