Cardiac problems seen as more likely for males with Dravet in study
Mouse model work also suggests 'sex-specific' nature of sudden death risk
In a mouse model study of Dravet syndrome, males were seen to be more vulnerable to abnormal heartbeats and heart deficits in energy-producing mitochondria than female mice.
These findings suggest that male Dravet patients may be particularly vulnerable to sudden unexpected death in epilepsy (SUDEP), a fatal seizure complication that is thought to be associated with several factors, including abnormal heartbeats, or arrhythmias.
As such, sex differences should be considered when developing treatments to reduce the risk of SUDEP, the researchers noted.
The study, “Sex differences in cardiac mitochondrial respiration and reactive oxygen species production may predispose Scn1a−/+ mice to cardiac arrhythmias and Sudden Unexpected Death in Epilepsy,” was published in the Journal of Molecular and Cellular Cardiology Plus.
SUDEP can follow severe seizures, affecting breathing and heart rhythm
Marked by seizures that typically start in the first year of life, a frequent cause of Dravet is mutations in the SCN1A gene, which codes for part of a sodium channel needed for nerve cells to transmit electrical signals.
The mutations result in abnormal electrical activity that affects not only brain activity, leading to seizures, but also heart’s electrical function, causing arrhythmias, which may contribute to SUDEP.
SUDEP usually happens after episodes of severe, uncontrolled seizures that can affect breathing, heart rhythm, or brain function, especially during sleep.
To evaluate whether changes in the heart’s mitochondria, the energy-producing structures in cells, may explain arrhythmias and SUDEP in Dravet, researchers in the U.S. used a mouse model of the disease, with the animals genetically modified to lack one copy of the Scn1a gene.
In these mice, seizures begin about 20 days after birth and females are more likely to have shorter lives than males. But for these mice of either sex, lifespans are shorter relative to healthy mice.
Mitochondria use oxygen to produce the energy that cells need to function, and they do this through a process called the electron transport chain, which involves a series of steps or complexes.
When the scientists stimulated complex I, one step in the mitochondrial electron transport chain, they found no significant difference between mice with Dravet-like disease and unaffected mice.
However, when they activated both complex I and II together, males with Dravet-like disease consumed significantly less oxygen than their healthy counterparts, signifying their mitochondria weren’t working as efficiently. No significant differences were observed between diseased and healthy female mice.
Male mice in model live longer than females, but with more arrhythmias
These findings suggested that while Dravet-like male mice lived longer than females, they may be more likely to experience arrhythmias. To test this, the researchers administered norepinephrine, a hormone that increases heart rate and mimics stress conditions, to male and female mice with Dravet-like disease.
They found that males were significantly more likely to develop spontaneous arrhythmias under these stress conditions than females, supporting the idea that males may be at a higher risk of cardiac problems.
Heart cells from male mice, but not female mice, also showed a reduced ability to manage an accumulation of potentially harmful molecules called reactive oxygen species or ROS (mainly derived from mitochondria’s function) and a type of cellular damage called oxidative stress.
Oxidative stress results from an imbalance between ROS production and the cells’ ability to clear them with antioxidants.
According to the researchers, the fact that females with Dravet-like disease live shorter lives but don’t show significant arrhythmic heartbeats or problems with mitochondria in heart cells points to sex-specific causes of death.
“Multiple physiological mechanisms may contribute to how [heart] arrhythmias have the potential to underly SUDEP,” the researchers wrote.
Females may die more from seizures, while males seem to be more likely to develop arrhythmias, especially under stress. These findings could help in developing treatments that are better suited to each sex, targeting the heart for males and focusing on seizure control for females.
“Given the complex nature of SUDEP and mortality in DS [Dravet syndrome], we have shown that sex differences may play an important role in risk factors associated with early mortality,” the researchers wrote. “When developing new therapeutics to address SUDEP risk in DS, sex should be considered,” they concluded.
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