Long-term survival in permanent middle cerebral artery occlusion: a model of malignant stroke in rats.
ABSTRACT: Occlusion of the middle cerebral artery (MCA) by an intraluminal filament is widely used to study focal brain ischemia in male Sprague-Dawley rats. However, permanent occlusion goes along with a high fatality. To overcome this drawback we designed a new filament carrying a bowling pin-shaped tip (BP-tip) and compared this with three conventionally tipped filaments. Follow-up periods were 24?h (all groups) and 72 and 120?h in BP-tip group. Ischemic damage and swelling were quantified using silver nitrate staining. Collateral flow via the posterior cerebral artery (PCA) was assessed using selective dye perfusion of the internal carotid artery. Despite a comparable decrease of brain perfusion in all groups, ischemic damage was significantly smaller in BP-tips (p?
Project description:Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n?=?118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30?min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57?mm<sup>3</sup> absolute mean difference; p?<?0.001) and higher chance of good functional outcome (OR 4.58, p?<?0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p?<?0.001) and lateral (+19.2%; p?=?0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.
Project description:Acute tandem cervical dissecting internal carotid artery (ICA) occlusion and intracranial embolic middle cerebral artery (MCA) occlusion can be devastating, and the optimal treatment strategy for this condition has not been established yet.A 45-year-old male presented with aphasia and right hemiparesis preceded by neck pain. Computed tomography showed a high-density signal along the left MCA, suggesting extensive emboli. Magnetic resonance angiography demonstrated tandem occlusion of the left cervical ICA and intracranial MCA with minimal diffusion-weighted imaging lesion. Emergent surgical embolectomy was performed, and long intracranial MCA emboli were retrieved with collateral cross-flow restoration. The cervical ICA was exposed, and dissection was confirmed. The cervical ICA was ligated, and superficial temporal artery (STA)-MCA anastomosis was added. Postoperatively, the patient demonstrated recovery from right hemiparesis and aphasia. At the 6(th) postoperative month, follow-up studies demonstrated a robustly patent STA-MCA bypass and no additional ischemic lesion on T2-weighted imaging.Surgical embolectomy in conjunction with ligation of the cervical ICA followed by STA-MCA bypass might be a safe alternative method to endovascular recanalization, when the cervical dissection is extensive and when huge secondary emboli are present along the MCA.
Project description:Despite progress in reducing ischemic stroke damage, complete protection remains elusive. Here we demonstrate that, after permanent occlusion of a major cortical artery (middle cerebral artery; MCA), single whisker stimulation can induce complete protection of the adult rat cortex, but only if administered within a critical time window. Animals that receive early treatment are histologically and behaviorally equivalent to healthy controls and have normal neuronal function. Protection of the cortex clearly requires reperfusion to the ischemic area despite permanent occlusion. Using blood flow imaging and other techniques we found evidence of reversed blood flow into MCA branches from an alternate arterial source via collateral vessels (inter-arterial connections), a potential mechanism for reperfusion. These findings suggest that the cortex is capable of extensive blood flow reorganization and more importantly that mild sensory stimulation can provide complete protection from impending stroke given early intervention. Such non-invasive, non-pharmacological intervention has clear translational potential.
Project description:Vitamin E consists of tocopherols and tocotrienols, in which ?-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3±3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke.
Project description:PURPOSE:In acute middle cerebral artery (MCA) occlusion, collateral vessels provide retrograde supply to the occluded territory. We hypothesized that such collateral flow reduces perfusion of the non-occluded donor region (steal effect). MATERIALS AND METHODS:Patients with an MCA occlusion with opacification of both ipsi- and contralateral anterior cerebral arteries (ACA) on angiography prior to endovascular treatment were selected. Arteriovenous transit time (AVTT) for both ACA territories was compared for different grades of collateral supply to the MCA territory. In addition, the influence of diabetes and hypertension was analyzed. After successful revascularization, AVTT was re-assessed to determine reversibility. RESULTS:Forty-one patients were analyzed. An AVTT of 8.6 seconds (standard deviation [SD] 2.4 seconds) was seen in the ACA territory of the affected hemisphere in comparison to 6.6 seconds (SD 2.1 seconds) for the contralateral side (P<0.001). A more prolonged (but not significant) AVTT was seen in cases with a higher collateral grade. No difference in AVTT was seen in patients with diabetes or hypertension. After successful MCA revascularization, AVTT delay was 7.4 seconds (SD 2.1 seconds). CONCLUSION:A cerebral steal effect occurs in patients with an acute MCA occlusion, probably related to augmented flow to the penumbra area.
