In-Silico Trials for Treatment of Acute Ischemic Stroke

Despite improved treatment, a large portion of patients with acute ischemic stroke due to a large vessel occlusion have poor functional outcome. Further research exploring novel treatments and better patient selection has therefore been initiated. The feasibility of new treatments and optimized patient selection are commonly tested in extensive and expensive randomized clinical trials. in-silico trials, computer-based simulation of randomized clinical trials, have been proposed to aid clinical trials. In this white paper, we present our vision and approach to set up in-silico trials focusing on treatment and selection of patients with an acute ischemic stroke. The INSIST project (IN-Silico trials for treatment of acute Ischemic STroke, www.insist-h2020.eu) is a collaboration of multiple experts in computational science, cardiovascular biology, biophysics, biomedical engineering, epidemiology, radiology, and neurology. INSIST will generate virtual populations of acute ischemic stroke patients based on anonymized data from the recent stroke trials and registry, and build on the existing and emerging in-silico models for acute ischemic stroke, its treatment (thrombolysis and thrombectomy) and the resulting perfusion changes. These models will be used to design a platform for in-silico trials that will be validated with existing data and be used to provide a proof of concept of the potential efficacy of this emerging technology. The platform will be used for preliminary evaluation of the potential suitability and safety of medication, new thrombectomy device configurations and methods to select patient subpopulations for better treatment outcome. This could allow generating, exploring and refining relavant hypotheses on potential causal pathways (which may follow from the evidence obtained from clinical trials) and improving clinical trial design. Importantly, the findings of the in-silico trials will require validation under the controlled settings of randomized clinical trials

Limitations of Quantitative Blush Evaluator (QuBE) as myocardial perfusion assessment method on digital coronary angiograms

Background and Aim: Quantitative Blush Evaluator (QuBE) is a software application that allows quantifying myocardial perfusion in coronary angiograms after a percutaneous coronary intervention. QuBE has some limitations such as the application of a crude filter to remove large scale structures and the absence of correction for cardiac motion. This study investigates the extent of these limitations and we hypothesize that enhanced image analysis methods can provide improvements. Methods: We calculated QuBE scores of 117 patients from the HEBE Trial and determined its association with the Myocardial Blush Grade (MBG) score. Accuracy of large-structure removal is qualitatively assessed for various sizes of a median filter. The influence of cardiac motion was evaluated by comparing the blush curve and QuBE score of the native QuBE with manually motion-corrected QuBE for 40 patients. The effect of different kernel sizes and motion correction to a potential improvement of the association between QuBE score and MBG was studied. Results: In our population, there was no significant association between QuBE score and MBG (p = 0.14). Median filters of various kernel sizes were unable to remove large structure related noise. Variations in filters and cardiac movement correction did not result in an improvement in the association with MBG scores (observer 1: p = 0.66; observer 2: p = 0.72). Conclusions: There was no significant association of QuBE with MBG scores in our population, which suggests that QuBE is not suitable for a quantitative assessment of myocardial perfusion. Alternative kernel sizes for the large structure removal filter and cardiac motion correction did not improve QuBE performance. Relevance for patients: Further improvements of QuBE to overcome its inherent limitations are necessary in order to establish QuBE as a reliable myocardial perfusion assessment method

Coupling one-dimensional arterial blood flow to three-dimensional tissue perfusion models for in silico trials of acute ischaemic stroke

An acute ischaemic stroke is due to the sudden blockage of an intracranial blood vessel by an embolized thrombus. In the context of setting up in silico trials for the treatment of acute ischaemic stroke, the effect of a stroke on perfusion and metabolism of brain tissue should be modelled to predict final infarcted brain tissue. This requires coupling of blood flow and tissue perfusion models. A one-dimensional intracranial blood flow model and a method to couple this to a brain tissue perfusion model for patient-specific simulations is presented. Image-based patient-specific data on the anatomy of the circle of Willis are combined with literature data and models for vessel anatomy not visible in the images, to create an extended model for each patient from the larger vessels down to the pial surface. The coupling between arterial blood flow and tissue perfusion occurs at the pial surface through the estimation of perfusion territories. The coupling method is able to accurately estimate perfusion territories. Finally, we argue that blood flow can be approximated as steady-state flow at the interface between arterial blood flow and tissue perfusion to reduce the cost of organ-scale simulations

Posttreatment Ischemic Lesion Evolution Is Associated With Reduced Favorable Functional Outcome in Patients With Stroke

