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Background and purposeCollateral blood flow to the affected cerebral territory in acute ischemic stroke may modify the effect of intravenous alteplase treatment (IVT) prior to endovascular treatment (EVT). We assessed whether an interaction effect between arterial collateral status, assessed by both a visual and quantitative collateral score (CS), and administration of IVT plus EVT was present in the MR CLEAN-NO IV trial.MethodsBaseline CT or MR angiography (CTA and MRA) from patients included in MR CLEAN-NO IV was assessed using both a visual and automated quantitative score for arterial collateral status. We included 526 patients with visual CS and 401 with quantitative CS in this prespecified analysis. The primary outcome was functional outcome measured as the modified Rankin Scale score at 90 days. Interaction terms of treatment allocation (IVT plus EVT vs EVT alone) and collateral scores were included in regression models to assess whether the treatment effect of IVT differed by arterial collateral status.ResultsIVT plus EVT was not statistically significantly associated with better functional outcome compared with EVT alone (adjusted common odds ratio 1.14; 95% CI 0.84 to 1.55). There was no statistically significant modification of IVT treatment effect on functional outcome by either visual or quantitative CS (adjusted p-interaction=0.34; adjusted p-interaction=0.57, respectively).ConclusionIn the MR CLEAN-NO IV trial, we did not find evidence that arterial collateral status measured with a visual score or quantitative score can inform treatment decisions regarding IVT plus EVT for patients with acute ischemic stroke due to large vessel occlusion in the anterior circulation within 4.5 hours.

Changes in collateral blood flow, which sustains brain viability distal to arterial occlusion, may impact infarct evolution but have not previously been demonstrated in humans. We correlated leptomeningeal collateral flow, assessed using novel perfusion magnetic resonance imaging (MRI) processing at baseline and 3 to 5 days, with simultaneous assessment of perfusion parameters. Perfusion raw data were averaged across three consecutive slices to increase leptomeningeal collateral vessel continuity after subtraction of baseline signal analogous to digital subtraction angiography. Changes in collateral quality, Tmax hypoperfusion severity, and infarct growth were assessed between baseline and days 3 to 5 perfusion-diffusion MRI. Acute MRI was analysed for 88 patients imaged 3 to 6 hours after ischemic stroke onset. Better collateral flow at baseline was associated with larger perfusion-diffusion mismatch (Spearman's Rho 0.51, P < 0.001) and smaller baseline diffusion lesion volume (Rho − 0.70, P < 0.001). In 30 patients without reperfusion at day 3 to 5, deterioration in collateral quality between baseline and subacute imaging was strongly associated with absolute (P = 0.02) and relative (P < 0.001) infarct growth. The deterioration in collateral grade correlated with increased mean Tmax hypoperfusion severity (Rho − 0.68, P < 0.001). Deterioration in Tmax hypoperfusion severity was also significantly associated with absolute (P = 0.003) and relative (P = 0.002) infarct growth. Collateral flow is dynamic and failure is associated with infarct growth.

The MR CLEAN-LATE trial provided evidence for the safety and efficacy of endovascular treatment for acute ischaemic stroke within the late window (after 6–24 h) in patients who were preselected based on the presence of collateral flow on CT angiography. We aimed to evaluate clinical outcomes 2 years after randomisation. MR CLEAN-LATE was a phase 3, multicentre, open-label, blinded-endpoint, randomised controlled trial conducted at 18 stroke intervention centres in the Netherlands. If endovascular treatment could be initiated within 6–24 h of symptom onset or last seen well, patients (aged 18 years or older) with an acute ischaemic stroke due to a large vessel occlusion in the anterior circulation and at least some collateral flow in the affected middle cerebral artery territory on CT angiography were randomly assigned (1:1) to either endovascular treatment with best medical treatment (endovascular treatment group) or best medical treatment alone (control group). Web-based randomisation, stratified by centre, was performed with the use of permuted blocks (block size eight to 20). The researchers who collected clinical outcomes and analysed the results were masked to treatment allocation; treating physicians, local investigators, and patients were aware of the received treatment. The primary outcome of MR CLEAN-LATE was the modified Rankin Scale (mRS) score at 90 days after randomisation. For this 2-year prespecified analysis, the primary outcome was mRS score at 2 years (minus 3 months to plus 6 months). Primary and safety analyses were performed based on the modified intention-to-treat principle, and included patients who provided (deferred) consent or died before consent could be obtained. Missing data were handled with multiple imputation by chained equations. The trial is completed and is registered at ISRCTN, ISRCTN19922220. Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned in the MR CLEAN-LATE trial, of whom 502 (94%) gave deferred consent and comprised the modified intention-to-treat population (255 in the endovascular treatment group and 247 in the control group). 261 (52%) patients were female and 241 (48%) were male. Data for mRS score at 2 years were available for 226 (89%) patients in the endovascular treatment group and for 202 (82%) patients in the control group. The median mRS score at 2 years was 4 (IQR 2–6) in the endovascular treatment group and 6 (2–6) in the control group. The endovascular treatment group demonstrated a shift towards better functional outcomes on the mRS (adjusted common odds ratio 1·41 [95% CI 1·00–1·99]; p=0·049). All-cause mortality at 2 years was 34% (87 of 255) in the endovascular treatment group and 41% (101 of 247) in the control group (adjusted hazard ratio 0·81 [95% CI 0·60–1·08]; p=0·15). Major vascular events (ie, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, and cardiac events) were reported between 90 days and 2 years in 23 patients in the endovascular treatment group and 13 patients in the control group. Our results show that the effectiveness of late-window (after 6–24 h) endovascular treatment in improving clinical outcomes is sustained for up to 2 years in a population preselected based on the presence of collateral flow on CT angiography. This finding might be important for prompting further evaluations of cost-effectiveness, health-care policy development, and clinical decision making. The Dutch Organization for Health Research and Health Innovation (ZonMW), Collaboration for New Treatments of Acute Stroke Consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Health Holland Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

