Collateral Extent Research Articles

Combining Early Ischemic Change and Collateral Extent for Functional Outcomes After Endovascular Therapy: An Analysis From AcT Trial.

Early ischemic change and collateral extent are colinear with ischemic core volume (ICV). We investigated the relationship between a combined score using the Alberta Stroke Program Early Computed Tomography Score and multiphase computed tomography angiography (mCTA) collateral extent, named mCTA-ACE score, on functional outcomes in endovascular therapy-treated patients. We performed a post hoc analysis of a subset of endovascular therapy-treated patients from the Alteplase Compared to Tenecteplase trial which was conducted between December 2019 and January 2022 at 22 centers across Canada. Ten-point mCTA collateral corresponding to M2 to M6 regions of the Alberta Stroke Program Early Computed Tomography Score grid was evaluated as 0 (poor), 1 (moderate), or 2 (normal) and additively combined with the 10-point Alberta Stroke Program Early Computed Tomography Score to produce a 20-point mCTA-ACE score. We investigated the association of mCTA-ACE score with modified Rankin Scale score ≤2 and return to prestroke level of function at 90 to 120 days using mixed-effects logistic regression. In the subset of patients who underwent baseline computed tomography perfusion imaging, we compared the mCTA-ACE score and ICV for outcome prediction. Among 1577 intention-to-treat population in the trial, 368 (23%; 179 men; median age, 73 years) were included, with Alberta Stroke Program Early Computed Tomography Score, mCTA collateral, and combination of both (mCTA-ACE score: median [interquartile range], 8 [7-10], 9 [8-10], and 17 [16-19], respectively). The probability of modified Rankin Scale score ≤2 and return to prestroke level of function increased for each 1-point increase in mCTA-ACE score (odds ratio, 1.16 [95% CI, 1.06-1.28] and 1.22 [95% CI, 1.06-1.40], respectively). Among 173 patients in whom computed tomography perfusion data was assessable, the mCTA-ACE score was inversely correlated with ICV (ρ=-0.46; P<0.01). The mCTA-ACE score was comparable to ICV to predict a modified Rankin Scale score ≤2 and return to prestroke level of function (C statistics 0.71 versus 0.69 and 0.68 versus 0.64, respectively). The mCTA-ACE score had a significant positive association with functional outcomes after endovascular therapy and had a similar predictive performance as ICV.

Cerebral Collateral Circulation in the Era of Reperfusion Therapies for Acute Ischemic Stroke.

Clinical outcomes of patients with acute ischemic stroke depend in part on the extent of their collateral circulation. A good collateral circulation has also been associated with greater benefit of intravenous thrombolysis and endovascular treatment. Treatment decisions for these reperfusion therapies are increasingly guided by a combination of clinical and imaging parameters, particularly in later time windows. Computed tomography and magnetic resonance imaging enable a rapid assessment of both the collateral extent and cerebral perfusion. Yet, the role of the collateral circulation in clinical decision-making is currently limited and may be underappreciated due to the use of rather coarse and rater-dependent grading methods. In this review, we discuss determinants of the collateral circulation in patients with acute ischemic stroke, report on commonly used and emerging neuroimaging techniques for assessing the collateral circulation, and discuss the therapeutic and prognostic implications of the collateral circulation in relation to reperfusion therapies for acute ischemic stroke.

Abstract TP155: Sex Differences In Outcome And Workflow Of Endovascular Treatment In Late Window Stroke Patients

