Introduction: The drivers of delayed ischemic neurological deficits and infarction (DINDI) subsequent to subarachnoid hemorrhage (SAH) are likely multifactorial encompassing cerebral vasospasm and neuronal dysfunction. We performed genome-wide analyses in inbred mice to assess genetic determinants of cerebral vasospasm and neurological outcome after SAH.
Methods: An intra-cisterna magna injection model of SAH was utilized. Just prior to sacrifice 24 hours after injection, a neurological exam was performed. At the time of sacrifice, mice were perfused with India Ink to determine cerebrovascular luminal diameter. Arterial diameters in SAH model mice were benchmarked against control diameters in respective strains. 132,285 single nucleotide polymorphisms (SNPs) were obtained from the Broad Institute HapMap project and efficient mixed models were constructed to analyze SNPs associated with the degree of vasospasm and neurological score while accounting for strain interrelatedness.
Results: 428 mice across 32 strains were included in this study, including 279 mice subjected to SAH. The degree of cerebral vasospasm (F = 2.04, P = 0.002) and neurological outcome (F = 9.05, P < 0.001) differed significantly across strains. Vasospasm was weakly correlated with neurological outcome (? = 0.17, P = 0.005). Genome-wide analysis identified 17 SNPs significantly associated with the degree of vasospasm, including SNPs within two protein coding genes. 29 SNPs were significantly associated with neurological outcome, encompassing seven protein coding genes. No SNPs were significantly associated with both outcomes. PDE10A was among the genes associated with neurological outcome and is a reported target of papaverine.
Conclusions: Cerebral vasospasm and neurological outcome following SAH in mice are associated with unique SNPs and protein coding genes. PDE10A was found to be associated with neurological outcome and not cerebral vasospasm, indicating papaverine may have a mechanism distinct from vascular tone.
Patient Care: This study aims to identify genetic markers associated with cerebral vasospasm and neurological score after SAH in mice. The ultimate goal is to identify proteins and pathways that enable a better understanding of the mechanisms contributing to these processes and potentially identifying novel opportunities for intervention.
Learning Objectives: 1. DINDI following SAH is multifactorial including both vasospasm and additional processes.
2. Genetic determinants of cerebral vasospasm and neurological outcome after SAH differ in mice.
3. The use of genome-wide analysis in inbred mice enables controlled experiments of cerebrovascular pathology in animals with identical environments and well characterized genomes.