https://doi.org/10.1007/s00392-025-02625-4
1LMU Klinikum der Universität München Medizinische Klinik und Poliklinik I München, Deutschland; 2Faculty of Engineering, Yeditepe University Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering İstanbul, Türkei
Background: Atrial arrhythmias such as atrial fibrillation (AF) are a major cause of morbidity and mortality worldwide. Improved therapies are urgently needed, but require a better understanding of the underlying pathophysiology. Genome-wide association studies have identified a genetic variant in the MEIS1 gene that is linked to the PR interval and AF. MEIS1 (myeloid ecotropic insertion site 1) has been shown to play a role in cardiovascular regeneration and tumorigenesis, but the precise mechanisms how MEIS1 may influence atrial electrophysiology and arrhythmogenesis are unknown.
Objective: This study aimed to elucidate the functional role of MEIS1 in cardiac electrophysiology and arrhythmogenesis in vivo using a MEIS1 inhibitor in mice.
Methods: Echocardiography, ECG, invasive electrophysiology (EP) studies, qPCR as well as immunofluorescence staining were performed to assess cardiac dimensions and function, conduction properties, sinus node and atrio-ventricular (AV) node function, and susceptibility to atrial arrhythmias in Balb/c mice treated with a MEIS1 inhibitor.
Results: Mice were divided into four experimental groups: 1) saline (control group), 2) low dose (1 μM i.p., n=10), 3) medium dose (10 μM i.p., n=10), or 4) high dose MEIS1 inhibitor (100 μM i.p., n=18). While mice receiving low or medium doses of the MEIS1 inhibitor did not show an increased risk for arrhythmias, mice treated with a high dose of the MEIS1 inhibitor demonstrated a significantly enhanced inducibility of atrial arrhythmias (Figure 1A). Cardiac structure or function was not affected by treatment with high dose MEIS1 inhibitor (Figure 1B), but it resulted in impaired sinus node function (Figure 1C) and a prolongation of atrial effective refractory periods (Figure 1D). While we did not observe a direct suppression of Meis1 gene expression, MEIS1 inhibition affected the expression of downstream target genes, including an upregulation of CCND2 in both right and left atrium, and a downregulation of TP53 in right and left ventricle. In parallel, cardiomyocyte proliferation was enhanced in right atrium following MEIS1 inhibition (Figure 1E).
Conclusion: In vivo MEIS1 inhibition in BALB/c mice increases the inducibility of atrial arrhythmias, affects sinus node function and atrial conduction properties but does not affect cardiac structure or function. Further analyses suggest that MEIS1 inhibition modulates the expression of cell cycle-related genes, thus promoting cardiomyocyte proliferation in the atria. These results highlight the potential role of MEIS1 as a mediator of atrial arrhythmogenesis.