Cerebral Collateral Research Articles

Moderate to Severe Anemia Is Associated with Poor Functional Outcome in Acute Stroke Patients Treated with Mechanical Thrombectomy

Background: Anemia will negatively affect cerebral collaterals and penumbra. Eventually, it may cause worse clinical outcomes and even increase mortality rates in stroke patients. Anemia has recently been suggested to be an independent risk factor for ischemic stroke. Therefore, we aimed to investigate the effects of the presence of anemia on clinical outcomes in ischemic stroke patients undergoing mechanical thrombectomy. Methods: This was a retrospective study involving the prospectively and consecutively collected data of 90 adult patients between January 2015 and August 2016. Hemoglobin (Hb) cutoff levels were accepted as 12 g/dL for women and 13 g/dL for men. Patients having anemia were further divided into three subgroups as severe anemia (Hb <8 g/dL for both genders), moderate anemia (Hb <10 g/dL for both genders), and mild anemia (Hb <13 g/dL for men and Hb <12 g/dL for women). Results: Forty of the subjects (44.4%) had anemia. Moderate anemia was detected in 14 out of 90 patients (15.5%) and severe anemia was found in only four of them (4.4%). Poor functional outcome (mRS 3-6) was similar in both anemic and non-anemic patients (37.5% vs. 38%, respectively, p = 0.08), but poor functional outcome was found to be statistically significant with severe anemic group (Hb <8 mg/dL) (p = 0.003). In multiple logistic regression analysis, moderate and severe anemia has been found to increase the mortality (p = 0.032). Conclusions: Our study demonstrated a poor functional outcome only in moderate to severe anemic patients. Clinicians should keep in mind the negative effect of moderate to severe anemia in the clinical course of acute stroke patients treated with mechanical thrombectomy.

Long-term hemodynamic changes and blood pressure in atherosclerotic major cerebral artery disease

In patients with major cerebral artery disease, lower blood pressure might reduce blood flow in the collateral pathways, thereby impairing the growth of cerebral collaterals, inhibiting hemodynamic improvement. We evaluated the hemodynamic status twice using positron emission tomography and 15O-gas, over time, in 89 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery disease that had no ischemic episodes during follow-up (mean, 28 ± 23 months). Changes in the mean hemispheric values of hemodynamic parameters in the territory of the diseased artery at follow-up were correlated with the mean blood pressure values at the baseline and follow-up examinations. There was a positive linear relationship between the degree of hemodynamic improvement and systolic blood pressure. Patients with low systolic blood pressure (<130 mmHg) (n = 18) showed hemodynamic deterioration as indicated by significant decreases in cerebral blood flow, cerebral blood flow/cerebral blood volume ratio, and increases in oxygen extraction fraction during follow-up. In contrast, there were no significant changes in patients without low systolic blood pressure. In patients with atherosclerotic internal carotid artery or middle cerebral artery disease and no ischemic episodes of stroke during follow-up, lower systolic blood pressure was associated with lesser hemodynamic improvement.

Effect of collateral circulation on prognoses of patients with acute cerebral ischemia after thrombolysis

Objective The goal of this study is to compare the prognosis of recombinant tissue plasminogen activator (rt-PA) thrombolysis for middle cerebral artery (MCA) occlusion with patients with good and poor cerebral collateral circulation. Methods This retrospective study included 49 patients diagnosed with acute MCA occlusion and treated with rt-PA in the First Affiliated Hospital of Nanjing Medical University between October 1, 2014 and February 1, 2016. Patients were divided into good collaterals group (n=31) and poor collaterals group (n=18) according to their distribution of leptomeningeal arteries with CTA. Thirty day mortality rate, the incidence of symptomatic intracranial hemorrhage, 24h and 30 day Stroke scores with National Institute of Health Stroke Scale (NIHSS) were compared between the two groups. Corrected chi-squared test, Fisher’s exact test, or t test was used to statistical analysis as appropriate. Results The 30 day mortality rate of good collaterals group was significantly lower than that of poor collaterals group (0% vs. 16.7%, P 0.05), however, 30 day NIHSS score of good collaterals group was significantly lower than that of poor collaterals group (7.2±3.1 vs. 9.6±2.7, P<0.05). Conclusion For patients with MCA occlusion and receiving intravenous thrombolysis, good cerebral collateral circulation may reduce their mortality and improve their clinical outcome after thrombolysis. However, good cerebral collateral circulation does not reduce the risk of symptomatic intracranial hemorrhage in those patients. Key words: Retrospective studies; Middle cerebral artery occlusion; Recombinant tissue plasminogen activator; Collateral circulation; Computed tomography angiography; National Institute of Health Stroke Scale; Symptomatic cerebral hemorrhage; Mortality

