Reinduction of Atrial Fibrillation Immediately After Termination of the Arrhythmia Is Mediated by Late Phase 3 Early Afterdepolarization–Induced Triggered Activity

Abstract

Background-Atrial fibrillation (AF) at times recurs immediately after termination of the arrhythmia. The mechanism (s) responsible for the extrasystole that reinduces AF is largely unknown. We hypothesized that abbreviation of action potential duration (APD) would permit very rapid rates of excitation, known to induce intracellular calcium loading, which in turn could promote delayed and/or early afterdepolarizations (EADs). Methods and Results-Acetylcholine (ACh, 1 mol/L) was used to abbreviate atrial APD and permit rapid-pacing induction of AF in isolated coronary-perfused canine right atria. Transmembrane action potentials, pseudo-ECG, and tension development were recorded. AF or rapid pacing was associated with an increase in tonic tension. Termination of AF or rapid pacing (cycle length, 150 to 80 ms) resulted in a dramatic rise of phasic tension, prolongation of repolarization of the initial beats at the regular rate (cycle length, 700 ms), and the development of late phase 3 EADs and extrasystoles. These extrasystoles initiated AF in 15 cases (involving 9 right atria) within the first 11 seconds after termination of AF or rapid pacing. This novel EAD mechanism is observed only in association with marked APD abbreviation. The calcium channel blocker nifedipine reduced, and the sarcoplasmic reticulum calcium release blocker ryanodine eliminated, the post-rapid pacing-induced increase in phasic tension, late phase 3 EADs, and extrasystoles that initiate AF. Conclusions-These data suggest that calcium overload conditions present after termination of vagally mediated AF contribute to the development of late phase 3 EAD-induced triggered activity and that this mechanism may be responsible for the extrasystolic activity that reinitiates AF. Key Words: action potentials Ⅲ fibrillation Ⅲ calcium Ⅲ triggered activity A number of studies have documented the reinitiation of atrial fibrillation (AF) by an atrial extrasystole arising soon after termination of the arrhythmia. [1][2][3][4] Although a reentrant mechanism is thought to underlie the maintenance of the arrhythmia, the mechanism(s) responsible for the premature beat(s) that reinduce AF is largely unknown. Immediate recurrence of AF (IRAF) was found to be unexpectedly high in patients with implanted atrial defibrillators, occurring after 27% of successful shocks. 5 Patients who experience early AF recurrence after cardioversion have been shown to display briefer mean AF cycle lengths (CLs) than those who do not. 6 In addition, acute treatment with the calcium channel blocker verapamil has been shown to reduce IRAF after electrical cardioversion in the clinic. 4 These observations highlight the importance of rapid rates and calcium homeostasis in the early reinitiation of AF.Like electrical remodeling, 7 vagal influences are known to cause a marked abbreviation of atrial action potential duration (APD), permitting activation of atrial cells at much higher frequencies than otherwise possible. We hypothesized that immediately after termination of these rapid ra...

Intracellular calcium dynamics and acetylcholine-induced triggered activity in the pulmonary veins of dogs with pacing-induced heart failure

“…A long preceding pause increases accumulation of intracellular Ca, leading to larger sarcoplasmic reticulum Ca release in the first beat after the pause. 3 This latter phenomenon, in addition to APD shortening induced by acetylcholine, contributes to the development of late phase 3 Ca i elevation. The combination of late phase 3 Ca i elevation and the hyperactive NCX current facilitates the development of focal discharge from the PVs in heart failure.…”

“…Persistent Ca i elevation in phase 3 of the action potential may activate the NCX current and induce late phase 3 early afterdepolarizations. 3,4,9 These late phase 3 early afterdepolarizations initiate focal discharge and AF. We propose that this mechanism underlies the focal discharges observed in the present study.…”

“…1 Vagal activation is thought to promote atrial fibrillation (AF) by shortening the refractory period, which accelerates and stabilizes reentrant excitation. 2 However, acetylcholine infusion also may induce late phase 3 early afterdepolarizations and triggered activity in normal canine atria 3 if acetylcholine-induced action potential duration (APD) shortening is coupled with increased intracellular calcium (Ca i ) transient. The large and persistent Ca i transient that occurs in late diastole activates the Na + /Ca 2+ exchanger (NCX), leading to afterdepolarizations and triggered activity.…”

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

“…Adaptation to this new situation results in profound changes in the ion channels controlling Ca 2+ reuptake and release by the sarcoplasmic reticulum 13,21 . These changes persist for some time after the restoration of a normal sinus rhythm (for example, after cardioversion), rendering the recurrence of AF more likely 58 . Increases in spontaneous electrical activity have been suggested to have a major role in abnormal intracellular Ca 2+ handling in the genesis of AF 59 .…”

Expression of tyrosine hydroxylase and growth-associated protein 43 in aging atrial fibrillation patients of Xinjiang Uygur and Han nationality

“…Abnormal activity of the autonomic nerve could also induce AF by inducing cardiac intracellular calcium overload and early after depolarization (EAD). Burashnikov and Antzelevitch (2003) found that injecting Ach into the coronary artery could shorten the action potential of atrial muscle cells and cause rapid atrial pacemaking, which could easily induce AF. They also found that the sudden stop of AF or the increasing of the rapid pacemaking frequency could instantly improve the tension of atrial muscle cells, which would cause 3 phases of rapid EAD of action potential and extrasystole, which would induce AF.…”