- In a mouse model of intracranial aneurysm formation, vagus nerve stimulation (VNS) significantly reduced rupture in a mild version of the model and significantly improved postrupture survival and neurological deficits in a more severe version
- Expression of proinflammatory markers was reduced in cerebral circulation, including a significant reduction of matrix metalloproteinase-9, suggesting suppression of inflammation is the mechanism of VNS action in this model
- Noninvasive VNS is already known to have an excellent safety and tolerability profile, so presumably these findings could be rapidly translated into clinical use
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Inflammation is known to have a principal role in the formation, growth and rupture of intracranial aneurysms. Anti-inflammatory chemicals have reduced aneurysm rupture in mouse models, but it has been difficult to translate these interventions into human use.
Vagus nerve stimulation (VNS), which has potent anti-inflammatory properties, is currently used to treat intractable epilepsy and depression. Its clinical applications have been limited by the need to surgically implant electrodes around the nerve, but noninvasive VNS techniques have recently been developed.
Cenk Ayata, MD, PhD, a neurologist in the Department of Neurology at Massachusetts General Hospital, Aman B. Patel, MD, director of Cerebrovascular and Endovascular Neurosurgery and director of the Neuroendovascular Program, and colleagues have reported in Stroke that a noninvasive VNS approach inhibits aneurysm rupture in mice. The technique also improves post rupture survival, regardless of the degree of subarachnoid hemorrhage (SAH).
A Model with Two Levels of Severity
The researchers induced intracranial aneurysms and systemic hypertension in C57BL/6 mice through intracranial injection of elastase and deoxycorticosterone acetate. One cohort of the mice, termed the severe model, was also given a high-salt diet and supplemental doses of deoxycorticosterone acetate, resulting in higher average arterial pressure.
Starting the day after elastase injection, the animals were randomly assigned to receive either transcutaneous VNS to the neck or, as a control, transcutaneous femoral nerve stimulation (FNS). Both treatments were delivered twice daily.
- Survival was nearly 100%, so the mild model did not allow assessment of the effect of VNS on survival
- Deficit-free survival was higher in the VNS group than in the FNS group (P = .055)
- Neurological deficit grades were milder in the VNS group, but the difference was not significant
- Postmortem examinations revealed aneurysmal rupture in 29% of animals in the VNS group vs. 80% of those in the FNS group (P = .04)
- SAH grades were significantly lower in the VNS group (P = .02)
- Survival and deficit-free survival were significantly better in the VNS group than in the FNS group (P = .03 for both comparisons)
- Neurological deficit grades and SAH grades did not differ significantly between the VNS and FNS groups
- Nearly all animals in the severe model had an aneurysm rupture, so it was not possible to assess rupture rates
The improved survival in the severe model, despite comparable rupture rates and SAH grades, strongly suggests VNS has a protective effect on brain tissue. Thus, in addition to preventing aneurysm growth and rupture, VNS may improve outcome after SAH.
To explore whether the effects of VNS were anti-inflammatory, the researchers measured mRNA expression of certain proinflammatory mediators (e.g., interleukin-6, tumor necrosis factor alpha) in cerebral circulation in the severe model seven days after elastase injection.
Expression of the mediators was generally suppressed with VNS compared with FNS, although the difference was significant only for matrix metalloproteinase-9 (MMP-9). The researchers note that MMP-9 has been linked to cerebral aneurysm rupture and may predict poor prognosis.
Opportunity for Rapid Translation
The findings could be rapidly translated into bedside or ambulatory use, the research team believes, because noninvasive VNS is already known to have an outstanding safety and tolerability profile.
The researchers envision that daily VNS could be used prophylactically to prevent aneurysm formation in patients with known propensity (e.g., those with fibromuscular dysplasia) or to prevent aneurysm growth in those with known unruptured aneurysms. VNS might also be used after rupture, at the bedside, to improve outcomes.
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