Decreased ability to manage increases in reactive oxygen species may underlie susceptibility to arrhythmias in mice lacking <i>Scn1b</i>

<i>Scn1b</i> plays essential roles in the heart, where it encodes β₁-subunits that serve as modifiers of gene expression, cell surface channel activity, and cardiac conductivity. Reduced β₁ function is linked to electrical instability in various diseases with cardiac manifestations and increased susceptibility to arrhythmias. Recently, we demonstrated that loss of <i>Scn1b</i> in mice leads to compromised mitochondria energetics and reactive oxygen species (ROS) production. In this study, we examined the link between increased ROS and arrhythmia susceptibility in <i>Scn1b</i>^-/- mice. In addition, ROS-scavenging capacity can be overwhelmed during prolonged oxidative stress, increasing arrhythmia susceptibility. Therefore, we isolated whole hearts and cardiomyocytes from <i>Scn1b</i>^-/- and <i>Scn1b^+/+</i> mice and subjected them to an oxidative challenge with diamide, a glutathione oxidant. Next, we analyzed gene expression and activity of antioxidant enzymes in <i>Scn1b^-/-</i> hearts. Cells isolated from <i>Scn1b^-/-</i> hearts died faster and displayed higher rates of ROS accumulation preceding cell death compared with those from <i>Scn1b^+/+</i>. Furthermore, <i>Scn1b^-/-</i> hearts showed higher arrhythmia scores and spent less time free of arrhythmia. Lastly, we found that protein expression and enzymatic activity of glutathione peroxidase is increased in <i>Scn1b^-/-</i> hearts compared with wild type. Our results indicate that <i>Scn1b^-/-</i> mice have decreased capability to manage ROS during prolonged oxidative stress. ROS accumulation is elevated and appears to overwhelm ROS scavenging through the glutathione system. This imbalance creates the potential for altered cell energetics that may underlie increased susceptibility to arrhythmias or other adverse cardiac outcomes.<b>NEW & NOTEWORTHY</b> Using an oxidative challenge, we demonstrated that isolated cells from <i>Scn1b^-/-</i> mice are more susceptible to cell death and surges in reactive oxygen species accumulation. At the whole organ level, they were also more susceptible to the formation of cardiac arrhythmias. This may in part be due to changes to the glutathione antioxidant system.