Objective To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD). Methods This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. Results During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by –8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to −0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113). Conclusions Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD. ClinicalTrials.gov Identifier: NCT01039389.

Cardiovascular disease remains the leading global cause of death, and the number of patients with coronary artery disease (CAD) and exhausted therapeutic options (i.e., percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) and medical treatment) is on the rise. Therefore, the evaluation of new therapeutic approaches to offer an alternative treatment strategy for these patients is necessary. A promising research field is the promotion of the coronary collateral circulation, an arterio-arterial network able to prevent or reduce myocardial ischemia in CAD. This review summarizes the basic principles of the human coronary collateral circulation, its extracardiac anastomoses as well as the different therapeutic approaches, especially that of stimulating the extracardiac collateral circulation via permanent occlusion of the internal mammary arteries.

Collaterals are unique blood vessels present in the microcirculation of most tissues that, by cross-connecting a small fraction of the outer branches of adjacent arterial trees, provide alternate routes of perfusion. However, collaterals are especially susceptible to rarefaction caused by aging, other vascular risk factors, and mouse models of Alzheimer’s disease—a vulnerability attributed to the disturbed hemodynamic environment in the watershed regions where they reside. We examined the hypothesis that endothelial and smooth muscle cells (ECs and SMCs, respectively) of collaterals have specializations, distinct from those of similarly-sized nearby distal-most arterioles (DMAs) that maintain collateral integrity despite their continuous exposure to low and oscillatory/disturbed shear stress, high wall stress, and low blood oxygen. Examination of mouse brain revealed the following: Unlike the pro-inflammatory cobble-stoned morphology of ECs exposed to low/oscillatory shear stress elsewhere in the vasculature, collateral ECs are aligned with the vessel axis. Primary cilia, which sense shear stress, are present, unexpectedly, on ECs of collaterals and DMAs but are less abundant on collaterals. Unlike DMAs, collaterals are continuously invested with SMCs, have increased expression of Pycard, Ki67, Pdgfb, Angpt2, Dll4, Ephrinb2, and eNOS, and maintain expression of Klf2/4. Collaterals lack tortuosity when first formed during development, but tortuosity becomes evident within days after birth, progresses through middle age, and then declines—results consistent with the concept that collateral wall cells have a higher turnover rate than DMAs that favors proliferative senescence and collateral rarefaction. In conclusion, endothelial and SMCs of collaterals have morphologic and functional differences from those of nearby similarly sized arterioles. Future studies are required to determine if they represent specializations that counterbalance the disturbed hemodynamic, pro-inflammatory, and pro-proliferative environment in which collaterals reside and thus mitigate their risk factor-induced rarefaction.

At least 17 million people die from acute myocardial infarction (AMI) every year, ranking it first among causes of death of human beings, and its incidence is gradually increasing. Typical characteristics of AMI include acute onset and poor prognosis. At present, there is no satisfactory treatment, but development of coronary collateral circulation (CCC) can be key to improving prognosis. Recent research indicates that the levels of cytokines, including those related to promoting inflammatory responses and angiogenesis, increase after the onset of AMI. In the early phase of AMI, cytokines play a vital role in inducing development of collateral circulation. However, when myocardial infarction is decompensated, cytokine secretion increases greatly, which may induce a cytokine storm and worsen prognosis. Cytokines can regulate the activation of a variety of signal pathways and form a complex network, which may promote or inhibit the establishment of collateral circulation. We searched for published articles in PubMed and Google Scholar, employing the keyword “acute myocardial infarction”, “coronary collateral circulation” and “cytokine storm”, to clarify the relationship between AMI and a cytokine storm, and how a cytokine storm affects the growth of collateral circulation after AMI, so as to explore treatment methods based on cytokine agents or inhibitors used to improve prognosis of AMI.