Abstract 76: Long-term Regular Remote Ischemic Conditioning Promotes Arterial Collateral Opening and Reconstruction in Patients with Intracranial Atherosclerotic Stenosis

Background and purpose: A previous study (NCT01570231) showed that long-term remote ischemic preconditioning (RIPC) prevents cerebral ischemic events in patients with symptomatic intracranial atherosclerotic stenosis (SIAS). This study aims to further evaluate its beneficial impact on cerebral collateral flow and its underlying mechanisms. Methods: Patients with SIAS were randomized to RIPC group (n=30) or sham group (n=28, NCT01570231). RIPC was achieved by blocked bilateral arm arterial blood flow 5-min with double cuffs inflated to 200mmHg, followed by deflation for 5-min, and this was repeated 5 times automatically in every training cycle by the RIPC training device. Sham-RIPC was done in the same fashion with the exception of Inflating pressure at 60mmHg, which make the subjects feel a pressure but does not block the blood flow. RIPC and sham-RIPC were performed twice a day for 180 consecutive days. All subjects received standard background medical treatment. Status of cerebral collateral flow was evaluated with the regional leptomeningeal collateral (rLMC) score either by MRA and/or CTA. Plasma levels of VEGF were measured by ELISA, and circulating endothelial progenitor cells (EPCs) marked of CD45-CD133+CD34+VEGF-R2+ were quantified by flow cytometry from the mononuclear cells, which were isolated from venous blood samples at Day 0, Day 30 and 180. Results: 23(76.7%) patients in RIPC and 19(67.9%) in sham group completed MRA evaluation, and 7(23.5%) in RIPC and 9(32.1%) sham group finished CTA evaluation. The average rLMC score were 0.233±0.37, 1.133±0.24, and 2.066±0.31 in RIPC versus 0.214±0.35, 0.535±0.49 and 0.964±0.34 in sham group at Day0, 30 and 180(p 0 &gt;0.05, p 30 &lt;0.01, and p 180 &lt;0.01). Plasma VEGF levels were 33.03±7.41, 136.88±60.79, and 285.37±77.75 in RIPC group versus 34.31±8.41, 66.85±16.89, and 93.86±18.97 in sham group (p 0 &gt;0.05, p 30 &lt;0.01, and p 180 &lt;0.001). The ratios of EPCs were 0.018±0.012%, 0.086±0,015%, and 0.115±0.013% in RIPC group versus 0.019±0,011%, 0.045±0,012%, and 0.067±0,012% in sham group. Conclusions: Long-term regular RIPC appears to accelerate cerebral collateral open and vascular remodeling. It is associated with the elevated level of plasma VEGF and an increased ratio of circulating EPCs.

Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies

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 mm3 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.

Physiological Ischemic Training Promotes Brain Collateral Formation and Improves Functions in Patients with Acute Cerebral Infarction.

