A novel murine model of atrial fibrillation by diphtheria toxin-induced injury

Theresa Trieu; Philbert Mach; Kaitlyn Bunn; Vincent Huang; Jamie Huang; Christine Chow; Haruko Nakano; Viviana M Fajardo; Marlin Touma; Shuxun Ren; Yibin Wang; Atsushi Nakano

doi:10.3389/fphys.2022.977735

A novel murine model of atrial fibrillation by diphtheria toxin-induced injury

Front Physiol. 2022 Oct 31:13:977735. doi: 10.3389/fphys.2022.977735. eCollection 2022.

Authors

Theresa Trieu¹, Philbert Mach¹, Kaitlyn Bunn¹, Vincent Huang¹, Jamie Huang¹, Christine Chow¹, Haruko Nakano¹, Viviana M Fajardo², Marlin Touma², Shuxun Ren³, Yibin Wang^{3

4}, Atsushi Nakano^{1

4

5}

Affiliations

¹ Department of Molecular, Cell, Developmental Biology, School of Life Science, University of California, Los Angeles, Los Angeles, CA, United States.
² Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
³ Departments of Anesthesiology, Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
⁴ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
⁵ Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.

Abstract

The treatment of atrial fibrillation (AF) continues to be a significant clinical challenge. While genome-wide association studies (GWAS) are beginning to identify AF susceptibility genes (Gudbjartsson et al., Nature, 2007, 448, 353-357; Choi et al., Circ. Res., 2020, 126, 200-209; van Ouwerkerk et al., Circ. Res., 2022, 127, 229-243), non-genetic risk factors including physical, chemical, and biological environments remain the major contributors to the development of AF. However, little is known regarding how non-genetic risk factors promote the pathogenesis of AF (Weiss et al., Heart Rhythm, 2016, 13, 1868-1877; Chakraborty et al., Heart Rhythm, 2020, 17, 1,398-1,404; Nattel et al., Circ. Res., 2020, 127, 51-72). This is, in part, due to the lack of a robust and reliable animal model induced by non-genetic factors. The currently available models using rapid pacing protocols fail to generate a stable AF phenotype in rodent models, often requiring additional genetic modifications that introduce potential sources of bias (Schüttler et al., Circ. Res., 2020, 127, 91-110). Here, we report a novel murine model of AF using an inducible and tissue-specific activation of diphtheria toxin (DT)-mediated cellular injury system. By the tissue-specific and inducible expression of human HB-EGF in atrial myocytes, we developed a reliable, robust and scalable murine model of AF that is triggered by a non-genetic inducer without the need for AF susceptibility gene mutations.

Keywords: amiodarone; atrial fibrillation; diphtheria toxin; non-genetic cause; sarcolipin (SLN).

Grants and funding

R01 HL142801/HL/NHLBI NIH HHS/United States