Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Figures

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  Figure 1. Histological sections of trichrome staining of LA epicardial appendages in a young/adult (A) versus an old (B) rat heart. Note the increased interstitial fibrosis (blue stain) in the old rat myocardium, causing separation of myocardial bundles (stained red).

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  Figure 2. Patterns of spontaneous initiation of AF in isolated-perfused aged hearts exposed to H2O2 (hydrogen peroxide) (0.1 mM) in three different aged hearts. Panel A shows sudden onset of AF arising during sinus rhythm. In panel B, AF starts after a prior transient period of AT at a CL of 120 ms and panel C shows the sudden emergence of AT at a cycle length of 116 ms that last more than 30 sec before degenerating to AF.

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  Figure 3. Prevention and suppression of acute oxidative AF with the CaMKII inhibitor KN-93 (1 μM). Pretreatment with KN-93 prevents emergence of H2O2-induced AF over a 50 min of observation (panel A). However, subsequent replacement of KN-93 with its inactive form, KN-92 (1 μM) causes AF to emerge within 6 minutes of the switch (panel B). Note below the panel B a faster sweep recording showing the onset of AF (arrow) followed immediately by VF. Panel C shows another aged heart in which the AF was initiated with H2O2 (0.1 mM) and was effectively suppressed by the addition of KN-93(1 μM) in the continuous presence of H2O2

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  Figure 4. Optical APs (OAPs) and voltage snapshots of epicardial LA and RA activation during sinus rhythm and at the onset of oxidative AF in an aged rat heart. Panel A shows four rows of OAPs recorded from the LA epicardial surface from sites shown in panel D during perfusion with normal Tyrode’s. Panel B shows the influence of 8 min of perfusion with H2O2 (0.1 mM) on these OAPs with the emergence of subthreshold EADs. Panel C shows the last three sinus beats just before the onset of EAD-mediated triggered activity (T1–T3). Note that the EAD amplitude during the sinus beat#1 and #2 manifest subthreshold EAD (arrows). However, the 3rd sinus beat initiates triggered activity (T1–T3). Double-headed arrows indicate the CL of the specified intervals. Panel E shows the snap shots of the six beats SR1, SR2, SR3, T1, T2, and T3, with the origination of the sinus beats from the RA and triggered beats arising from the LA. Adjoining the maps is a color bar showing depolarization and repolarization respectively.

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  Figure 5. Glass microelectrode recordings of LA epicardial APs showing Premature Atrial Complexes (PAC) in panel A; atrial tachycardia (panel B) and AF (panel C) initiated with H2O2 (0.1 mM). Notice the onset of these arrhythmias by EAD-mediated triggered beats. While DADs also appear after a prior run of EAD-mediated triggered activity DAD-mediated causing triggered (Panels A and B), DADs cause only single triggered beats (PAC) as shown in panel D.

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  Figure 6. Suppression of H2O2-mediated AF with 1 μM GS-967 Notice an initial transition from AF to rapid AT before converting to sinus rhythm (panel A). Panels B demonstrates that the anti-AF effect of the GS-967 is reversible as AF re-emerges upon the washout of the drug. Also notice the simultaneous emergence of oxidative VF upon the washout of the GS-967 (panel B).