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

<div><p>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.</p></div

Regions of interest (ROIs).

<p>(A) Apparent diffusion coefficient (ADC) maps and (B) T2 weighted images with examples of ADC lesion and T2 lesion ROIs (red). (C) Cerebral blood flow (CBF) maps. (D) CBF maps with ADC overlay. ROIs used to examine the CBF of the Ischemic Core (cyan) were drawn initially in ADC maps at 60 min after reperfusion and subsequently transferred to CBF maps. ROIs delineating the Penumbra (white), regions supplied by the anterior cerebral artery (purple), and regions supplied by the posterior cerebral artery (yellow) were drawn in CBF maps.</p

The recruitment of the penumbra to the ischemic core.

<p>(A) The progression of absolute growth of the ischemic lesion, defined by the decrease of the apparent diffusion coefficient (ADC), during M2 occlusion (M2CAO), presented as means and standard deviations (SD) for all 25 animals in the Short, Intermediate and Extended M2CAO groups. (B) The growth of the ADC lesion, presented as means and standard deviations of the percentage of the perfusion deficit volume at the initial examination in the Short (n = 4 animals), Intermediate (n = 7) and Extended M2CAO groups (n = 6).</p

Study design outline.

<p>Three groups of animals were subjected to different durations of Middle Cerebral Artery M2 segment occlusion (M2CAO); Short 90 min M2CAO, Intermediate 180 min M2CAO, or Extended 600 min M2CAO. Animals were examined longitudinally with Magnetic Resonance Imaging (MRI) during M2CAO and after in-bore recanalization of the occluded vessel (reperfusion).</p

The correlation between blood flow in the Penumbra and blood flow in the anterior cerebral artery supply region (ACAR) during M2 segment occlusion (M2CAO).

<p>(A-B) Perfusion-weighted images (PWI) from a single animal at the initial examination at 30 min (A) and at the examination performed at 90 min (B) since the start of M2 occlusion (M2CAO), shown here in two slices, 1 and 2. Dotted lines show the levels of the coronal images. (A) There is hypoperfusion of the Penumbra (solid lines), as well as of the supero-medial cortical regions of the ACAR. (B) A substantial increase of ACAR perfusion in the supero-medial cortex occurs in tandem with an increase in blood flow through the Penumbra. C; Apparent diffusion coefficient (ADC) maps of Slice 1 (C1-2) and Slice 2 (C3-4), with C1, C3 showing the initial examination at 30 min M2CAO and in C2, C4 the final infarction at 60 min after reperfusion subsequent to Extended M2CAO (600 min). A localized image artifact resulting from the microwire positioned in the M2 can be seen in A-C.</p

The emergence and progression of ischemic injury.

<p>Apparent diffusion coefficient (ADC) and T2 signal ratios between regions of interest and control regions (y-axes), measured at subsequent time points (x-axes) during M2 occlusion (A, C) and after reperfusion (B, D). Individual data points (diamonds), equation trend lines (solid lines), confidence intervals (dotted lines). Equations; A, y = 0.000328x – 0.0733log(x) + 0.93616, B, y = 0.0256log(x) +0.5967, C, y = 0.000180x + 0.02109 log(x) + 0.9317; D, y = 0.000470x + 1.14845.</p