Dear Sir:

Approximately 70% of cerebral blood is stored in veins [1]; therefore, cerebral blood volume (CBV) is a surrogate of venous capacity and expresses blood availability. CBV index is a derived parameter, obtained by dividing the average CBV in Tmax >6 s region by the average CBV in normal brain tissue [2]. Quantification of blood availability in the area at risk during acute ischemic stroke (AIS) may serve as an indicator of tissue fate, although its predictive power remains underexplored, especially in patients receiving endovascular treatment (EVT). Additionally, it could reflect the availability of potential cytoprotective treatments. In recent years, many agents have been tested alongside thrombectomy through blinded administration without considering territorial blood availability, yet most have not succeeded in phase III trials [3]. This study aimed (1) to evaluate the impact of CBV index on tissue fate despite successful recanalization, comparing it with hypoperfusion index ratio (HIR) and Alberta Stroke Program Early CT Score (ASPECTS), and (2) to explore whether the CBV index could serve as a proxy for tissue blood availability, potentially informing future evaluation of drug delivery strategies.

The study design involved a single-center, retrospective analysis of prospectively collected data from adult patients who underwent EVT for proximal anterior circulation (intracranial internal carotid artery and/or M1 or proximal M2 segments of middle cerebral artery) large vessel occlusions from January 2021 to June 2024. Inclusion criteria required successful recanalization (expanded Thrombolysis in Cerebral Infarction score ≥2b50), adequate pretreatment computed tomography perfusion (CTP), and follow-up magnetic resonance imaging (MRI) within 24-48 hours. Patients with intracranial hemorrhage at baseline were excluded from the study. This study was approved by the Institutional Review Board of University of California at Los Ageles (IRB#10-001280) and conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Demographic (age, sex), clinical (baseline modified Rankin Scale and National Institutes of Health Stroke Scale), therapeutic (intravenous thrombolysis administration), imaging (baseline ASPECTS, ischemic core, and penumbra volumes on CTP), and time interval data were collected for each patient. Additionally, CBV index and HIR were calculated based on perfusion parameters obtained from CTP acquisitions that were post-processed using RAPID software (iSchemaView, Menlo Park, CA, USA). The final ischemic lesion volume was manually segmented on the diffusion-weighted imaging sequences of MR that were previously registered to CTP slices. The outcomes of this study included ischemic lesion growth (ILG), measured as the difference between final infarct volume on MRI and baseline ischemic core volume on CTP, and considered significant if >1 mL, and the percentage of penumbra saved by the acute treatment. Spearman correlation was used to identify relationships between continuous variables, while stepwise backward regression and analysis of covariance models were applied to identify significant predictors of ILG and tissue salvage.

Ninety-nine patients met the inclusion criteria, and the main baseline characteristics of the population are summarized in Table 1 and Supplementary Figure 1. The major findings of our study indicate that, although CBV index, HIR, and ASPECTS all correlate with baseline ischemic core volume, only the CBV index was an independent predictor of infarct growth and the percentage of penumbra saved by EVT, even after successful recanalization (Supplementary Table 1). In fact, a higher CBV index before EVT was associated with a significantly reduced likelihood of penumbral tissue death (Figure 1), thereby limiting the growth of the baseline ischemic lesion (Figure 2). Specifically, patients with a CBV index of 0.7 or higher were less likely to experience infarct expansion, regardless of their baseline ASPECTS or HIR values. Conversely, a lower CBV index (<0.7) correlated with an increased likelihood of infarct growth, even in the presence of successful recanalization (Supplementary Figure 2).

These findings highlight the importance of venous capacity, which is often overshadowed by the focus on arterial occlusion in AIS management, and suggest that CBV index may serve as an indicator of potential tissue salvage during acute ischemia, with higher values correlating with better evolutions. Previous studies have primarily focused on functional outcomes, demonstrating that higher CBV values are associated with better prognosis in AIS [4,5]; however, they have poorly explored the impact of CBV on tissue fate, particularly in patients undergoing EVT. The lack of a significant association between ASPECTS and infarct growth, despite ASPECTS being widely used to guide treatment decisions, suggests that this score alone may not fully capture the complexities of cerebral perfusion. In contrast, our results emphasize the role of perfusion parameters over non-contrast computed tomography in predicting AIS tissue fate. When arterial inflow is successfully restored, regional venous availability appears to drive infarction evolution, regardless of baseline ASPECTS. This finding supports the beneficial effect of EVT observed in recent large-core trials [6]. Notably, CBV index outperformed HIR in predicting ILG before EVT, reinforcing the idea that these two parameters reflect distinct aspects of collateral flow dynamics, with venous capacity playing a dominant role in tissue perfusion in AIS via collaterals, as suggested by a post-hoc analysis of the Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) trial [7]. The implications of these findings should be further explored in future trials. Incorporating the CBV index into treatment planning and decision-making may help clinicians better identify patients most likely to benefit from EVT, even when traditional metrics such as ASPECTS suggest a poor prognosis. Additionally, conceivably quantifying blood availability, the CBV index could help refine strategies for delivering cytoprotective drugs to hypoperfused area, potentially improving patient selection or optimizing drug dosing based on perfusion parameters. However, this study has several limitations. The retrospective design and small sample size may limit the generalizability of our findings. Furthermore, the lack of advanced perfusion imaging availability in some clinical settings poses a challenge to the widespread adoption of these parameters. Larger, multicenter studies are needed to validate our results and assess the clinical utility of CBV index in guiding AIS management.

In conclusion, our study demonstrates that the CBV index, a measure of venous capacity, is a robust predictor of tissue fate in AIS patients undergoing EVT. It provides valuable information about blood availability in hypoperfused territories and may inform future cytoprotective trials by serving as a standardized measure for drug delivery. As neuroimaging technology advances, integrating venous capacity into clinical practice may significantly enhance AIS management, ultimately leading to better patient outcomes.