Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant

• Published in: Journal of Molecular and Cellular Cardiology Plus (Online) Vol. 12; p. 100455
• Main Authors: Noureddine, Maya, Broadway-Stringer, Sophie, O'Shea, Christopher, Jones, Bethany A.I., Hayes, Abbie, Denning, Chris, Loughna, Siobhan, Mohammed, Fiyaz, Pavlovic, Davor, Gehmlich, Katja
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2025; Elsevier
• Subjects: Alpha-actinin-2 (ACTN2); Atrial electrophysiology; Cardiac remodelling; Hypertrophic cardiomyopathy (HCM); Original; Pathogenic variants; Pathogenic variants; Hypertrophic cardiomyopathy (HCM); Atrial electrophysiology; Alpha-actinin-2 (ACTN2); Cardiac remodelling
• ISSN: 2772-9761; 2772-9761
• DOI: 10.1016/j.jmccpl.2025.100455

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 depolarisation 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. [Display omitted] •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.