BackgroundThe adequacy of leptomeningeal collateral flow has a pivotal role in determining clinical outcome in acute ischemic stroke. The American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral score is among the most commonly used scales for measuring this flow. It is based on the extent and rate of retrograde collateral flow to the impaired territory on angiography.ObjectiveTo evaluate inter- and intraobserver agreementin angiographic leptomeningeal collateral flow assessment.Materials and methodsThirty pretreatment angiogram video loops (frontal and lateral view), chosen from the randomized controlled trial THRombectomie des Artères CErebrales (THRACE), were sent for grading in an electronic file. 19 readers participated, including eight who had access to a training set before the first grading. 13 readers made a double evaluation, 3 months apart.ResultsOverall agreement among the 19 observers was poor (κ = 0,16 ± 6,5.10 -3), and not improved with prior training (κ = 0,14 ± 0,016). Grade 4 showed the poorest interobserver agreement (κ=0.18±0.002) while grades 0 and 1 were associated with the best results (κ=0.52±0.001 and κ=0.43±0.004, respectively). Interobserver agreement increased (κ = 0,27± 0,014) when a dichotomized score, ‘poor collaterals’ (score of 0, 1 or 2) versus ‘good collaterals’ (score of 3 or 4) was used. The intraobserver agreements varied between slight (κ=0.18±0.13) and substantial (κ=0.74±0.1), and were slightly improved with the dichotomized score (from κ=0.19±0.2 to κ=0.79±0.11).ConclusionInter- and intraobserver agreement of collateral circulation grading using the ASITN/SIR score was poor, raising concerns about comparisons among publications. A simplified dichotomized judgment may be a more reproducible assessment when images are rated by the same observer(s) in randomized trials.

ObjectivesWe tested whether FLAIR vascular hyperintensities (FVH)–DWI mismatch could identify candidates for thrombectomy most likely to benefit from revascularization.MethodsWe retrospectively reviewed 100 patients with proximal MCA occlusion from 18 stroke centers randomized in the IV-thrombolysis plus mechanical thrombectomy arm of the THRACE trial (2010–2015). We tested the associations between successful revascularization on digital subtraction angiography (modified Thrombolysis in Cerebral Infarction 2b/3) and 3-month favorable outcome (modified Rankin Scale score ≤ 2), stratified on FVH–DWI mismatch status, with secondary analyses adjusted on National Institutes of Health Stroke Scale (NIHSS) and DWI lesion volume.ResultsFVH–DWI mismatch was present in 79% of patients, with a similar prevalence at 1.5 T (80%) and 3 T (78%). Successful revascularization (74%) was more frequent in patients with FVH–DWI mismatch (63/79, 80%) than in patients without (11/21, 52%), p = 0.01. The OR of favorable outcome for revascularization were 15.05 (95% CI 3.12–72.61, p < 0.001) in patients with FVH–DWI mismatch and 0.83 (95% CI 0.15–4.64, p = 0.84) in patients without FVH–DWI mismatch (p = 0.011 for interaction). Similar results were observed after adjustment for NIHSS (OR = 12.73 [95% CI 2.69–60.41, p = 0.001] and 0.96 [95% CI 0.15–6.30, p = 0.96]) or for DWI volume (OR = 12.37 [95% CI 2.76–55.44, p = 0.001] and 0.91 [95% CI 0.16–5.33, p = 0.92]) in patients with and without FVH–DWI mismatch, respectively.ConclusionsThe FVH–DWI mismatch identifies patients likeliest to benefit from revascularization, irrespective of initial DWI lesion volume and clinical stroke severity, and could serve as a useful surrogate marker for penumbral evaluation.Key Points• The FVH–DWI mismatch, defined by FLAIR vascular hyperintensities (FVH) located beyond the boundaries of the DWI lesion, is associated with large penumbra.• Among stroke patients with proximal middle cerebral artery occlusion referred for thrombectomy, those with FVH–DWI mismatch are most likely to benefit from revascularization.• FVH–DWI mismatch provides an alternative to PWI–DWI mismatch in order to select patients who are candidates for thrombectomy.

Background and Purpose This study aimed to investigate the effect of collateral circulation on the outcomes of thrombectomy versus medical management alone in basilar artery occlusion (BAO) patients with varying stroke severities. Methods Data from the ATTENTION cohort were used to perform a post‐hoc analysis comparing the outcomes of thrombectomy with medical management in BAO patients with varying degrees of collateral circulation and stroke severity. Basilar Artery on Computed Tomography Angiography (BATMAN) scores were used to quantify the collateral circulation, and the effect was estimated through a primary outcome of 90‐day functional independence (modified Rankin Scale score, mRS ≤2). Favorable versus unfavorable BATMAN scores were analyzed as both continuous and categorical variables, and an adjusted multivariate regression model was applied. Results Among 221 BAO patients, thrombectomy significantly improved functional independence compared to medical management in patients with favorable BATMAN scores (aOR 7.75, 95% CI 2.78–26.1), but not in those with unfavorable BATMAN scores (aOR 1.33, 95% CI 0.28–6.92; pinteraction = 0.028). When treated as a continuous variable, increased BATMAN score was found to be associated with a higher likelihood of functional independence in the thrombectomy group (aOR 1.97, 95% CI 1.44–2.81; pinteraction = 0.053). In severe stroke patients with higher BATMAN scores (National Institutes of Health Stroke Scale (NIHSS) ≥21), we identified a significant interaction for treatment effect with thrombectomy compared to medical management (pinteraction = 0.042). Conclusion An increased BATMAN score was significantly associated with a higher probability of functional independence after thrombectomy than after medical management, particularly in patients with severe BAO.