Recent advances in the molecular pathophysiology of atrial fibrillation
Reza Wakili, … , Dobromir Dobrev, Stanley Nattel
Reza Wakili, … , Dobromir Dobrev, Stanley Nattel
Published August 1, 2011
Citation Information: J Clin Invest. 2011;121(8):2955-2968. https://doi.org/10.1172/JCI46315.
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Science in Medicine

Recent advances in the molecular pathophysiology of atrial fibrillation

Abstract

Atrial fibrillation (AF) is an extremely common cardiac rhythm disorder that causes substantial morbidity and contributes to mortality. The mechanisms underlying AF are complex, involving both increased spontaneous ectopic firing of atrial cells and impulse reentry through atrial tissue. Over the past ten years, there has been enormous progress in understanding the underlying molecular pathobiology. This article reviews the basic mechanisms and molecular processes causing AF. We discuss the ways in which cardiac disease states, extracardiac factors, and abnormal genetic control lead to the arrhythmia. We conclude with a discussion of the potential therapeutic implications that might arise from an improved mechanistic understanding.

Authors

Reza Wakili, Niels Voigt, Stefan Kääb, Dobromir Dobrev, Stanley Nattel

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Figure 8

Remodeling of ICa,L and inward-rectifier K+ currents by AF/tachycardia.

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Remodeling of ICa,L and inward-rectifier K+ currents by AF/tachycardia. ...
(A) The high atrial rate in AF increases intracellular Ca2+ load, activating calcineurin via the Ca2+/calmodulin system. Calcineurin stimulates nuclear translocation of nuclear factor of activated T lymphocytes (NFAT), reducing transcription of the principal ICa,L subunit, Cav1.2. Increased mRNA degradation/impaired protein translation of Cav1.2 and breakdown of Cav1.2 protein by calpains may also contribute. Increased expression of zinc transporter–1 (ZnT-1) impairs membrane trafficking of Cav1.2. Reduced Cav1.2 phosphorylation due to increased protein phosphatase (PP) activity and increased channel nitrosylation may also decrease ICa,L. GSH, glutathione. (B) Increased IK1 density results from upregulation of the principle Kir2.1 subunit, likely due to reduced levels of inhibitory miRNAs (miR-101, miR-26, miR-1). Increased IK,AChc is caused by altered PKC regulation: increased membrane abundance of stimulatory PKCε and reduced expression of inhibitory PKCα.