BACKGROUND AND PURPOSE: Ischemic lesion volume can increase even 24 hours after onset of an acute ischemic stroke. In this study, we investigated the association of lesion evolution with functional outcome and the influence of successful recanalization on this association. METHODS: We included patients from the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) who received good quality noncontrast CT images 24 hours and 1 week after stroke onset. The ischemic lesion delineations included infarct, edema, and hemorrhagic transformation. Lesion evolution was defined as the difference between the volumes measured on the 1-week and 24-hour noncontrast CTs. The association of lesion evolution with functional outcome was evaluated using unadjusted and adjusted logistic regression. Adjustments were made for baseline, clinical, and imaging parameters that were associated P<0.10) in univariate analysis with favorable functional outcome, defined as modified Rankin Scale score of ≤2. Interaction analysis was performed to evaluate the influence of successful recanalization, defined as modified Arterial Occlusion Lesion score of 3 points, on this association. RESULTS: Of the 226 patients who were included, 69 (31%) patients achieved the favorable functional outcome. Median lesion evolution was 22 (interquartile range, 10–45) mL. Lesion evolution was significantly inversely correlated with favourable functional outcome: unadjusted odds ratio, 0.76 (95% CI, 0.66–0.86; per 10 mL of lesion evolution; P<0.01) and adjusted odds ratio: 0.85 (95% CI, 0.72–0.97; per 10 mL of lesion evolution; P=0.03). There was no significant interaction of successful recanalization on the association of lesion evolution and favorable functional outcome (odds ratio, 1.01 [95% CI, 0.77–1.36]; P=0.94). CONCLUSIONS: In our population, subacute ischemic lesion evolution is associated with unfavorable functional outcome. This study suggests that even 24 hours after onset of stroke, deterioration of the brain continues, which has a negative effect on functional outcome. This finding may warrant additional treatment in the subacute phase

Risk factors of late lesion growth after acute ischemic stroke treatment

BackgroundEven days after treatment of acute ischemic stroke due to a large vessel occlusion, the infarct lesion continues to grow. This late, subacute growth is associated with unfavorable functional outcome. In this study, we aim to identify patient characteristics that are risk factors of late, subacute lesion growth. MethodsPatients from the MR CLEAN trial cohort with good quality 24 h and 1-week follow up non-contrast CT scans were included. Late Lesion growth was defined as the difference between the ischemic lesion volume assessed after 1-week and 24-h. To identify risk factors, patient characteristics associated with lesion growth (categorized in quartiles) in univariable ordinal analysis (p < 0.1) were included in a multivariable ordinal regression model. ResultsIn the 226 patients that were included, the median lesion growth was 22 (IQR 10-45) ml. In the multivariable model, lower collateral capacity [aOR: 0.62 (95% CI: 0.44-0.87); p = 0.01], longer time to treatment [aOR: 1.04 (1-1.08); p = 0.04], unsuccessful recanalization [aOR: 0.57 (95% CI: 0.34-0.97); p = 0.04], and larger midline shift [aOR: 1.18 (95% CI: 1.02-1.36); p = 0.02] were associated with late lesion growth. ConclusionLate, subacute, lesion growth occurring between 1 day and 1 week after ischemic stroke treatment is influenced by lower collateral capacity, longer time to treatment, unsuccessful recanalization, and larger midline shift. Notably, these risk factors are similar to the risk factors of acute lesion growth, suggesting that understanding and minimizing the effects of the predictors for late lesion growth could be beneficial to mitigate the effects of ischemia

Sex differences in clot, vessel and tissue characteristics in patients with a large vessel occlusion treated with endovascular thrombectomy

Introduction: To improve our understanding of the relatively poor outcome after endovascular treatment (EVT) in women we assessed possible sex differences in baseline neuroimaging characteristics of acute ischemic stroke patients with large anterior vessel occlusion (LVO). Patients and methods: We included all consecutive patients from the MR CLEAN Registry who underwent EVT between 2014 and 2017. On baseline non-contrast CT and CT angiography, we assessed clot location and clot burden score (CBS), vessel characteristics (presence of atherosclerosis, tortuosity, size, and collateral status), and tissue characteristics with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Radiological outcome was assessed with the extended thrombolysis in cerebral infarction score (eTICI) and functional outcome with the modified Rankin Scale score (mRS) at 90 days. Sex-differences were assessed with multivariable regression analyses with adjustments for possible confounders. Results: 3180 patients were included (median age 72 years, 48% women). Clots in women were less often located in the intracranial internal carotid artery (ICA) (25%vs 28%, odds ratio (OR) 0.85;95% confidence interval: 0.73–1.00). CBS was similar between sexes (median 6, IQR 4–8). Intracranial (aOR 0.73;95% CI:0.62–0.87) and extracranial (aOR 0.64;95% CI:0.43–0.95) atherosclerosis was less prevalent in women. Vessel tortuosity was more frequent in women in the cervical ICA (aOR 1.89;95% CI:1.39–2.57) and women more often had severe elongation of the aortic arch (aOR 1.38;95% CI:1.00–1.91). ICA radius was smaller in women (2.3vs 2.5 mm, mean difference 0.22;95% CI:0.09–0.35) while M1 radius was essentially equal (1.6vs 1.7 mm, mean difference 0.09;95% CI:−0.02–0.21). Women had better collateral status (⩾50% filling in 62%vs 53% in men, aOR 1.48;95% CI:1.29–1.70). Finally, ASPECT scores were equal between women and men (median 9 in both sexes, IQR 8–10vs 9–10). Reperfusion rates were similar between women and men (acOR 0.94;95% CI:0.83–1.07). However, women less often reached functional independence than men (34%vs 46%, aOR 0.68;95% CI:0.53–0.86). Discussion and conclusion: On baseline imaging of this Dutch Registry, men and women with LVO mainly differ in vessel characteristics such as atherosclerotic burden, extracranial vessel tortuosity, and collateral status. These sex differences do not result in different reperfusion rates and are, therefore, not likely to explain the worse functional outcome in women after EVT.</p

