https://doi.org/10.1007/s00392-025-02625-4
1LMU Klinikum der Universität München Medizinische Klinik und Poliklinik I München, Deutschland; 2Universitätsmedizin Göttingen Institut für Pharmakologie und Toxikologie Göttingen, Deutschland
Background: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, has a complex pathophysiology involving both electrical and structural remodeling, leading to limited effectiveness of current treatments. MicroRNAs play a critical role in the remodeling processes underlying AF. In screening studies, miR-144 was identified as significantly downregulated in AF patients, suggesting its role in AF pathogenesis.
Objective: To investigate the impact of in vivo miR-144 knockout (KO) on atrial electrophysiology and arrhythmogenesis with a focus on structural remodeling.
Methods: We used C57BL/6 mice with wildtype (WT), heterozygous, and homozygous miR-144 KO genotypes. Phenotypic assessments included electrocardiography (ECG), echocardiography and electrophysiological (EP) testing. Atrial fibrosis was quantified by Masson’s trichrome staining, and expression of genes associated with structural remodeling was evaluated by qPCR.
Results: miR-144 KO resulted in left atrial enlargement (WT: 1.72 mm vs. KO/KO: 1.94 mm, ****p < 0.0001) and increased atrial susceptibility to tachyarrhythmia (WT: 2.79% vs. KO/KO: 5.79%, *p=0.015). Baseline parameters, including animal weight, heart mass, ECG parameters, and left ventricular function, were unaffected across genotypes. Increased fibrosis was observed in both the right atrium (WT: 0.94% vs. KO/KO: 3.03%, **p=0.0025) and left atrium (WT: 0.86% vs. KO/KO: 3.69%, **p=0.0044) in homozygous KO mice. Smad6 was elevated in both the right atrium (WT: 1.00 vs. KO/KO: 2.99, **p=0.0066) and left atrium (WT: 1.00 vs. KO/KO: 1.65, *p=0.0401). Additionally, WNT5a levels increased in the right atrium (WT: 1.00 vs. KO/KO: 2.19, **p=0.0034), as did TGFBR1 (WT: 1.00 vs. KO/KO: 1.97, *p=0.0443).
Conclusion: Our findings demonstrate that miR-144 KO enhances atrial arrhythmogeneity in mice, likely through fibrosis formation, and subsequent structural remodeling. These insights provide a basis for further exploration of miR-144's signaling pathways and suggest potential avenues for pharmacological intervention targeting this mechanism in AF.