Background: The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (I) blockade.
Method And Results: High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting. Aged atria (23-24 months) manifested 10-fold increase in atrial tissue fibrosis compared to young/adult (2-4 months) atria (P<0001. Spontaneous AF arose in 39 out of 41 of the aged atria but in 0 out of 12 young/adult hearts (P<001) during arterial perfusion of with 0.1 mm of hydrogen peroxide (HO). Optical Action Potential (AP) activation maps showed that the AF was initiated by a focal mechanism in the LA suggestive of EAD-mediated triggered activity. Cellular AP recordings with glass microelectrodes from the LA epicardial sites showing focal activity confirmed optical AP recordings that the spontaneous AF was initiated by late phase 3 EAD-mediated triggered activity. Inhibition of CaMKII activity with KN-93 (1 μM) (N=6) or its downstream target, the enhanced I with GS-967 (1 μM), a specific blocker of I (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to HO (n=6).
Conclusions: Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity. Specific block of the I with GS-967 effectively suppresses the AF. Drug therapy of oxidative AF in humans with traditional antiarrhythmic drugs remains suboptimal; suppressing I offers a potential new strategy for effective suppression of oxidative human AF that remains suboptimal.
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| http://dx.doi.org/10.16966/2379-769X.146 | DOI Listing |
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