- Massachusetts General Hospital researchers conducted the first systematic investigation of how murine strain differences and sex affect outcomes of intracranial aneurysm formation and rupture in an elastase model
- Rupture rates, neurological deficits and survival were worse in the 129S2/SvPasCrl and 129S1/SvImJ strains, intermediate in the C57BL/6NCrl strain and mild in the Crl:CD1(ICR) strain, just as genetic background affects these outcomes in patients
- Females did significantly worse than males within the C57BL/6NCrl strain, just as women have a higher incidence of rupture than men
- Thus, the elastase model is a good approximation of clinical subarachnoid hemorrhage, well suited to test interventions against intracranial aneurysm formation, growth and spontaneous rupture
Most cases of subarachnoid hemorrhage (SAH)—about 85%—are caused by rupture of an intracranial aneurysm. Two factors that influence the risk of rupture are sex (the incidence is somewhat higher in women than men) and genetic background.
SAH pathophysiology and potential treatments are studied in various mouse models, including one in which intracranial aneurysm is induced by injecting elastase into cerebrospinal fluid. Massachusetts General Hospital researchers have now found that sex and genetic differences influence the effects of intracranial aneurysm in the elastase model, providing assurance that it closely approximates human aneurysmal SAH.
Cenk Ayata, MD, PhD, radiologist in the Neurovascular Research Laboratory in the Department of Radiology at Mass General; Aman B. Patel, MD, director of Cerebrovascular and Endovascular Neurosurgery at Mass General's Department of Neurosurgery; Takeshi Yanagisawa, MD, a research fellow in the Department of Radiology, and colleagues published their findings in Stroke.
The researchers injected elastase or vehicle into four groups of mice representing three strains commonly used in cerebrovascular research (total=231 animals):
- Male Crl:CD1(ICR)—abbreviated CD1
- Male C57BL/6NCrl—abbreviated C57
- Female C57
- Male 129S2/SvPasCrl or 129S1/SvImJ—abbreviated 129Sv
Overall Case Fatality Rate
The overall case fatality rate in elastase-injected mice was 47%. Interestingly, clinical case fatality rates in aneurysmal SAH are 30%–44%. (Unlike in humans there was no attempt in this study to reduce mortality after the onset of neurological deficits.)
Moreover, clinical case fatality rates often do not account for the 12%–15% of patients who die before reaching the hospital. The comparable figure in this study was 13%—mortality from a rupture within 24 hours after last seen well.
Differences by Strain and Sex
There were striking differences in outcomes among groups:
- 129SV mice had the highest rates of aneurysm (80%), neurological deficits (>90%) and case fatality (64%)
- CD1 mice had the lowest rate of aneurysm (21%), neurological deficits (~40%) and case fatality (13%)
- C57 mice had intermediate rates of aneurysm (36% females, 27% males) and unruptured aneurysm (7% females, 23% males). Similar rates were observed for neurological deficits and case fatality.
The differences among groups in survival, deficit-free survival and neurological deficit scores were statistically significant, as were the differences between female and male C57 mice.
An Appropriate Model of Clinical SAH
The researchers also observed anatomic differences in the circle of Willis in 129Sv mice that seemed to contribute to their poorer outcomes. Taken together, the data suggest that the elastase model is a good approximation of clinical SAH and is well suited to test interventions against intracranial aneurysm formation, growth and spontaneous rupture.
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