Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant
Background: 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 exp...
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Elsevier
2025-06-01
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| Series: | Journal of Molecular and Cellular Cardiology Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772976125001746 |
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| author | Maya Noureddine Sophie Broadway-Stringer Christopher O'Shea Bethany A.I. Jones Abbie Hayes Chris Denning Siobhan Loughna Fiyaz Mohammed Davor Pavlovic Katja Gehmlich |
| author_facet | Maya Noureddine Sophie Broadway-Stringer Christopher O'Shea Bethany A.I. Jones Abbie Hayes Chris Denning Siobhan Loughna Fiyaz Mohammed Davor Pavlovic Katja Gehmlich |
| author_sort | Maya Noureddine |
| collection | DOAJ |
| description | Background: 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. Methods: 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. Results: 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. Conclusion: 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. |
| format | Article |
| id | doaj-art-9df63262b35d4591a8812c9facc7c316 |
| institution | Kabale University |
| issn | 2772-9761 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Molecular and Cellular Cardiology Plus |
| spelling | doaj-art-9df63262b35d4591a8812c9facc7c3162025-08-20T03:45:10ZengElsevierJournal of Molecular and Cellular Cardiology Plus2772-97612025-06-011210045510.1016/j.jmccpl.2025.100455Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variantMaya Noureddine0Sophie Broadway-Stringer1Christopher O'Shea2Bethany A.I. Jones3Abbie Hayes4Chris Denning5Siobhan Loughna6Fiyaz Mohammed7Davor Pavlovic8Katja Gehmlich9Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UKDepartment of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UKDepartment of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK; Division of Biomedical Sciences, Warwick Medical School, Clinical Sciences Research Laboratory, Coventry, UKDepartment of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UKDepartment of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UKBiodiscovery Institute, University of Nottingham, Nottingham, UKSchool of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UKDepartment of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UKDepartment of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UKDepartment of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford, UK; Corresponding author at: Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK.Background: 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. Methods: 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. Results: 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. Conclusion: 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.http://www.sciencedirect.com/science/article/pii/S2772976125001746Alpha-actinin-2 (ACTN2)Hypertrophic cardiomyopathy (HCM)Pathogenic variantsAtrial electrophysiologyCardiac remodelling |
| spellingShingle | Maya Noureddine Sophie Broadway-Stringer Christopher O'Shea Bethany A.I. Jones Abbie Hayes Chris Denning Siobhan Loughna Fiyaz Mohammed Davor Pavlovic Katja Gehmlich Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant Journal of Molecular and Cellular Cardiology Plus Alpha-actinin-2 (ACTN2) Hypertrophic cardiomyopathy (HCM) Pathogenic variants Atrial electrophysiology Cardiac remodelling |
| title | Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant |
| title_full | Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant |
| title_fullStr | Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant |
| title_full_unstemmed | Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant |
| title_short | Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant |
| title_sort | atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an hcm linked actn2 variant |
| topic | Alpha-actinin-2 (ACTN2) Hypertrophic cardiomyopathy (HCM) Pathogenic variants Atrial electrophysiology Cardiac remodelling |
| url | http://www.sciencedirect.com/science/article/pii/S2772976125001746 |
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