To observe the effectiveness and mechanisms of physiological ischemic training (PIT) on brain cerebral collateral formation and functional recovery in patients with acute cerebral infarction. 20 eligible patients with acute cerebral infarction were randomly assigned to either PIT group (n = 10) or Control group (n = 10). Both groups received 4 weeks of routine rehabilitation therapy, while an additional session of PIT, which consisted of 10 times of maximal voluntary isometric handgrip for 1 min followed by 1 min rest, was prescribed for patients in the PIT groups. Each patient was trained with four sections a day and 5 days a week for 4 weeks. The Fugl-Meyer Assessment (FMA), the Modified Barthel Index (MBI), and the short-form 36-item health survey questionnaire (SF-36) were applied for the evaluation of motor impairment, activity of daily living, and quality of life at the baseline and endpoint. MRI was applied to detect the collateral formation in the brain. The concentration of vascular endothelial growth factor (VEGF) and endothelial progenitor cells (EPCs) number in plasma were also tested at the endpoint. Demographic data were consistent between experimental groups. At the endpoint, the scores of the FMA, MBI, and SF-36 were significantly higher than that at baseline. As compared to the Control group, the score of FMA and SF-36 in PIT group was significantly higher, while no significant difference was detected between groups in terms of MBI. Both groups had significantly higher cerebral blood flow (CBF) level at endpoint as compared to that at baseline. Moreover, the CBF level was even higher in the PIT group as compared to that in the Control group after 4 weeks of training. The same situations were also found in the plasma VEGF and EPCs assessment. In addition, positive correlations were found between FMA score and CBF level (r = 0.686, p < 0.01), CBF level and VEGF concentration (r = 0.675, p < 0.01), and VEGF concentration and EPC number (r = 0.722, p < 0.01). PIT may be effective in increasing the expression of VEGF and recruitment of EPCs and in turn promote the formation of brain collateral circulation. The positive correlations may demonstrate a potential association between biological and functional parameters, and PIT may be able to improve the motor function, activity of daily living, and quality of life in patients with stroke.

Impaired Collateral Flow Compensation During Chronic Cerebral Hypoperfusion in the Type 2 Diabetic Mice.

The presence of collaterals is associated with a reduced risk of stroke and transient ischemic attack in patients with steno-occlusive carotid artery disease. Although metabolic syndrome negatively impacts collateral status, it is unclear whether and to what extent type 2 diabetes mellitus affects cerebral collateral flow regulation during hypoperfusion. We examined the spatial and temporal changes of the leptomeningeal collateral flow and the flow dynamics of the penetrating arterioles in the distal middle cerebral artery and anterior cerebral artery branches over 2 weeks after unilateral common carotid artery occlusion (CCAO) using optical coherent tomography in db/+ and db/db mice. We also assessed the temporal adaptation of the circle of Willis after CCAO by measuring circle of Willis vessel diameters. After unilateral CCAO, db/db mice exhibited diminished leptomeningeal collateral flow compensation compared with db/+ mice, which coincided with a reduced dilation of distal anterior cerebral artery branches, leading to reduced flow not only in pial vessels but also in penetrating arterioles bordering the distal middle cerebral artery and anterior cerebral artery. However, no apparent cell death was detected in either strain of mice during the first week after CCAO. db/db mice also experienced a more severe early reduction in the vessel diameters of several ipsilateral main feeding arteries in the circle of Willis, in addition to a delayed post-CCAO adaptive response by 1 to 2 weeks, compared with db/+ mice. Type 2 diabetes mellitus is an additional risk factor for hemodynamic compromise during cerebral hypoperfusion, which may increase the severity and the risk of stroke or transient ischemic attack.

Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI

High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.

Multi-mode CT in the evaluation of leptomeningeal collateral flow and the related factors: comparing with digital subtraction angiography

Objectives: Less ischemic volume and better functional outcome are related with good cerebral collaterals in ischemic stroke. But the method of assessing collateral circulation is still undetermined.Methods: Collateral status was assessed using a computed tomography angiography (CTA) source image (CTA-SI) based and digital subtraction angiography (DSA) based assessment system. CTP maps were quantitatively analyzed. CBF, CBV, MTT, and TTP were calculated within the hypoperfusion and in the equivalent region of unaffected hemisphere. ASTIN-ASN system based on DSA and leptomeningeal collaterals (LMC) system based on CTA were adopted separately, and the intra-rater and inter-rater were determined by Kappa testing. Receiver Operating Characteristic (ROC) curves were used to analyze the relationship between CTP quantitative parameters and DSA. The related factors of collateral flow were also explored in this study.Results: Of 52 patients, 12(23.1%) were women, and the average age was 59.4y. The κ-coefficients were 0.794 and 0.890 in the CTA and DSA collateral grade systems, respectively. The κ-coefficients were 0.679 comparing with the CTA and DSA collateral grade systems. By means of ROC curves, a relative MTT (rMTT) was obtained as relative variables of collaterals. The cut-off value is 1.37 emerged as the only predictor of good collaterals. The multi-mode CT collaterals scores showed excellent consistency comparing with DSA (κ-coefficients 0.770). Based on univariate and multivariate analysis, the rate of stenosis is the only predictor in the development of collateral circulation.Discussion: Our data showed that multi-mode CT score has a high value in predicting leptomeningeal collateral flow in ischemic stroke.

