Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.

Uma Mahesh R Avula,Elaine Ma,Yejun Lin,Samantha Parsons,Parmanand Dasrat,Steven O Marx,Maura Greiser,Andrew R Marks,Qi Yuan,Bi-Xing Chen,Haikel Dridi,Amar D Desai,Humberto C Joca,Ruiping Ji,Haajra Baksh,Christine Sison,Alexander N Katchman,W Jonathan Lederer,Christopher W Ward,Steve Reiken ,Elaine Wan

doi:10.1172/jci.insight.147371

Uma Mahesh R Avula, Elaine Ma + Show 19 more

Open Access

https://doi.org/10.1172/jci.insight.147371

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Abstract

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.

Highlights

The incidence of atrial fibrillation (AF) increases with age, affecting 1% of individuals 60–65 years old and 8%–10% of individuals older than 80 years [1, 2]
The increased persistent Na+ current in the F1759A-NaV1.5 atrial cardiomyocytes led to an elevation in the intracellular Na+ concentration ([Na+]i) of quiescent and field-stimulated atrial cardiomyocytes compared with nontransgenic mice (Figure 1D)
We demonstrate that increased persistent Na+ current in cardiomyocytes induces mitochondrial oxidative stress, Figure 6

Summary

Introduction

The incidence of atrial fibrillation (AF) increases with age, affecting 1% of individuals 60–65 years old and 8%–10% of individuals older than 80 years [1, 2]. AF treatments, in general, have suboptimal efficacy, toxicities, and high rates of recurrences. These challenges persist because many of the therapies, both pharmacological and ablative, are not directed at the underlying atrial myopathy, focusing instead on modifying the properties of the action potential or conduction. In most patients with AF, the predisposing contributors to AF are systemic and cardiac disorders, including hypertension, heart failure, and valvular disease, which may lead to atrial enlargement, fibrosis, and electrical abnormalities [3]. AF caused by primary electrical abnormalities and the more commonly occurring AF, secondary to systemic factors, may share at least some common mechanisms

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