Project description:Severity of stroke varies widely among individuals. Whether differences in the extent of the native (preexisting) pial collateral circulation exist and contribute to this variability is unknown. We addressed these questions and probed for potential genetic contributions using morphometric analysis of the collateral circulation in 15 inbred mouse strains recently shown to exhibit wide differences in infarct volume. Morphometrics were determined in the unligated left hemisphere (for native collaterals) and ligated right hemisphere (for remodeled collaterals) 6 days after permanent middle cerebral artery (MCA) occlusion. Variation among strains in native collateral number, diameter, MCA, anterior cerebral artery (ACA), and posterior cerebral artery (PCA) tree territories were, respectively: 56-fold, 3-fold, 42%, 56%, and 61%. Collateral length (P<0.001) and the number of penetrating arterioles branching from them also varied (P<0.05). Infarct volume correlated inversely with collateral number (P<0.0001), diameter (P<0.0001), and penetrating arteriole number (P<0.05) and directly with MCA territory (P<0.05). Relative collateral conductance and MCA territory, when factored together, strongly predicted infarct volume (P<0.0001). Outward remodeling of collaterals in the ligated hemisphere varied approximately 3-fold. These data show that the extent of the native pial collateral circulation and collateral remodeling after obstruction vary widely with genetic background, and suggest that this variability, due to natural polymorphisms, is a major contributor to variability in infarct volume.
Project description: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.
Project description:Anterior circulation large artery occlusion (AC-LAO) related acute ischemic stroke (AIS) is particularly common in clinics in China. We retrospectively analyzed 787 consecutively hospitalized AIS patients with AC-LAO in Hebei Province, China. AC-LAO was defined as a complete occlusion of at least one intracranial internal carotid artery (ICA) or middle cerebral artery (MCA) based on computed tomography or magnetic resonance angiography. Among eight subtypes of AC-LAO, unilateral MCA occlusion is the most common one (49.8%, n?=?392), while bilateral ICA/unilateral MCA occlusion is the least (0.3%, n?=?2). Compared with unilateral MCA and unilateral ICA occlusion, patients with tandem ICA/MCA and bilateral ICA/MCA occlusion had poor outcomes after suffering AIS. Age (OR 1.022; 95%CI, 1.007 to 1.036) was an independent risk factor for single artery progressed to multiple artery occlusion, while ApoA1 (OR 0.453; 95% CI, 0.235 to 0.953) was a protective factor. Patients with unilateral MCA occlusion were prone to artery-to-artery embolism infarction subtype, unilateral ICA occlusion group were the most vulnerable to hypoperfusion/impaired emboli clearance subtype. Our results suggested various AC-LAO subtypes have different clinical characteristics and prognosis and were prone to different subtypes of infarction. Customized preventive measures based on AC-LAO subtypes may be more targeted preventions of stroke recurrences for AIS patients and could improve their prognoses.
Project description:The cerebral circulation is unique in its ability to maintain blood flow to the brain under widely varying physiologic conditions. Incorporating this autoregulatory response is necessary for cerebral blood flow (CBF) modeling, as well as investigations into pathological conditions. We discuss a one-dimensional (1D) nonlinear model of blood flow in the cerebral arteries coupled to autoregulatory lumped-parameter (LP) networks. The LP networks incorporate intracranial pressure (ICP), cerebrospinal fluid (CSF), and cortical collateral blood flow models. The overall model is used to evaluate changes in CBF due to occlusions in the middle cerebral artery (MCA) and common carotid artery (CCA). Velocity waveforms at the CCA and internal carotid artery (ICA) were examined prior and post MCA occlusion. Evident waveform changes due to the occlusion were observed, providing insight into cerebral vasospasm monitoring by morphological changes of the velocity or pressure waveforms. The role of modeling of collateral blood flows through cortical pathways and communicating arteries was also studied. When the MCA was occluded, the cortical collateral flow had an important compensatory role, whereas the communicating arteries in the circle of Willis (CoW) became more important when the CCA was occluded. To validate the model, simulations were conducted to reproduce a clinical test to assess dynamic autoregulatory function, and results demonstrated agreement with published measurements.
Project description:Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model. In the present study, we modified the homologous clots formation by addition of thrombin and fibrinogen which produced even distribution of fibrin with tight cross linkage of red blood cells. We optimized the embolic MCA occlusion model in rats using different size of the mixed clots. A precise lodgment of the clots at the MCA bifurcation and highly reproducible ischemic lesion in the MCA territory were demonstrated in the embolic MCA occlusion model induced by injection of 10 pieces of 1-mm long mixed clots made in PE-60 catheter. We further tested the effect of recombinant tissue plasminogen activator (rtPA) in this embolic MCA occlusion model. rtPA induced thrombolysis, improved neurological outcome, and significantly reduced ischemic lesion volume when administered at 1h after embolism as compared with control. In summary, we have established a reproducible embolic MCA occlusion model using clots made of homologous blood, thrombin and fibrinogen. The mixed clots enable precise lodgment at the MCA bifurcation which is responsive to thrombolytic therapy of rtPA.