Aging‐Related Increase to Inducible Atrial Fibrillation in the Rat Model

Hayashi, Hideki; Wang, Charles; Miyauchi, Yasushi; Omichi, Chikaya; Pak, Hui Nam; Zhou, Shengmei; Ohara, Toshihiko; Mandel, William J.; Lin, Shien Fong; Fishbein, Michael C.; Chen, Peng Sheng; Karagueuzian, Hrayr S.

doi:10.1046/j.1540-8167.2002.00801.x

Cited by 134 publications

(135 citation statements)

References 4 publications

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“…These findings are consistent with our previous findings in aged rats and rabbits atria [1,7,20,22] as well as in aged human atria [23]. …”

Section: Resultssupporting

confidence: 94%

“…Furthermore, elevation of the H 2 O 2 concentration for up to 2 mM (N=5) in the young/adult hearts still failed to promote EADs and/or atrial ectopic activity consistent with our previous findings [1,7,22] and by Lin CS et al [24]. The discrepancy between the ease of oxidative EAD formation at the single myocyte level isolated from young/adult atria [18,25] and the resistance to EAD formation at the atrial tissue level in young/adult hearts, suggests that atrial tissue factor(s) must have been responsible in the aged tissue to readily promote EAD and EAD-mediated triggered activity.…”

Section: Resultssupporting

confidence: 91%

“…Longitudinal and transverse sections (5 μm thickness) were made in the LA appendage and the free wall and stained with trichrome that stain collagen fibers blue. Percent LA fibrosis was determined as we previously described [7,20]. …”

Section: Methodsmentioning

confidence: 99%

“…Increased systemic and atrial myocardial oxidative stress is often observed in post-operative patients with new onset (acute) paroxysmal AF (POAF) [3,4] with an incidence of up to 50% [5]. Diverse etiological factors such as fibrosis [6,7] and increased Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity [8,9] among others, are thought to play a key role in the initiation of oxidative AF [4,10]. While the causative and signaling factors of oxidative AF are reasonably well identified, the mechanism of spontaneous initiation (i.e., not induced by electrical stimulation) of acute oxidative AF in experimental and human studies, remains undefined [10].…”

Section: Introductionmentioning

confidence: 99%

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

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

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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 (INa-L) 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 (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). Conclusions 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.

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“…These findings are consistent with our previous findings in aged rats and rabbits atria [1,7,20,22] as well as in aged human atria [23]. …”

Section: Resultssupporting

confidence: 94%

Section: Resultssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

View full text Add to dashboard Cite

show abstract

“…20) The intra-atrial conduction velocity (CV) from the upper to lower RA was obtained during upper RA pacing at a cycle length of 200 msec. These electrophysiological studies were repeated just after a 5-second SNS (n = 8 in each group) or 5-second PNS (n = 8 in each group).…”

Section: Methodsmentioning

confidence: 99%

Influences of Autonomic Nervous System on Atrial Arrhythmogenic Substrates and the Incidence of Atrial Fibrillation in Diabetic Heart

et al. 2009

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SummaryDiabetes mellitus (DM) is clinically associated with an increased incidence of atrial fibrillation (AF), but the underlying mechanism remains unclear. We hypothesized that neural remodeling enhances AF vulnerability in diabetic hearts. Eight weeks after creating streptozotocin-induced diabetic rats (DM rats) or control rats, the hearts were perfused according to the Langendorff method. Inducibility of AF was evaluated by 5 times burst pacing from the right atrium and the atrial effective refractory period (AERP) was measured. The protocol was repeated during sympathetic nerve stimulation (SNS) or parasympathetic nerve stimulation (PNS). In tissue samples taken from the right atrium, the density of nerves positive for tyrosine hydroxylase (TH) and acetylcholinesterase (AChE) were determined. SNS significantly increased the incidence of AF in DM rats (14 ± 6 to 30 ± 8%, P < 0.01), but not in control rats (11 ± 4 to 14 ± 6%, NS). Although AERP was significantly decreased by SNS in both rats (each P < 0.01), increased heterogeneity of AERP by SNS was seen only in DM rats. PNS significantly decreased AERP and increased the incidence of AF (9 ± 5 to 30 ± 5% in control rats, 12 ± 6 to 27 ± 6% in DM rats, each P < 0.01) in both rats. The density of TH-positive nerves was heterogeneous in DM rats compared with control rats, whereas the heterogeneity of AChE-positive nerves was not different in the rats. The prevalence of AF was enhanced by adrenergic activation in diabetic hearts, in which heterogeneous sympathetic innervation was evident. These results suggest that neural remodeling may play a crucial role for increased AF vulnerability in DM. (Int Heart J 2009; 50: 627-641)

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