Circle of Willis Collateral During Temporary Internal Carotid Artery Occlusion II: Observations From Computed Tomography Angiography.

The Circle of Willis (CoW) is the most effective collateral circulation to the brain during internal carotid artery (ICA) occlusion. Carotid stump pressure (CSP) is an established surrogate measure of the cerebral collateral circulation. This study aims to use hemodynamic and computed tomography angiography measurements to determine the strongest influences upon the dependent variable, CSP. These findings could help clinicians noninvasively assess the adequacy of the collateral circulation and facilitate surgical risk assessment in an outpatient setting. CSP and mean arterial pressure were measured during carotid endarterectomy or during carotid balloon test occlusion in 92 patients. Intracranial arterial diameters were measured on computed tomography angiography at 16 different locations. Univariate and multivariate analyses were used to determine the key factors associated with CSP. In a subgroup of individuals (n=27) with severe (>70% North American Symptomatic Carotid Endarterectomy Trial) contralateral stenosis or occlusion, the same analysis was performed. The contralateral anterior cerebral artery proximal to anterior communicating artery (A1) of the CoW had the strongest influence upon CSP, followed by the mean arterial pressure, the contralateral ICA diameter, and the anterior communicating artery diameter (R 2=0.364). In the subgroup with high-grade contralateral ICA stenosis, the ipsilateral posterior communicating artery exerted the strongest influence (R 2=0.620). During ICA occlusion, the anterior CoW dominates in preserving collateral flow, especially the contralateral A1 segment. In individuals with high-grade contralateral carotid stenosis, the posterior communicating artery calibre becomes a dominant influence. The most favourable anatomy consists of large contralateral A1 and anterior communicating arteries, and no contralateral carotid stenosis.

Lack of improvement following endovascular therapy in patients with acute ischemic stroke

Background: Recent randomized trials have consistently demonstrated a clinical benefit of endovascular therapy (ET) over best medical therapy (including intravenous (IV) thrombolysis in eligible patients) or IV thrombolysis only in selected patients with acute ischemic stroke (AIS) due to proximal occlusion in the carotid territory. Previous study demonstrates that lack of improvement (LOI) at 24 hours is an independent predictor of poor outcome and death at 3 months in patients with AIS treated with IV alteplase. However, LOI at 24 hours following ET has not been studied systematically. The purpose of this study is to identify predictors of LOI at 24 hours in patients with AIS after ET as well as the relationship between LOI and unfavorable outcome at 3 months. Methods: A total of 98 consecutive patients with AIS treated with ET in two separate stroke centers from 2010 to 2014 were retrospectively reviewed. Data on demographics, preexisting vascular risk factors, occlusion site, pre- and post-treatment modified Treatment in Cerebral Ischemia (mTICI) classification, collaterals and National Institutes of Health Stroke Scale (NIHSS) score on admission as well as 24 hours after the endovascular procedurals were collected. LOI was defined as a reduction of 3 points or less on the NIHSS at 24 hours compared with baseline. A 3-month functional outcome was assessed using the modified Rankin scale (mRS). Unfavorable outcome was prespecified as a score of more than 2 on the mRS. The onset-to-reperfusion time (ORT) was defined as time to mTICI 2b or 3 or end of procedure. Long ORT was defined as time to reperfusion beyond 6 hours. Poor reperfusion was defined as mTICI ≦2a. The pretreatment collateral circulation extent was graded as poor (grades 0–1) or good (grades 2–4). Results: Among the 98 patients with AIS who were treated with ET, LOI was present in 48 (49%) subjects. Multivariate analysis indicated that poor collaterals (odds ratio [OR] 3.25; 95% confidence interval [CI]: 1.29–8.19; p = 0.012) and long ORT (OR 3.97, 95% CI: 1.66–9.54; p = 0.002) were independent predictors of LOI. LOI (OR 7.18, 95% CI: 2.39–21.61; p < 0.001) was independently associated with unfavorable outcome at 3 months. Conclusion: Among patients with AIS treated with ET, as an independent predictor of unfavorable outcome, LOI at 24 hours is associated with poor collaterals and long ORT.