Background and Purpose: Sex-related differences exist in many aspects of stroke and were mainly investigated in the early time window with conflicting results. However, data regarding sex disparities in late presenters are scarce. Therefore, we sought to investigate differences in outcomes between women and men treated with endovascular treatment (EVT) in the late time window. Methods: Analyses were based on the Selection Of Late-window Stroke for Thrombectomy by Imaging Collateral Extent Consortium, which was an individual-patient level analysis of seven trials and registries. Baseline characteristics, functional independence (modified Rankin Scale ≤ 2), mortality, and symptomatic intracranial hemorrhage (sICH) were compared between women and men. Effect of sex on the association between age, successful reperfusion (Thrombolysis in cerebral infarction 2b-3) and outcomes was assessed using multivariable logistic regression with interaction terms. Results: Among 608 patients treated with EVT, 50.5% were women. Women were older than men by median 4 years and had a lower prevalence of tandem occlusions (14.0% vs. 22.9%). In the subset of patients with available perfusion volumes (n= 195), women had smaller penumbra (median IQR:97 mL [60- 130] vs. 109 mL [73-189]; p= 0.008), and mismatch volumes, (79 mL [49-101] vs. 91 mL [57-158] ; p= 0.02). Pre and intrahospital times were similar between sexes. Outcomes did not differ between women and men, and there was no sex-by-age interaction on functional independence. However, men had higher likelihood of mortality (p interaction = 0.004) and sICH (p interaction = 0.016) with advancing age. Sex did not influence the relation between successful reperfusion and outcomes. Conclusions: In this multicenter analysis of late presenters treated with EVT, sex was not associated with clinical outcomes. However, sex influenced the association between age and safety outcomes with men experiencing worse outcomes with advancing age.

Sex-Related Differences in Outcomes After Endovascular Treatment of Patients With Late-Window Stroke.

Sex-related differences exist in many aspects of acute stroke and were mainly investigated in the early time window with conflicting results. However, data regarding sex disparities in late presenters are scarce. Therefore, we sought to investigate differences in outcomes between women and men treated with endovascular treatment in the late time window. Analyses were based on the SOLSTICE Consortium (Selection of Late-Window Stroke for Thrombectomy by Imaging Collateral Extent), which was an individual-patient level analysis of seven trials and registries. Baseline characteristics, 90-day functional independence (modified Rankin Scale score ≤2), mortality, and symptomatic intracranial hemorrhage were compared between women and men. Effect of sex on the association of age and successful reperfusion (final Thrombolysis in Cerebral Infarction 2b-3) with outcomes was assessed using multivariable logistic regression adjusted for age, National Institutes of Health Stroke Scale score, Alberta Stroke Program Early CT Score, time from onset to puncture, occlusion location, intravenous thrombolysis, and successful reperfusion, with interaction terms. Among 608 patients treated with endovascular treatment, 50.5% were women. Women were older than men (median age of 72 versus 68 years, P=0.02) and had a lower prevalence of tandem occlusions (14.0% versus 22.9%, P=0.005). Workflow times were similar between sexes. Adjusted outcomes did not differ between women and men. Functional independence at 90 days was achieved by 127 out of 292 women (43.5%) and 135 out of 291 men (46.4%). Mortality at 90 days (54 [18.5%] versus 48 [16.5%]) and symptomatic intracranial hemorrhage (37 [13.3%] versus 33 [11.6%]) were similar between women and men. There was no sex-by-age interaction on functional outcomes. However, men had higher likelihood of mortality (Pinteraction=0.003) and symptomatic intracranial hemorrhage (Pinteraction=0.017) with advancing age. Sex did not influence the relation between successful reperfusion and outcomes. In this multicenter analysis of late patients treated with endovascular treatment, sex was not associated with functional outcome. However, sex influenced the association between age and safety outcomes, with men experiencing worse outcomes with advancing age.

Utility of Time-Variant Multiphase CTA Color Maps in Outcome Prediction for Acute Ischemic Stroke Due to Anterior Circulation Large Vessel Occlusion.

