New Strategies for the Treatment of Atrial Fibrillation

Figure 1. General scheme presenting the main factors, which are implicated in provoking and sustaining atrial fibrillation (AF). AF is usually initiated by spontaneous ectopic beats (extrasystole) originating from a pacemaker region (PVs, left upper pulmonary vein) and later is maintained by mechanism of atrial remodelling. The atrial fibrillation forms (lone, persistent and permanent) are promoted by single/mother wave and/or multiple wave/circuit re-entries. The main factors that may promote reentry are atrial ischaemia and inflammation, while the structural/morphological remodellings are sustained by atrial (micro)fibrosis and left atrial dilation. DAD and EAD—delayed and early afterdepolarization; PVs—pulmonary veins.

Figure 2. The most important transmembrane ionic inward and outward currents determining atrial action potential in sinus rhythm (SR, A) and in permanent atrial fibrillation (AF, B). The ion channel/current (functional elements) density changes are presented in bottom left column, while the expression level current subunit forming proteins and mRNA genes, respectively, are depicted in middle and right columns. The corresponding pictograms near each ion current name present the magnitude and time course of the current reflection of relative real sizes. ↓—decreased current or downregulated protein/gene, respectively; ↑—increased current or upregulated protein/gene, respectively; ↔—unchanged current, protein or gene, respectively; n.d.—no data.

Figure 3. Three proposed positive feedback loops to present the progredient development of atrial remodelling in AF. The electric and contractile remodelling are associated with the downregulation of L-type Ca2+-channels which as a result will cause the alteration of the whole Ca2+-homeostasis process. The loss of contractility and increase in compliance will induce the stretch of the atrial myocardium, which is considered to be the main inducing factor of the structural remodelling. The resulting intra-atrial circuits due to a reduction in wavelength and increased non-uniform tissue anisotropy and even zig-zag conduction (anatomical basis of re-entry or rotors). Reprinted with permission from ref [10]. Copyright year 2002, Oxford Academic.

Figure 4. Possible pharmacological investigational strategies for developing new antiarrhythmic drugs for treating AF.

Figure 5. The chemical structures of the reviewed drugs in the present paper (specific-, multiple-, atrial selective ion channel blocker drugs and gap-junction modulator antiarrhythmic peptides.