Underlying mechanism of atrial fibrillation-associated Nppa-I137T mutation and cardiac effect of potential drug therapy.
Heart Rhythm
; 21(2): 184-196, 2024 Feb.
Article
em En
| MEDLINE
| ID: mdl-37924963
ABSTRACT
BACKGROUND:
More than a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved.OBJECTIVE:
This study aimed to investigate the mechanism and potential treatment of NPPA mutation-associated AF.METHODS:
Nppa knock-in (KI, p.I137T) rats were generated, and cardiac function was evaluated. Blood pressure was recorded using a tail-cuff system. The expression levels were measured using real-time polymerase chain reaction, enzyme-linked immunosorbent assay or Western blot analysis, and RNA-sequence analysis. Programmed electrical stimulation, patch clamp, and multielectrode array were used to record the electrophysical characteristics.RESULTS:
Mutant rats displayed downregulated expression of atrial natriuretic peptide but elevated blood pressure and enlarged left atrial end-diastolic diameter. Further, gene topology analysis suggested that the majority of differently expressed genes in Nppa KI rats were related to inflammation, electrical remodeling, and structural remodeling. The expression levels of C-C chemokine ligand 5 and galectin-3 involved in remodeling were higher, while there were declined levels of Nav1.5, Cav1.2, and connexin 40. AF was more easily induced in KI rats. Electrical remodeling included abbreviated action potentials, effective refractory period, increased late sodium current, and reduced calcium current, giving rise to conduction abnormalities. These electrophysiological changes could be reversed by the late sodium current blocker ranolazine and the Nav1.8 blocker A-803467.CONCLUSION:
Our findings suggest that structural remodeling related to inflammation and fibrosis and electrical remodeling involved in late sodium current underly the major effects of the Nppa (p.I137T) variant to induce AF, which can be attenuated by the late sodium current blocker and Nav1.8 blocker.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Procainamida
/
Fibrilação Atrial
/
Remodelamento Atrial
Limite:
Animals
Idioma:
En
Revista:
Heart Rhythm
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China