Cerebral collateral circulation in experimental ischemic stroke.

Cerebral collateral circulation is a subsidiary vascular network, which is dynamically recruited after arterial occlusion, and represents a powerful determinant of ischemic stroke outcome. Although several methods may be used for assessing cerebral collaterals in the acute phase of ischemic stroke in humans and rodents, they are generally underutilized. Experimental stroke models may play a unique role in understanding the adaptive response of cerebral collaterals during ischemia and their potential for therapeutic modulation. The systematic assessment of collateral perfusion in experimental stroke models may be used as a “stratification factor” in multiple regression analysis of neuroprotection studies, in order to control the within-group variability. Exploring the modulatory mechanisms of cerebral collaterals in stroke models may promote the translational development of therapeutic strategies for increasing collateral flow and directly compare them in term of efficacy, safety and feasibility. Collateral therapeutics may have a role in the hyperacute (even pre-hospital) phase of ischemic stroke, prior to recanalization therapies.

Collateral Circulation in Ischemic Stroke: Assessment Tools and Therapeutic Strategies.

Revascularization encompasses all treatment-related improvements in blood flow, including recanalization of the proximal arterial occlusion and reperfusion of the downstream territory. Recanalization is required for antegrade tissue reperfusion, but recanalization may not necessarily lead to reperfusion in regions where distal emboli or established infarctions are present.1,2 On the contrary, acute reperfusion without recanalization may occur in patients who received or did not received endovascular therapies, and reperfusion ≤6 hours was consistently superior to recanalization in predicting tissue and clinical outcome.3 The cerebral collateral circulation refers to the subsidiary network of vascular channels that stabilize cerebral blood flow when principal conduits fail. Collateral status differs among patients with acute ischemic stroke. Relatively sparse attention has been devoted to the role of baseline collateral circulation in patients with acute ischemic stroke who are candidates for revascularization. The Interventional Management of Stroke (IMS) III,4 Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE),5 and Intra-Arterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS EXP) trials6 were 3 multicenter, prospective, randomized controlled trials, which failed to show a benefit from endovascular intervention for acute ischemic stroke. In addition, successful recanalization failed to improve the functional outcome in a significant proportion of patients, ranging from 26% to 49% (futile and dangerous recanalization), stimulating the need to improve the selection of patients based on individual pathophysiology.7,8 Among neuroimaging parameters, a large core and poor collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcome,9–13 and excluding patients with large core and poor collateral circulation may improve the therapeutic benefit from endovascular therapy. In the subgroup analysis of the IMS III trial, more robust collateral grade was associated with better clinical outcomes.14 Adequate collateral circulation …

Chloride intracellular channel 4 is required for maturation of the cerebral collateral circulation.

The number and diameter of native collaterals in tissues of healthy mice vary widely, resulting in large differences in tissue injury in occlusive diseases. Recent studies suggest similar variation may exist in humans. Collateral variation in mice is determined by genetic background-dependent differences in embryonic collateral formation, by variation in maturation of the nascent collaterals, and by environmental factors such as aging that cause collateral rarefaction in the adult. Recently, formation of the collateral circulation in the brain was found to involve a unique VEGF-A-dependent "arteriolar" angiogenic sprouting-like mechanism. Elsewhere, chloride intracellular protein 4 (CLIC4) was implicated but not investigated directly, prompting the present study. Deletion of Clic4 had no effect on embryonic collaterogenesis. However, during collateral maturation from embryonic day 18.5 to postnatal day 7, reduced mural cell investment was observed and excessive pruning of collaterals occurred. Growth in collateral diameter was reduced. This resulted in 50% fewer collaterals of smaller diameter in the adult and thus larger infarct volume after middle cerebral artery occlusion. During collateral maturation, CLIC4 deficiency resulted in reduced expression of Vegfr2, Vegfr1, Vegfc, and mural cell markers, but not notch-pathway genes. Overexpression of VEGF-A in Clic4(-/-) mice had no effect on collaterogenesis, but rescued the above defects in collateral maturation by preventing mural cell loss and collateral pruning, thus restoring collateral number and diameter and reducing stroke severity in the adult. CLIC4 is not required for collaterogenesis but is essential for perinatal maturation of nascent collaterals through a mechanism that supports VEGF signaling.

