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Irbesartan prevents sodium channel remodeling in a canine model of atrial fibrillation.

ABSTRACT: Activation of the renin-angiotensin system (RAS) plays an important role in atrial electrical remodeling (AER). The purpose of the present study was to evaluate the effects of irbesartan on cardiac sodium current (INa) in a canine model of atrial fibrillation.Eighteen dogs were randomized into sham, pacing or pacing+irbesartan groups ( n = 6 in each group). The dogs in the pacing and irbesartan group were paced at 500?bpm for two weeks. Irbesartan (60?mg·kg-1·d-1) was administered orally in the pacing+irbesartan groups. INa was recorded using the whole-cell patch clamp technique from canine atrial myocytes. The expressions of cardiac Na+ channels (Nav1.5) mRNA were semi-quantified by reverse transcription-polymerase chain reaction.Our results showed that INa density and Nav1.5 mRNA expression in the pacing group decreased significantly ( p < 0.05 vs. sham). However, rapid atrial pacing had no effects on the half-activation voltage (V1/2act) and half-inactivation voltage (V1/2inact) of INa ( p > 0.05 vs. sham). Irbesartan significantly increased INa densities and gene expression and hyperpolarized V1/2act without concomitant changes in V1/2inact.Irbesartan significantly increased INa densities, which contributed to improving intra-atrial conduction and prevented the induction and promotion of AF in atrial pacing dogs.

SUBMITTER: Wang X

PROVIDER: S-EPMC5843850 | biostudies-literature | 2018 Jan-Mar

REPOSITORIES: biostudies-literature

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Irbesartan prevents sodium channel remodeling in a canine model of atrial fibrillation.

Wang Xuewen X Li Guangping G

Journal of the renin-angiotensin-aldosterone system : JRAAS 20180101 1

<h4>Introduction</h4>Activation of the renin-angiotensin system (RAS) plays an important role in atrial electrical remodeling (AER). The purpose of the present study was to evaluate the effects of irbesartan on cardiac sodium current (I<sub>Na</sub>) in a canine model of atrial fibrillation.<h4>Materials and methods</h4>Eighteen dogs were randomized into sham, pacing or pacing+irbesartan groups ( n = 6 in each group). The dogs in the pacing and irbesartan group were paced at 500 bpm for two week ...[more]

PMID: 29378480

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Project description:Importance:The association between obesity, an established risk factor for atrial fibrillation (AF), and response to antiarrhythmic drugs (AADs) remains unclear. Objective:To test the hypothesis that obesity differentially mediates response to AADs in patients with symptomatic AF and in mice with diet-induced obesity (DIO) and pacing induced AF. Design, Setting, and Participants:An observational cohort study was conducted including 311 patients enrolled in a clinical-genetic registry. Mice fed a high-fat diet for 10 weeks were also evaluated. The study was conducted from January 1, 2018, to June 2, 2019. Main Outcomes and Measures:Symptomatic response was defined as continuation of the same AAD for at least 3 months. Nonresponse was defined as discontinuation of the AAD within 3 months of initiation because of poor symptomatic control of AF necessitating alternative rhythm control therapy. Outcome measures in DIO mice were pacing-induced AF and suppression of AF after 2 weeks of treatment with flecainide acetate or sotalol hydrochloride. Results:A total of 311 patients (mean [SD] age, 65 [12] years; 120 women [38.6%]) met the entry criteria and were treated with a class I or III AAD for symptomatic AF. Nonresponse to class I AADs in patients with obesity was less than in those without obesity (30% [obese] vs 6% [nonobese]; difference, 0.24; 95% CI, 0.11-0.37; P?=?.001). Both groups had similar symptomatic response to a potassium channel blocker AAD. On multivariate analysis, obesity, AAD class (class I vs III AAD [obese] odds ratio [OR], 4.54; 95% Wald CI, 1.84-11.20; P?=?.001), female vs male sex (OR, 2.31; 95% Wald CI, 1.07-4.99; P?=?.03), and hyperthyroidism (OR, 4.95; 95% Wald CI, 1.23-20.00; P?=?.02) were significant indicators of the probability of failure to respond to AADs. Pacing induced AF in 100% of DIO mice vs 30% (P?<?.001) in controls. Furthermore, DIO mice showed a greater reduction in AF burden when treated with sotalol compared with flecainide (85% vs 25%; P?<?.01). Conclusions and Relevance:Results suggest that obesity differentially mediates response to AADs in patients and in mice with AF, possibly reducing the therapeutic effectiveness of sodium channel blockers. These findings may have implications for the management of AF in patients with obesity.

Dataset Information

Irbesartan prevents sodium channel remodeling in a canine model of atrial fibrillation.

Publications

Irbesartan prevents sodium channel remodeling in a canine model of atrial fibrillation.

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