Abstract
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 (INa-L) blockade. 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 (H2O2). 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 INa-L with GS-967 (1 μM), a specific blocker of INa-L (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to H2O2 (n=6). Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity. Specific block of the INa-L with GS-967 effectively suppresses the AF. Drug therapy of oxidative AF in humans with traditional antiarrhythmic drugs remains suboptimal; suppressing INa-L offers a potential new strategy for effective suppression of oxidative human AF that remains suboptimal.
Highlights
Oxidative stress has been shown to increase the susceptibility of the heart to ventricular and atrial fibrillation (VF and AF respectively) in animal models that manifest increased cardiac fibrosis [1,2]
Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity
The purpose of this study is to test the following two hypotheses; 1) oxidative stress-mediated activation of CaMKII signaling with hydrogen peroxide (H2O2) in structurally remodeled atria characterized with increased atrial tissue fibrosis promotes AF by the mechanism of EAD and DAD-mediated triggered activity; and 2) selective inhibition of the enzymatic activity of CaMKII or its distal target, the INa-L with the specific INa-L blocker, GS-967, [18] suppresses the oxidative AF
Summary
Oxidative stress has been shown to increase the susceptibility of the heart to ventricular and atrial fibrillation (VF and AF respectively) in animal models that manifest increased cardiac fibrosis [1,2]. Beta-blockers [12] and Amiodarone, [13] considered first line preventive drugs against POAF, are only partially effective Both human and animal studies have shown increased atrial CaMKII activity as the molecular signal that couples oxidative stress with AF [10]. The purpose of this study is to test the following two hypotheses; 1) oxidative stress-mediated activation of CaMKII signaling with hydrogen peroxide (H2O2) in structurally remodeled atria characterized with increased atrial tissue fibrosis promotes AF by the mechanism of EAD and DAD-mediated triggered activity; and 2) selective inhibition of the enzymatic activity of CaMKII or its distal target, the INa-L with the specific INa-L blocker, GS-967, [18] suppresses the oxidative AF. Inhibition of CaMKII activity with KN-93 (1 μM) (N=6) or its downstream target, the enhanced INa-L with GS-967 (1 μM), a specific blocker of INa-L (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to H2O2 (n=6)
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