Multiphase CTA (mCTA) is an established tool for endovascular treatment decision-making and outcome prediction in acute ischemic stroke, but its interpretation requires some degree of experience. We aimed to determine whether mCTA-based prediction of clinical outcome and final infarct volume can be improved by assessing collateral status on time-variant mCTA color maps rather than using aconventional mCTA display format. Patients from the PRove-IT cohort study with anterior circulation large vessel occlusion were included in this study. Collateral status was assessed with athree-point scale using the conventional display format. Collateral extent and filling dynamics were then graded on athree-point scale using time-variant mCTA color-maps (FastStroke, GE Healthcare, Milwaukee, WI, USA). Multivariable logistic regression was performed to determine the association of conventional collateral score, color-coded collateral extent and color-coded collateral filling dynamics with good clinical outcome and final infarct volume (volume below vs. above median infarct volume in the study sample). A total of 285 patients were included in the analysis and 53% (152/285) of the patients achieved agood outcome. Median infarct volume on follow-up was 12.6 ml. Color-coded collateral extent was significantly associated with good outcome (adjusted odds ratio [adjOR] 0.53, 95% confidence interval [CI]:0.36-0.77) while color-coded collateral filling dynamics (adjOR 1.30 [95%CI:0.88-1.95]) and conventional collateral scoring (adjOR 0.72 [95%C:0.48-1.08]) were not. Both color-coded collateral extent (adjOR 2.67 [95%CI:1.80-4.00]) and conventional collateral scoring (adjOR 1.84 [95%CI:1.21-2.79]) were significantly associated with follow-up infarct volume, while color-coded collateral filling dynamics were not (adjOR 1.21 [95%CI:0.83-1.78]). In this study, collateral extent assessment on time-variant mCTA maps improved prediction of good outcome and has similar value in predicting follow-up infarct volume compared to conventional mCTA collateral grading.

Role of Genetic Variation in Collateral Circulation in the Evolution of Acute Stroke: A Multimodal Magnetic Resonance Imaging Study.

No studies have determined the effect of differences in pial collateral extent (number and diameter), independent of differences in environmental factors and unknown genetic factors, on severity of stroke. We examined ischemic tissue evolution during acute stroke, as measured by magnetic resonance imaging and histology, by comparing 2 congenic mouse strains with otherwise identical genetic backgrounds but with different alleles of the Determinant of collateral extent-1 (Dce1) genetic locus. We also optimized magnetic resonance perfusion and diffusion-deficit thresholds by using histological measures of ischemic tissue. Perfusion, diffusion, and T2-weighted magnetic resonance imaging were performed on collateral-poor (congenic-Bc) and collateral-rich (congenic-B6) mice at 1, 5, and 24 hours after permanent middle cerebral artery occlusion. Magnetic resonance imaging-derived penumbra and ischemic core volumes were confirmed by histology in a subset of mice at 5 and 24 hours after permanent middle cerebral artery occlusion. Although perfusion-deficit volumes were similar between strains 1 hour after permanent middle cerebral artery occlusion, diffusion-deficit volumes were 32% smaller in collateral-rich mice. At 5 hours, collateral-rich mice had markedly restored perfusion patterns showing reduced perfusion-deficit volumes, smaller infarct volumes, and smaller perfusion-diffusion mismatch volumes compared with the collateral-poor mice (P<0.05). At 24 hours, collateral-rich mice had 45% smaller T2-weighted lesion volumes (P<0.005) than collateral-poor mice, with no difference in perfusion-diffusion mismatch volumes because of penumbral death occurring 5 to 24 hours after permanent middle cerebral artery occlusion in collateral-poor mice. Variation in collateral extent significantly alters infarct volume expansion, transiently affects perfusion and diffusion magnetic resonance imaging signatures, and impacts salvage of ischemic penumbra after stroke onset.

Sex Differences in the Cerebral Collateral Circulation.

