Underlying mechanism of atrial fibrillation–associated Nppa-I137T mutation and cardiac effect of potential drug therapy

BACKGROUND Over 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 aims to investigate the mechanism and potential treatment of NPPA mutation associated AF. METHODS The Nppa KI (p.I137T) rats were generated and cardiac function was evaluated. Blood pressure was recorded by a tail cuff system. The expression levels were measured by RT-PCR, ELISA or western blot, and RNA sequence analysis. The programmed electrical stimulation, the patch clamp, and multielectrode array were used to record the electrophysical characteristics. RESULTS The mutant rats displayed down-regulated expression of ANP, but elevated blood pressure and enlarged left atrial end-diastolic diameter. Further gene topology analysis suggested the majority of differently expressed genes in Nppa KI rats were related to inflammation, electrical remodeling and structural remodeling. The CCL5 and Galetin-3 expressions involved in remodeling were higher, while there were declined levels of Nav1.5, Cav1.2, and Cx40. AF was more easily induced in KI rat. 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 the 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 INa,L blocker and Nav1.8 blocker.