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Review
. 2013 Oct 15;168(6):5135-42.
doi: 10.1016/j.ijcard.2013.08.022. Epub 2013 Aug 15.

Impact of aldosterone antagonists on the substrate for atrial fibrillation: aldosterone promotes oxidative stress and atrial structural/electrical remodeling

Fadia Mayyas  1 , Karem H Alzoubi, David R Van Wagoner
Affiliations
Review

Impact of aldosterone antagonists on the substrate for atrial fibrillation: aldosterone promotes oxidative stress and atrial structural/electrical remodeling

Fadia Mayyas et al. Int J Cardiol. .

Abstract

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an electrocardiographic description of a condition with multiple and complex underlying mechanisms. Oxidative stress is an important driver of structural remodeling that creates a substrate for AF. Oxidant radicals may promote increase of atrial oxidative damage, electrical and structural remodeling, and atrial inflammation. AF and other cardiovascular morbidities activate angiotensin (Ang-II)-dependent and independent cascades. A key component of the renin-angiotensin-aldosterone system (RAAS) is the mineralocorticoid aldosterone. Recent studies provide evidence of myocardial aldosterone synthesis. Aldosterone promotes cardiac oxidative stress, inflammation and structural/electrical remodeling via multiple mechanisms. In HF patients, aldosterone production is enhanced. In patients and in experimental HF and AF models, aldosterone receptor antagonists have favorable influences on cardiac remodeling and oxidative stress. Therapeutic approaches that seek to reduce AF burden by modulating the aldosterone system are likely beneficial but underutilized.

Keywords: Aldosterone; Aldosterone antagonist; Atrial fibrillation; Oxidative stress.

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Figures

Fig. 1
Fig. 1
The substrates of atrial fibrillation. During AF, profound increases in expression of inflammatory proteins such as C reactive protein (CRP), tumor necrosis factor α (TNFα), nuclear factor κb (NFκb), interferon γ (Fγ), interleukin 6 (IL6), and inducible nitric oxide synthase (iNOS) occur. Generation of reactive oxygen species (ROS) is also increased in AF via activation of NADPH oxidase activity and expression, mitochondrial (mit) ROS generation, superoxide generation as well as reduction in antioxidants defenses such as glutathione peroxidase. Atrial fibrosis and hypertrophy also promotes atrial arrhythmogenesis through increased expression of profibrotic proteins such as tumor growth factor β (TGF β), platelet derived growth factor (PDGF), connective tissue growth factor (CTGF), and metalloproteinase (MMP). The decrease in outward (Ito) or rectifier (kur) K + current, the down regulation in connexin 43 (Cx 43) or intracellular Mg+, and the increase in native I (K1) current and L-type Ca + channel current (Cav1.2) promote atrial electrical remodeling leading to AF. These substrates are highly related where one substrate promotes generation of other substrates (AF begets AF).
Fig. 2
Fig. 2
The primary intracellular pathways activated downstream of aldosterone. Several stimuli increase aldosterone expression and release. Aldosterone acts through the mineralocorticoid receptor (MR) and a putative unknown membrane receptor (membrane R??). Aldosterone diffuses through the plasma membrane to the cytosol where it binds the MR and induces MR homodimerization, activation, and translocation to the nucleus. Activated MR promotes gene transcription of fibrotic and hypertrophic proteins (PDGF, CTGF, TGF β), and inflammatory cytokines and chemokines. Aldosterone acts through the MR and membrane Rs and promotes ROS generation via NADPH oxidase (NOX) and the mitochondria. ROS generation and inflammatory molecules activate the iNOS and NFκb signaling. Activated NFκb translocates to the nucleus promoting transcription of genes involved in atrial oxidative damage and inflammation. Aldosterone rapid signaling on membrane receptors also leads to phospholipase C (PLC) activation and other cellular signal-transduction cascades such as those mediated by inositol 1,4,5 trisphosphate (IP3), protein kinase C (PKC). Phosphorylation of membrane Na+/H+ antiporters increases intracellular pH and modulates cardiac myocyte myofilament Ca2+ sensitivity. Influx of Na+ can activate reverse mode activity of the Na+/Ca2+ exchanger (NCX), resulting in elevated intracellular Ca2+, positive inotropy, and arrhythmogenesis. Hydrolysis of phosphatidylinositol 4,5-bis-phosphate (PIP2) increases intracellular IP3, which subsequently promotes Ca2+ release through IP3 receptors (IP3Rs) that are located under the plasma-lemma adjacent to ryanodine receptors (RyRs). Ca2+ release through the IP3Rs may also contribute to the inotropic and arrhythmogenic activity of aldosterone, by sensitizing RyRs located there. Gene transcription pathways are also activated resulting in atrial apoptosis and connexin remodeling. During atrial fibrillation, aldosterone signaling may be enhanced, promoting oxidative damage, increased intracellular Ca2+and hypertrophic/fibrotic remodeling.
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