Premenopausal women and intact female rodents sustain smaller cerebral infarctions than males. Several sex-dependent differences have been identified as potential contributors, but many questions remain unanswered. Mice exhibit wide variation in native collateral number and diameter (collateral extent) that is dependent on differences in genetic background, aging, and other comorbidities and that contributes to their also-wide differences in infarct volume. Likewise, variation in infarct volume correlates with differences in collateral-dependent blood flow in patients with acute ischemic stroke. We examined whether extent of pial collateral arterioles and posterior communicating collateral arteries (PComAs) differ depending on sex in young, aged, obese, hypertensive, and genetically different mice. We combined new data with meta-analysis of our previously published data. Females of C57BL/6J (B6) and BALB/cByJ (BC) strains sustained smaller infarctions than males after permanent MCA occlusion. This protection was unchanged in BC mice after introgression of the B6 allele of Dce1, the major genetic determinant of variation in pial collaterals among mouse strains. Consistent with this, collateral extent in these and other strains did not differ with sex. Extent of PComAs and primary cerebral arteries also did not vary with sex. No dimorphism was evident for loss of pial collateral number and/or diameter (collateral rarefaction) caused by aging, obesity, and hypertension, nor for collateral remodeling after pMCAO. However, rarefaction was greater in females with long-standing hypertension. We conclude that smaller infarct volume in female mice is not due to greater collateral extent, greater remodeling, or less rarefaction caused by aging, obesity, or hypertension.

Variants of Rab GTPase-Effector Binding Protein-2 Cause Variation in the Collateral Circulation and Severity of Stroke.

The extent (number and diameter) of collateral vessels varies widely and is a major determinant, along with arteriogenesis (collateral remodeling), of variation in severity of tissue injury after large artery occlusion. Differences in genetic background underlie the majority of the variation in collateral extent in mice, through alterations in collaterogenesis (embryonic collateral formation). In brain and other tissues, ≈80% of the variation in collateral extent among different mouse strains has been linked to a region on chromosome 7. We recently used congenic (CNG) fine mapping of C57BL/6 (B6, high extent) and BALB/cByJ (BC, low extent) mice to narrow the region to a 737 Kb locus, Dce1. Herein, we report the causal gene. We used additional CNG mapping and knockout mice to narrow the number of candidate genes. Subsequent inspection identified a nonsynonymous single nucleotide polymorphism between B6 and BC within Rabep2 (rs33080487). We then created B6 mice with the BC single nucleotide polymorphism at this locus plus 3 other lines for predicted alteration or knockout of Rabep2 using gene editing. The single amino acid change caused by rs33080487 accounted for the difference in collateral extent and infarct volume between B6 and BC mice attributable to Dce1. Mechanistically, variants of Rabep2 altered collaterogenesis during embryogenesis but had no effect on angiogenesis examined in vivo and in vitro. Rabep2 deficiency altered endosome trafficking known to be involved in VEGF-A→VEGFR2 signaling required for collaterogenesis. Naturally occurring variants of Rabep2 are major determinants of variation in collateral extent and stroke severity in mice.

Added Value of Vessel Wall Magnetic Resonance Imaging in the Differentiation of Moyamoya Vasculopathies in a Non-Asian Cohort.

Although studies have evaluated the differential imaging of moyamoya disease and atherosclerosis, none have investigated the added value of vessel wall magnetic resonance imaging (MRI). This study evaluates the added diagnostic value of vessel wall MRI in differentiating moyamoya disease, atherosclerotic-moyamoya syndrome (A-MMS), and vasculitic-MMS (V-MMS) with a multicontrast protocol. We retrospectively reviewed the carotid artery territories of patients with clinically defined vasculopathies (moyamoya disease, atherosclerosis, and vasculitis) and steno-occlusive intracranial carotid disease. Two neuroradiologists, blinded to clinical data reviewed the luminal imaging of each carotid, evaluating collateral extent and making a presumed diagnosis with diagnostic confidence. After 3 weeks, the 2 readers reviewed the luminal imaging+vessel wall MRI for the presence, pattern and intensity of postcontrast enhancement, T2 signal characteristics, pattern of involvement, and presumed diagnosis and confidence. Ten A-MMS, 3 V-MMS, and 8 moyamoya disease cases with 38 affected carotid segments were included. There was significant improvement in diagnostic accuracy with luminal imaging+vessel wall MRI when compared with luminal imaging (87% versus 32%, P<0.001). The most common vessel wall MRI findings for moyamoya disease were nonenhancing, nonremodeling lesions without T2 heterogeneity; for A-MMS eccentric, remodeling, and T2 heterogeneous lesions with mild/moderate and homogeneous/heterogeneous enhancement; and for V-MMS concentric lesions with homogeneous, moderate enhancement. Inter-reader agreement was moderate to substantial for all vessel wall MRI characteristics (κ=0.46-0.86) and fair for collateral grading (κ=0.35). There was 11% inter-reader agreement for diagnosis on luminal imaging when compared with 82% for luminal imaging+vessel wall MRI (P<0.001). Vessel wall MRI can significantly improve the differentiation of moyamoya vasculopathies when combined with traditional imaging techniques.

