Preserved Collateral Blood Flow in the Endovascular M2CAO Model Allows for Clinically Relevant Profiling of Injury Progression in Acute Ischemic Stroke

Abstract

Interventional treatment regimens have increased the demand for accurate understanding of the progression of injury in acute ischemic stroke. However, conventional animal models severely inhibit collateral blood flow and mimic the malignant infarction profile not suitable for treatment. The aim of this study was to provide a clinically relevant profile of the emergence and course of ischemic injury in cases suitable for acute intervention, and was achieved by employing a M2 occlusion model (M2CAO) that more accurately simulates middle cerebral artery (MCA) occlusion in humans. Twenty-five Sprague-Dawley rats were subjected to Short (90 min), Intermediate (180 min) or Extended (600 min) transient M2CAO and examined longitudinally with interleaved diffusion-, T2- and arterial spin labeling perfusion-weighted magnetic resonance imaging before and after reperfusion. We identified a rapid emergence of cytotoxic edema within tissue regions undergoing infarction, progressing in several distinct phases in the form of subsequent moderation and then reversal at 230 min (p < 0.0001). We identified also the early emergence of vasogenic edema, which increased consistently before and after reperfusion (p < 0.0001). The perfusion of the penumbra correlated more strongly to the perfusion of adjacent tissue regions than did the perfusion of regions undergoing infarction (p = 0.0088). This was interpreted as an effect of preserved collateral blood flow during M2CAO. Accordingly, we observed only limited recruitment of penumbra regions to the infarction core. However, a gradual increase in infarction size was still occurring as late as 10 hours after M2CAO. Our results indicate that patients suffering MCA branch occlusion stand to benefit from interventional therapy for an extended time period after the emergence of ischemic injury.

Oxygen metabolism MRI – A comparison with perfusion imaging in a rat model of MCA branch occlusion and reperfusion

“…DWI was acquired through multi-slice three shot SE echo-planar-imaging (EPI) as described previously by Little et al. 13 The central slice of the slice package was placed on the slice with the largest lesion size on the DWI scout.…”

“…If both R2 and R2* are known, the effect of microscopic tissue decay, contained in R2, can be subtracted from R2* to produce R2′ according to equation 2. R2′ more exclusively measures the effect of the concentration of dHb in venous blood and is, considering that R2 has been removed, not as affected by manifest pathology such as vasogenic edema or inflammatory gliosis (70,71). Please see Figure 2 for characteristic examples of R2, R2* and R2′ in an animal subject to M2CAO.…”

“…In contrast to the conventional MCAO, the M2CAO model causes only a marginal CBF reduction in the PCA supply region, and does not reduce the perfusion of the ACA supply region to an extent causing ischemic injury, making it more similar to the majority of clinical strokes (carotid T-occlusion and malignant infarction being exceptions). The M2CAO model effectively simulates human AIS cases suitable for intervention, in that the initial volume of irreversible damage within brain regions subjected to M2CAO is limited and surrounded by large regions of potentially salvageable tissue-at-risk (70).…”

“…The viability of the ischemic penumbra is sustained by the dilation of collateral vessels and by the increased extraction of oxygen from blood to brain tissue. 7–9 With the recently published DAWN and DEFUSE 3 trials, 10,11 along with reports on a prolonged time-period for penumbra viability in clinical and experimental studies, 12–14 there are now suggestions that a tissue window may come to replace the time window as the overriding prejudice in the triage of AIS patients. 15 This requires metabolic imaging capable of providing highly specific read-outs of ischemic yet viable tissue, not only in the acute but probably even more importantly in the sub-acute phase of AIS.…”

“…21 In contrast to the MCAO model, which causes a severe decrease of collateral blood flow through the circle of Willis and leptomeningeal anastomoses, the M2CAO model preserves collateral blood flow from the anterior and posterior cerebral arteries to the territory of the MCA, thereby providing a more accurate simulation of the subtype of AIS that occurs in patients who suffer typical cardio embolic or larger cortical or subcortical human AIS, and who are suitable candidates for revascularization treatment. 13,20–22 The primary objective of this study was to assemble a non-invasive magnetic resonance imaging (MRI) protocol capable of determining oxygen extraction fraction (OEF), and subsequently to compare the volume of the IC-OEF elevation mismatch with that of the IC-CBF deficit mismatch in regions affected by M2CAO. The M2CAO model also enables controlled, non-invasive, in-MRI-bore restoration of blood flow (reperfusion) which permitted us to examine the acute effects of reperfusion on the oxygen metabolism of ischemic regions.…”