Cerebral collaterals and collateral therapeutics for acute ischemic stroke.

Cerebral collaterals are vascular redundancies in the cerebral circulation that can partially maintain blood flow to ischemic tissue when primary conduits are blocked. After occlusion of a cerebral artery, anastomoses connecting the distal segments of the MCA with distal branches of the ACA and PCA (known as leptomeningeal or pial collaterals) allow for partially maintained blood flow in the ischemic penumbra and delay or prevent cell death. However, collateral circulation varies dramatically between individuals, and collateral extent is significant predictor of stroke severity and recanalization rate. Collateral therapeutics attempt to harness these vascular redundancies by enhancing blood flow through pial collaterals to reduce ischemia and brain damage after cerebral arterial occlusion. While therapies to enhance collateral flow remain relatively nascent neuroprotective strategies, experimental therapies including inhaled NO, transient suprarenal aortic occlusion, and electrical stimulation of the parasympathetic sphenopalatine ganglion show promise as collateral therapeutics with the potential to improve treatment of acute ischemic stroke.

Abstract 115: Genetic Variation in Retinal Vascular Patterning Predicts Variation in Pial Collateral Extent and Infarct Volume After Middle Cerebral Artery Occlusion

Introduction: The presence of a native (pre-existing) collateral circulation in tissues lessens injury in stroke and other occlusive diseases. However, differences in genetic background are accompanied by wide variation in the number and diameter (extent) of native collaterals in mice, resulting in large variation in protection. Indirect evidence suggests a similar wide variation also exists in humans. However, methods of measurement in humans are indirect, invasive and not widely available. Hypothesis: We sought to determine if differences in genetic background in mice result in variation in branch-patterning of the retinal circulation, and if these differences predict differences in collateral extent and, in turn, differences in severity of ischemic stroke. Methods: Patterning metrics were obtained for the retinal arterial trees of 10 mouse strains (n=8 per strain) that differ widely in collateral extent in brain and other tissues. We also obtained pial collateral number and diameter, and infarct volume 24h after permanent middle cerebral artery occlusion. Forward- and reverse-stepwise multivariate regression analysis was conducted and model performance assessed using K-fold cross-validation. Results: Twenty-one metrics varied significantly with genetic strain (p&lt;0.01). Ten metrics (eg, vessel caliber, bifurcation angle, lacunarity, optimality, branch length) strongly predicted collateral number and diameter across 7 regression models. The best models closely predicted (p&lt;0.0001) collateral number (K-fold R2 =0.83-0.98), diameter (0.73-0.88) and infarct volume (0.85-0.87). Conclusions: Differences in retinal tree patterning are specified by genetic background and closely predict genetic variation in pial collateral extent and, in turn, stroke severity. If these findings can be confirmed in humans, and given that genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar “retinal predictor index” could be developed as a biomarker for collateral extent in brain and other tissues. This could aid prediction of the risk-severity of tissue injury in occlusive disease as well as stratification of patients for treatment options and enrollment in clinical studies.

The collaterome: A novel conceptual framework of systems biology in cerebrovascular disorders

The collaterome is the elaborate neurovascular architecture within the brain that regulates and determines the compensatory ability, response, and outcome of cerebrovascular pathophysiology. Based on the fundamental aspects of the cerebral collateral circulation, this model provides a conceptual framework or novel approach to cerebrovascular disorders that endorses systems biology rather than traditional reductionism. The nature of this holistic approach mirrors the innate or endogenous compensatory ability of collaterals, extending this concept to reconsider current approaches to cerebrovascular disorders. The distinction of asymptomatic and symptomatic physiology, and normal brain health versus cerebrovascular disease and the management of cerebrovascular disorders from diagnosis to therapeutic strategies may be reconsidered from this conceptual framework that builds upon established knowledge in the stroke literature.

Flow Augmentation in Acute Ischemic Stroke.

