Abstract Body: Introduction
The rapid recanalization of occluded vessels and the restoration of cerebral blood flow (CBF) are critical for the outcome of stroke. Patients may exhibit poor reperfusion (no-flow) or hyperperfusion (hyperemia) after recanalization, and factors influencing these conditions are not fully understood. The Stroke Preclinical Assessment Network (SPAN) conducted a randomized, controlled, blinded, and highly heterogeneous multi-laboratory trial to identify effective interventions in the stroke animal model. Here, we examined the factors influencing the CBF recovery after filament removal and the effect of reperfusion CBF on stroke outcome in SPAN.
Methods
Both sexes of C57BL6 healthy young were subjected to 30 or 60-minutes transient endovascular filament middle cerebral artery occlusion (MCAO). For homogeneity of all other factors, we used subjects enrolled at Mass General Hospital only. We measured CBF at 5 (n=128) and 10 minutes (n=88) after filament removal by laser Doppler flowmetry. We first tested whether sex, surgeons, MCAO duration, circadian time (ZT) at MCAO, age, weight, surgical duration, and SPAN treatments (control, fasudil, fingolimod, tocilizumab, uric acid, veliparib) predicted the reperfusion CBF. We then assessed the influence of CBF on tissue (day-2 MRI lesion volume) and behavioral outcomes (acute neurological deficits score and day-7 and 28 corner test) and 30-day mortality. A generalized linear model with backward elimination and a mixed model were used for bivariate and multivariable analyses.
Results
CBF gradually increased after filament removal between 5 and 10 minutes (p=0.03). In bivariate analyses, CBF was significantly lower in animal that had MCAO in their active circadian phase (ZT12-24) (p=0.04). In multivariable analysis, reperfusion CBF was predicted to be higher in females, after 60 min MCAO, in inactive phase (ZT0-12), and short anesthesia duration. CBF also differed among the three surgeons. Only tocilizumab had lower CBF compared to the control group. Reperfusion CBF did not predict tissue and behavioral outcomes. However, higher CBF was related to lower day-1 weight loss (p<0.01) and lower mortality for 30 days (p<0.01).
Conclusion
In conclusion, we show that sex, ischemia duration, circadian stage at MCAO, and total anesthesia duration predict the reperfusion CBF after mouse endovascular filament MCAO. We also show that reperfusion CBF can predict mortality, independent of tissue and behavioral outcomes.