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A Neuroprotective Locus Modulates Ischemic Stroke Infarction Independent of Collateral Vessel Anatomy.

ABSTRACT: Although studies with inbred strains of mice have shown that infarct size is largely determined by the extent of collateral vessel connections between arteries in the brain that enable reperfusion of the ischemic territory, we have identified strain pairs that do not vary in this vascular phenotype, but which nonetheless exhibit large differences in infarct size. In this study we performed quantitative trait locus (QTL) mapping in mice from an intercross between two such strains, WSB/EiJ (WSB) and C57BL/6J (B6). This QTL mapping revealed only one neuroprotective locus on Chromosome 8 (Chr 8) that co-localizes with a neuroprotective locus we mapped previously from F2 progeny between C3H/HeJ (C3H) and B6. The allele-specific phenotypic effect on infarct volume at the genetic region identified by these two independent mappings was in the opposite direction of the parental strain phenotype; namely, the B6 allele conferred increased susceptibility to ischemic infarction. Through two reciprocal congenic mouse lines with either the C3H or B6 background at the Chr 8 locus, we verified the neuroprotective effects of this genetic region that modulates infarct volume without any effect on the collateral vasculature. Additionally, we surveyed non-synonymous coding SNPs and performed RNA-sequencing analysis to identify potential candidate genes within the genetic interval. Through these approaches, we suggest new genes for future mechanistic studies of infarction following ischemic stroke, which may represent novel gene/protein targets for therapeutic development.

SUBMITTER: Lee HK

PROVIDER: S-EPMC8366065 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeCollateral blood supply is a key determinant of outcome in large-vessel occlusion acute ischemic stroke. Single- and multiphase CTA collateral scoring systems have been described but are subjective and require training. We aimed to test whether the CTP-derived hypoperfusion intensity ratio is associated with CTA collateral status and whether a threshold hypoperfusion intensity ratio exists that predicts poor CTA collaterals.Materials and methodsImaging and clinical data of consecutive patients with large-vessel occlusion acute ischemic stroke were retrospectively reviewed. Single-phase CTA and multiphase CTA scoring were performed by 2 blinded neuroradiologists using the Tan, Maas, and Calgary/Menon methods. CTP was processed using RApid processing of PerfusIon and Diffusion software (RAPID). Hypoperfusion intensity ratio = ratio of brain volume with time-to-maximum >10 seconds over time-to-maximum >6-second volume. Correlation between the hypoperfusion intensity ratio and CTA collateral scores was calculated using the Pearson correlation. The optimal threshold of the hypoperfusion intensity ratio for predicting poor collaterals was determined using receiver operating characteristic curve analysis.ResultsFifty-two patients with large-vessel occlusion acute ischemic stroke were included. Multiphase CTA collateral scoring showed better interrater agreement (κ = 0.813) than single-phase CTA (Tan, κ = 0.587; Maas, κ = 0.273). The hypoperfusion intensity ratio correlated with CTA collateral scores (multiphase CTA: r = -0.55; 95% CI, -0.67 to -0.40; P ≤ .001). The optimal threshold for predicting poor multiphase CTA collateral status was a hypoperfusion intensity ratio of >0.45 (sensitivity = 78%; specificity = 76%; area under the curve = 0.86). Patients with high hypoperfusion intensity ratio/poor collateral status had lower ASPECTS/larger infarcts, higher NIHSS scores, and larger hypoperfused volumes.ConclusionsThe hypoperfusion intensity ratio is associated with CTA collateral status in patients with large-vessel occlusion acute ischemic stroke. The hypoperfusion intensity ratio is an automated and quantitative alternative to CTA collateral scoring methods for both clinical and future stroke trial settings.

Project description:BackgroundMixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial.MethodsIn this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05.ResultsAmong the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0).ConclusionsIn a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke.Trial registrationClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011.

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A Neuroprotective Locus Modulates Ischemic Stroke Infarction Independent of Collateral Vessel Anatomy.

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