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.

De-novo collateral formation following acute myocardial infarction: Dependence on CCR2+ bone marrow cells

Wide variation exists in the extent (number and diameter) of native pre-existing collaterals in tissues of different strains of mice, with supportive indirect evidence recently appearing for humans. This variation is a major determinant of the wide variation in severity of tissue injury in occlusive vascular disease. Whether such genetic-dependent variation also exists in the heart is unknown because no model exists for study of mouse coronary collaterals. Also owing to methodological limitations, it is not known if ischemia can induce new coronary collaterals to form (“neo-collaterals”) versus remodeling of pre-existing ones. The present study sought to develop a model to study coronary collaterals in mice, determine whether neo-collateral formation occurs, and investigate the responsible mechanisms. Four strains with known rank-ordered differences in collateral extent in brain and skeletal muscle were studied: C57BLKS>C57BL/6>A/J>BALB/c. Unexpectedly, these and 5 additional strains lacked native coronary collaterals. However after ligation, neo-collaterals formed rapidly within 1-to-2days, reaching their maximum extent in ≤7days. Rank-order for neo-collateral formation differed from the above: C57BL/6>BALB/c>C57BLKS>A/J. Collateral network conductance, infarct volume−1, and contractile function followed this same rank-order. Neo-collateral formation and collateral conductance were reduced and infarct volume increased in MCP1−/− and CCR2−/− mice. Bone-marrow transplant rescued collateral formation in CCR2−/− mice. Involvement of fractalkine➔CX3CR1 signaling and endothelial cell proliferation were also identified. This study introduces a model for investigating the coronary collateral circulation in mice, demonstrates that neo-collaterals form rapidly after coronary occlusion, and finds that MCP➔CCR2-mediated recruitment of myeloid cells is required for this process.

Salient features of the coronary collateral circulation and its clinical relevance.

The coronary collateral circulation provides an alternative source of blood supply to myocardium jeopardised by ischaemia. Collaterals enlarge with obstructive coronary artery disease to allow bulk flow, but blood flow deliverable by the native, pre-formed collateral extent can already be sizeable. Genetic determinants contribute significantly to the wide variability observed in both native collateral extent and its capacity to enlarge, and the severity of the coronary stenosis is the most significant environmental determinant for collateral enlargement. The protective effect of a well-developed coronary collateral circulation translates into relevant improvements in all-cause and cardiac mortality in the acute and chronic phases of coronary artery disease, as well as into a reduction of future adverse cardiovascular events.

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.

Abstract 182: Time is Brain on the Collateral Clock! Collaterals and Reperfusion Determine Tissue Injury

