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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.

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.

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.

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.

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.

BackgroundThe efficacy of external counterpulsation (ECP) on coronary collateral growth has not been investigated in a randomised controlled study.ObjectiveTo test the hypothesis that ECP augments collateral function during a 1 min coronary balloon occlusion.Patients and methodsTwenty patients with chronic stable coronary artery disease were studied. Before and after 30 h of randomly allocated ECP (20 90 min sessions over 4 weeks at 300 mm Hg inflation pressure) or sham ECP (same setting at 80 mm Hg inflation pressure), the invasive collateral flow index (CFI, no unit) was obtained in 34 vessels without coronary intervention. CFI was determined by the ratio of mean distal coronary occlusive pressure to mean aortic pressure with central venous pressure subtracted from both. Additionally, coronary collateral conductance (occlusive myocardial blood flow per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography, and brachial artery flow-mediated dilatation was obtained.ResultsCFI changed from 0.125 (0.073; interquartile range) at baseline to 0.174 (0.104) at follow-up in the ECP group (p=0.006), and from 0.129 (0.122) to 0.111 (0.125) in the sham ECP group (p=0.14). Baseline to follow-up change of coronary collateral conductance was from 0.365 (0.268) to 0.568 (0.585) ml/min/100 mm Hg in the ECP group (p=0.072), and from 0.229 (0.212) to 0.305 (0.422) ml/min/100 mm Hg in the sham ECP group (p=0.45). There was a correlation between the flow-mediated dilatation change from baseline to follow-up and the corresponding CFI change (r=0.584, p=0.027).ConclusionsECP appears to be effective in promoting coronary collateral growth. The extent of collateral function improvement is related to the amount of improvement in the systemic endothelial function.

ObjectivesRemote ischaemic conditioning (RIC) confers cardioprotection in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). We investigated whether preinfarction angina and coronary collateral blood flow (CCBF) to the infarct-related artery modify the efficacy of RIC.DesignPost hoc subgroup analysis of a randomised controlled trial.ParticipantsA total of 139 patients with STEMI randomised to treatment with pPCI or RIC+pPCI.InterventionsRIC was performed prior to pPCI as four cycles of 5 min upper arm ischaemia and reperfusion with a blood pressure cuff.Primary outcome measureMyocardial salvage index (MSI) assessed by single-photon emission computerised tomography. We evaluated the efficacy of RIC in subgroups of patients with or without preinfarction angina or CCBF.ResultsOf 139 patients included in the study, 109 had available data for preinfarction angina status and 54 had preinfarction angina. Among 83 patients with Thrombolysis In Myocardial Infarction flow 0/1 on arrival, 43 had CCBF. Overall, RIC+pPCI increased median MSI compared with pPCI alone (0.75 vs 0.56, p=0.045). Mean MSI did not differ between patients with and without preinfarction angina in either the pPCI alone (0.58 and 0.57; 95% CI −0.17 to 0.19, p=0.94) or the RIC+pPCI group (0.66 and 0.69; 95% CI −0.18 to 0.10, p=0.58). Mean MSI did not differ between patients with and without CCBF in the pPCI alone group (0.51 and 0.55; 95% CI −0.20 to 0.13, p=0.64), but was increased in patients with CCBF versus without CCBF in the RIC+pPCI group (0.75 vs 0.58; 95% CI 0.03 to 0.31, p=0.02; effect modification from CCBF on the effect of RIC on MSI, p=0.06).ConclusionsPreinfarction angina did not modify the efficacy of RIC in patients with STEMI undergoing pPCI. CCBF to the infarct-related artery seems to be of importance for the cardioprotective efficacy of RIC.Trial registration numberNCT00435266, Post-results.

Objective: With routine use of non-invasive methods to assess the internal carotid artery, it becomes increasingly important to clarify the diagnostic accuracy of transcranial Doppler (TCD) ultrasound and magnetic resonance angiography (MRA) compared with intra-arterial digital subtraction angiography (iaDSA) for the detection of collateral flow via the major intracerebral collateral branches. Subjects and Methods: In a prospective study, we compared TCD via a temporal bone window and MRA (flow direction sensitive phase contrast and time of flight) examinations of the intracranial collateral flow with iaDSA in a cohort of 97 consecutive patients with recent transient or minor disabling cerebral ischaemia associated with an occlusion of the carotid artery (38 contralateral stenosis >70%). Results: iaDSA allowed the evaluation of collateral flow via the anterior and posterior circle of Willis in 97 and 67 patients, respectively, TCD in 76 of 97 and 66 of 67 patients, MRA in 95 of 97 and 66 of 67 patients. MRA and TCD collateral flow measurements via the anterior part of the circle of Willis yielded a sensitivity of 83 and 82%, a specificity of 77 and 79% and a similar accuracy of 80%. MRA and TCD collateral flow measurements via the posterior communicating artery yielded a sensitivity of 33 and 76%, a specificity of 88 and 47% and an accuracy of 47 and 68%. Conclusion: As compared with iaDSA, combined MRA and TCD has a moderate to good diagnostic value for the examination of intracranial collateral flow in patients with symptomatic carotid occlusion.

Ischaemic stroke results from acute arterial occlusion leading to focal hypoperfusion. Thrombolysis is the only proven treatment. Advanced neuroimaging techniques allow a detailed assessment of the cerebral circulation in patients with acute stroke, and provide information about the status of collateral vessels and collateral blood flow, which could attenuate the effects of arterial occlusion. Imaging of the brain and vessels has shown that collateral flow can sustain brain tissue for hours after the occlusion of major arteries to the brain, and the augmentation or maintenance of collateral flow is therefore a potential therapeutic target. Several interventions that might augment collateral blood flow are being investigated.