Key result
ACTN2 M228T variant in mice prolongs atrial action potential duration and causes LV dyssynchrony without remodeling.
Why the study?
Atrial arrhythmias observed in families with the novel ACTN2 M228T variant had not been explored, despite patients exhibiting electrical abnormalities prior to clinical HCM onset.
The ACTN2 M228T variant causes atrial electrical alterations and contractile dyssynchrony independent of structural remodeling in a mouse model, potentially explaining arrhythmogenic phenotypes in HCM patients prior to structural changes.
Suggests ACTN2 M228T drives early atrial electrical and LV dyssynchrony phenotypes; hypothesis-generating for human HCM arrhythmogenesis.
Missense variants of Z -disk protein, alpha-actinin-2 (ACTN2), have been linked to hypertrophic cardiomyopathy (HCM). A novel ACTN2 missense variant, M228T, was identified in family members presenting with HCM and/or atrial arrhythmias. Embryonic lethality was previously shown in mice expressing this variant homozygously, whereas heterozygous (Het) expression did not manifest an overt HCM phenotype. Importantly, the atrial arrhythmias observed in the identified family have not been explored in the context of M228T, despite many patients exhibiting electrical abnormalities prior to the clinical onset of HCM. Six-month-old Het M228T and wild-type (WT) mice were used to evaluate electrophysiological properties using electrocardiography (ECG) and atrial optical mapping. Echocardiography and strain analysis were employed to assess cardiac structure and function. Het mice exhibited a prolongation in action potential duration and depolarization time at 30, 50, and 70 % repolarisation in both the left and right atria. No significant alterations in atrial conduction velocity were observed. No changes in atrial ECG parameters were detected. Het mice displayed no evidence of structural remodelling, nor were there any changes in systolic parameters or overt diastolic dysfunction, as assessed by conventional echocardiography and strain analysis. Signs of contractile dyssynchrony were present, specifically at the apex relative to WT controls. The Het M228T mouse model demonstrated atrial electrical alterations that occurred independently of any overt cardiac structural or functional remodelling. These findings may support the causative role for atrial electric phenotypes identified in a subset of patients carrying the variant. • Mouse model of ACTN2 HCM-associated M228T variant displays atrial electrical alterations. • Prolonged atrial action potential duration in Het mice may indicate an arrhythmogenic mechanism. • Het mice demonstrate apical left ventricular contractile dyssynchrony without structural remodelling or impairment. • Electrical alterations are independent of structural remodelling.
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Noureddine et al. (2025) studied Hypertrophic cardiomyopathy and atrial arrhythmias. Heterozygous expression of ACTN2 M228T variant vs. Wild-type (WT) mice was evaluated on Electrophysiological properties, cardiac structure and function. Heterozygous expression of the ACTN2 M228T variant in mice prolonged atrial action potential duration and caused apical left ventricular contractile dyssynchrony without overt structural remodelling.
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