Background: The pace of ischemic injury due to stroke may vary due to collaterals and degree of reperfusion. Previous linear models that estimate time is brain have not incorporated individual patient data from advanced imaging such as diffusion-weighted imaging (DWI) and angiographic assessment of collateral grade or reperfusion. We developed a realistic model of ischemic injury using detailed imaging data in a homogenous cohort of isolated M1 middle cerebral artery occlusions. Methods: Retrospective analysis of a consecutive series of isolated M1 occlusions was conducted at an expert core lab. ASITN collateral grade was assessed at baseline and extent of reperfusion after endovascular therapy (EVT) was scored with 3 distinct versions of TICI. A separate imaging expert measured DWI lesion volumes on serial MRI acquired from admission to discharge. Graphical analyses illustrated curves demarcating extent of injury over time, based on both collateral grade and extent of reperfusion. Results: 126 patients (median age 73; 88 women; median NIHSS 17; median time to 1 st DWI, 4h08min) with acute stroke due to M1 occlusion (61 proximal, 65 distal) underwent EVT during a 6-year period. Median collateral grade was 2 (range 0-4) and median TICI, 2B (range 0-3). mTICI scores were 0 (n=18), 1 (6), 2A (25), 2B (73), and 3 (4) with 24 TICI 2C scores when evaluated in detail. Total number of DWI scans was 323, with mean 2.5 per patient. Collateral grade strongly influenced pace of development of initial tissue injury (ASITN 0, 0.445 cc/min; 1, 0.276 cc/min; 2, 0.178 cc/min; 3, 0.106 cc/min; 4, 0.031 cc/min). The relationship between time and DWI lesion growth was not linear, but best fit logarithmically (R 2 = 0.985, RMSE 2.1 for log fit; R 2 = 0.757, RMSE 8.1 for linear fit). Individual lesion growth varied markedly with both collateral grade (ANOVA p&lt;0.001) and the degree (TICI 2B/3 vs. 0,1,2A) of reperfusion (ANOVA p=0.013). Conclusions: Collateral grade and the degree of reperfusion strongly dictate the timecourse of ischemic injury in the brain after stroke onset. Advanced imaging and angiographic assessment of collaterals and reperfusion confirm a logarithmic, not linear, model that can be used to differentiate stroke patients and streamline therapeutic strategies.

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

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

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.

A brief etymology of the collateral circulation.

It is well known that the protective capacity of the collateral circulation falls short in many individuals with ischemic disease of the heart, brain, and lower extremities. In the past 15 years, opportunities created by molecular and genetic tools, together with disappointing outcomes in many angiogenic trials, have led to a significant increase in the number of studies that focus on: understanding the basic biology of the collateral circulation; identifying the mechanisms that limit the collateral circulation's capacity in many individuals; devising methods to measure collateral extent, which has been found to vary widely among individuals; and developing treatments to increase collateral blood flow in obstructive disease. Unfortunately, accompanying this increase in reports has been a proliferation of vague terms used to describe the disposition and behavior of this unique circulation, as well as the increasing misuse of well-ensconced ones by new (and old) students of collateral circulation. With this in mind, we provide a brief glossary of readily understandable terms to denote the formation, adaptive growth, and maladaptive rarefaction of collateral circulation. We also propose terminology for several newly discovered processes that occur in the collateral circulation. Finally, we include terms used to describe vessels that are sometimes confused with collaterals, as well as terms describing processes active in the general arterial-venous circulation when ischemic conditions engage the collateral circulation. We hope this brief review will help unify the terminology used in collateral research.

Genetic determinants of the native collateral circulation (19.3)

Native (pre‐existing) collaterals connect adjacent arterial trees and limit ischemic tissue injury. I will review recent findings that collaterals have distinct features, including a unique process of formation and specialized endothelial and smooth muscle cell phenotypes. Moreover, the number and diameter of collaterals (“extent”) in tissues varies widely among different mouse strains and healthy humans, associated with wide differences in the severity of ischemic damage. A single locus, Dce1, is responsible for ~80% of the variation in mouse. Ongoing work is seeking to identify the underlying gene(s) and pathway, and whether this locus links to variation in collateral extent in humans. If so, Dce1 and its up‐ and down‐stream partners could provide markers for collateral abundance to help stratify patients for treatment options, to assess risk‐severity before disease occurs, and to provide targets for therapies to stimulate new collateral formation. Recent studies in mice have found that such “neo‐collateral” formation can be induced to occur rapidly after acute MI, resulting in increased collateral‐dependent flow and reduced infarct volume. Besides genetic factors, “environmental “ factors, ie, aging and other cardiovascular risk factors, cause reduced collateral extent, resulting in more severe ischemic injury. Studies are under way to identify the underlying mechanism and strategies to prevent it.