There is an urgent need for additional therapeutic options for acute ischemic stroke considering the major pitfalls of the options available. Herein, we briefly review the role of cerebral blood flow, collaterals, vasoreactivity, and reperfusion injury in acute ischemic stroke. Then, we reviewed pharmacological and interventional measures such as volume expansion and induced hypertension, intra-aortic balloon counterpulsation, partial aortic occlusion, extracranial-intracranial carotid bypass surgery, sphenopalatine ganglion stimulation, and transcranial laser therapy with regard to their effects on flow augmentation and neuroprotection.

Abstract 11511: Genetic Variation in Retinal Vascular Patterning Predicts Variation in Pial Collateral Extent and Infarct Volume After Middle Cerebral Artery Occlusion

Introduction: The presence of a native (pre-existing) collateral circulation in tissues lessens injury in stroke and other occlusive diseases. However, differences in genetic background are accompanied by wide variation in the number and diameter (extent) of native collaterals in mice, resulting in large variation in protection. Indirect evidence suggests a similar wide variation also exists in humans. However, methods of measurement in humans are indirect, invasive and not widely available. Hypothesis: We sought to determine if differences in genetic background in mice result in variation in branch-patterning of the retinal circulation, and if these differences predict differences in collateral extent and, in turn, differences in severity of ischemic stroke. Methods: Patterning metrics were obtained for the retinal arterial trees of 10 mouse strains (n=8 per strain) that differ widely in collateral extent in brain and other tissues. We also obtained pial collateral number and diameter, and infarct volume 24h after permanent middle cerebral artery occlusion. Forward- and reverse-stepwise multivariate regression analysis was conducted and model performance assessed using K-fold cross-validation. Results: Twenty-one metrics varied significantly with genetic strain (p&lt;0.01). Ten metrics (eg, vessel caliber, bifurcation angle, lacunarity, optimality, branch length) strongly predicted collateral number and diameter across 7 regression models. The best models closely predicted (p&lt;0.0001) collateral number (K-fold R 2 =0.83-0.98), diameter (0.73-0.88) and infarct volume (0.85-0.87). Conclusions: Differences in retinal tree patterning are specified by genetic background and closely predict genetic variation in pial collateral extent and, in turn, stroke severity. If these findings can be confirmed in humans, and given that genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar “retinal predictor index” could be developed as a biomarker for collateral extent in brain and other tissues. This could aid prediction of the risk-severity of tissue injury in occlusive disease as well as stratification of patients for treatment options and enrollment in clinical studies.

Genetic variation in retinal vascular patterning predicts variation in pial collateral extent and stroke severity.

The presence of a native collateral circulation in tissues lessens injury in occlusive vascular diseases. However, differences in genetic background cause wide variation in collateral number and diameter in mice, resulting in large variation in protection. Indirect estimates of collateral perfusion suggest that wide variation also exists in humans. Unfortunately, methods used to obtain these estimates are invasive and not widely available. We sought to determine whether differences in genetic background in mice result in variation in branch patterning of the retinal arterial circulation, and whether these differences predict strain-dependent differences in pial collateral extent and severity of ischemic stroke. Retinal patterning metrics, collateral extent, and infarct volume were obtained for 10 strains known to differ widely in collateral extent. Multivariate regression was conducted, and model performance was assessed using K-fold cross-validation. Twenty-one metrics varied with strain (p<0.01). Ten metrics (e.g., bifurcation angle, lacunarity, optimality) predicted collateral number and diameter across seven regression models, with the best model closely predicting (p<0.0001) number (±1.2-3.4 collaterals, K-fold R2=0.83-0.98), diameter (±1.2-1.9 μm, R2=0.73-0.88), and infarct volume (±5.1 mm3, R2=0.85-0.87). An analogous set of the most predictive metrics, obtained for the middle cerebral artery (MCA) tree in a subset of the above strains, also predicted (p<0.0001) collateral number (±3.3 collaterals, K-fold R2=0.78) and diameter (±1.6 μm, R2=0.86). Thus, differences in arterial branch patterning in the retina and the MCA trees are specified by genetic background and predict variation in collateral extent and stroke severity. If also true in human, and since genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar "retinal predictor index" could serve as a non- or minimally invasive biomarker for collateral extent in brain and other tissues. This could aid prediction of severity of tissue injury in the event of an occlusive event or development of obstructive disease and in patient stratification for treatment options and clinical studies.