Mouse models of spontaneous atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common arrhythmia in adults, with a prevalence increasing with age. Current clinical management of AF is focused on tertiary prevention (i.e., treating the symptoms and sequelae) rather than addressing the underlying molecular pathophysiology. Robust animal models of AF, particularly those that do not require supraphysiologic stimuli to induce AF (i.e., showing spontaneous AF), enable studies that can uncover the underlying mechanisms of AF. Several mouse models of AF have been described to exhibit spontaneous AF, but pathophysiologic drivers of AF differ among models. Here, we describe relevant AF mechanisms and provide an overview of large and small animal models of AF. We then provide an in-depth review of the spontaneous mouse models of AF, highlighting the relevant AF mechanisms for each model.

Fig. 1

Major AF mechanisms present in mouse models of spontaneous AF. Altered substrate and ectopic electrical activity are the two major mechanisms. Altered substrate is characterized by fibrosis and slowed conduction. Ectopy is characterized by EADs, DADs, and automaticity, which arise due to ion channel dysfunction and calcium dysregulation. AF atrial fibrillation, Ca²⁺ calcium, DADs delayed afterdepolarizations, EADs early afterdepolarizations

Fig. 2

AF incidence by age in the Lkb1-CKO, CREm-Tg, Ace-Tg, and Tnf-α-Tg mouse models. Incidence of spontaneous AF is plotted against age for Lkb1-KO (Ozcan et al. 2015; Hulsurkar et al. 2021) (A), CREm-Tg (Muller et al. 2005; Stumpel et al. 2018) (B), ACE-Tg (Xiao et al. 2004) (C), and Tnf-α-Tg (Saba et al. 2005) (D). Age was plotted through 20 weeks for all models. Ace angiotensin-converting enzyme; Anf atrial natriuretic factor; CREm cyclic AMP-responsive element modulator; Hom homozygous; Het heterozygous; Lkb1 liver kinase B1; α-MHC myosin heavy chain; KO knockout; Tg transgenic; Tnf-α tumor necrosis factor alpha