Expression of mitochondrial catalase in transgenic mice with persistent sodium current reduced spontaneous atrial fibrillation burden from approximately 35% to less than 1%.
Does reducing mitochondrial oxidative stress via mCAT expression prevent atrial myopathy and fibrillation in a mouse model of persistent sodium current?
Targeting mitochondrial oxidative stress attenuates atrial structural remodeling and fibrillation in a preclinical model of persistent sodium current-induced atrial myopathy.
Absolute Event Rate: 1% vs 35%
p-value: p=<0.0001
Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current-induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.
Avula et al. (Thu,) conducted a other in Atrial fibrillation. Mitochondrial catalase (mCAT) expression vs. F1759A-NaV1.5 mice (without mCAT) was evaluated on Spontaneous AF burden (p=<0.0001). Expression of mitochondrial catalase in transgenic mice with persistent sodium current reduced spontaneous atrial fibrillation burden from approximately 35% to less than 1%.