Mechanisms and Drug Development in Atrial Fibrillation

Abstract

Atrial fibrillation is a highly prevalent cardiac arrhythmia and the most important cause of embolic stroke. Although genetic studies have identified an increasing assembly of AF-related genes, the impact of these genetic discoveries is yet to be realized. In addition, despite more than a century of research and speculation, the molecular and cellular mechanisms underlying AF have not been established, and therapy for AF, particularly persistent AF, remains suboptimal. Current antiarrhythmic drugs are associated with a significant rate of adverse events, particularly proarrhythmia, which may explain why many highly symptomatic AF patients are not receiving any rhythm control therapy. This review focuses on recent advances in AF research, including its epidemiology, genetics, and pathophysiological mechanisms. We then discuss the status of antiarrhythmic drug therapy for AF today, reviewing molecular mechanisms, and the possible clinical use of some of the new atrial-selective antifibrillatory agents, as well as drugs that target atrial remodeling, inflammation and fibrosis, which are being tested as upstream therapies to prevent AF perpetuation. Altogether, the objective is to highlight the magnitude and endemic dimension of AF, which requires a significant effort to develop new and effective antiarrhythmic drugs, but also improve AF prevention and treatment of risk factors that are associated with AF complications.

Graphical abstract

Fig. 1.

Examples of rotor domains localized in human atria and their ablation. (A) A rotor domain, defined as an anatomic location displaying repetitive rotational activity organized by a meandering singularity point, is displayed at the floor of the left atrium. The ablation line (pink dots) crosses the distribution of the singularity points up to the right circumferential pulmonary vein isolation. (B) A rotor domain in the lateral wall of the right atrium. The ablation line (pink and red dots) crosses the distribution of the singularity points on the right atrium lateral wall. Corresponding unipolar recordings are displayed on the right hand side. IVC, inferior vena cava; LIPV, left inferior pulmonary vein; RIPV, right inferior pulmonary vein; SVC, superior vena cava. Reproduced with permission from Calvo et al. (2017).

Fig. 2.

Docking of chloroquine in the ion permeation pathway of the Kir3.1 channel. (A and B) Two lowest energy poses. Top: Magnified view of the binding poses of chloroquine (cyan sticks) in Kir3.1. The D260 and F255 residues from each of the 4 Kir3.1 subunits are shown in green and orange sticks, respectively. (A) The amine nitrogen of chloroquine forms a hydrogen bond (red line) with the side-chain of D260 in 1 subunit, whereas the aminoquinoline ring of chloroquine is involved in an aromatic-aromatic interaction with the phenylalanine ring of F255 in the adjacent subunit. (B) The amine nitrogen of chloroquine hydrogen bonds (red line) the carbonyl oxygen of F255 in 1 subunit, whereas the aminoquinoline ring of chloroquine is involved in an aromatic-aromatic interaction with the phenylalanine ring of F255 in the opposing subunit. Middle, bottom: van der Waals representations of the channel bound to chloroquine (cyan), viewed from the intracellular and extracellular sides, respectively. (C) Computational model of chloroquine docking in the aqueous region of the transmembrane domain in the homology model for Kir3.1 using the PDB of Kir3.2 (PDB ID: 3SYO). Chloroquine (in cyan) binds the transmembrane domain of the channel at residue. Modified with permission from figures 4 and 9 of Takemoto et al. (2018).

Fig. 3.

Diagrammatic representation of the main effects exerted by renin-angiotensin-aldosterone system blockers. ACEIs, ARBs, and MRBs block inflammatory and profibrotic pathways that promote atrial remodeling and favor AF initiation and maintenance. ACEIs, angiotensin-converting enzyme inhibitors; AG-I, angiotensin I; AG-II, angiotensin II; AG-III, angiotensin III; APA, aminopeptidase A; ARB, angiotensin II type 1 receptor blocker; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; ECM, extracellular matrix; JNK, c-Jun N-terminal kinases; MMP, matrix metalloproteinase; MR, mineralocorticoid receptor; MRB, mineralocorticoid receptor blocker; MT1-MMP, membrane type 1 metalloprotease; Nox2, nicotinamide adenine dinucleotide phosphate oxidase 2; P, phosphorylation; p38 MAPK, p38 mitogen-activated protein kinase; PKC, protein kinase C; ROS, reactive oxygen species; SMA, α-smooth muscle actin; TFs, transcription factors; TNF-α, tumor necrosis factor-α.