Association of thrombus density and endovascular treatment outcomes in patients with acute ischemic stroke due to M1 occlusions

PURPOSE: We aimed to study the association of non-contrast CT (NCCT) thrombus density with procedural and clinical outcomes in patients with acute ischemic stroke who underwent endovascular treatment (EVT). Since thrombus density is associated with thrombus location, we focused on M1 occlusions only.METHODS: Patients with available thin-slice (&lt; 2.5 mm) NCCT were included from a nationwide registry. Regression models were used to assess the relation between thrombus density (per Hounsfield unit [HU]) and the following outcomes. For reperfusion grade, adjusted common odds ratios (acOR) indicated a 1-step shift towards improved outcome per HU increase in thrombus density. For the binary outcomes of first-pass reperfusion (first-pass extended thrombolysis in cerebral infarction [eTICI] 2C-3, FPR), functional independence [90-day modified Rankin Scale (mRS) score of 0-2] and mortality), aORs were reported. Adjusted β coefficients (aβ) were reported for 24-h NIHSS and procedure duration in minutes. Outcome differences between first-line treatment devices (stent retriever versus aspiration) were assessed with interaction terms.RESULTS: In 566 patients with M1 occlusions, thrombus density was not associated with reperfusion (acOR 1.01, 95% CI 0.99-1.02), FPR (aOR 1.01, 95% CI 0.99-1.03), mortality (aOR 0.98, 95% CI 0.95-1.00), 24-h NIHSS (aβ - 0.7%, 95% CI - 1.4-0.2), or procedure duration (aβ 0.27, 95% CI - 0.05-0.58). In multivariable analysis, thrombus density was associated with functional independence (aOR 1.02, 95% CI 1.00-1.05). No interaction was found between thrombus density and first-line treatment device for any outcome.CONCLUSION: In patients with M1 occlusions, thrombus density was not clearly associated with procedural and clinical outcomes after EVT.</p

Sex differences in clot, vessel and tissue characteristics in patients with a large vessel occlusion treated with endovascular thrombectomy

Introduction: To improve our understanding of the relatively poor outcome after endovascular treatment (EVT) in women we assessed possible sex differences in baseline neuroimaging characteristics of acute ischemic stroke patients with large anterior vessel occlusion (LVO). Patients and methods: We included all consecutive patients from the MR CLEAN Registry who underwent EVT between 2014 and 2017. On baseline non-contrast CT and CT angiography, we assessed clot location and clot burden score (CBS), vessel characteristics (presence of atherosclerosis, tortuosity, size, and collateral status), and tissue characteristics with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Radiological outcome was assessed with the extended thrombolysis in cerebral infarction score (eTICI) and functional outcome with the modified Rankin Scale score (mRS) at 90 days. Sex-differences were assessed with multivariable regression analyses with adjustments for possible confounders. Results: 3180 patients were included (median age 72 years, 48% women). Clots in women were less often located in the intracranial internal carotid artery (ICA) (25%vs 28%, odds ratio (OR) 0.85;95% confidence interval: 0.73–1.00). CBS was similar between sexes (median 6, IQR 4–8). Intracranial (aOR 0.73;95% CI:0.62–0.87) and extracranial (aOR 0.64;95% CI:0.43–0.95) atherosclerosis was less prevalent in women. Vessel tortuosity was more frequent in women in the cervical ICA (aOR 1.89;95% CI:1.39–2.57) and women more often had severe elongation of the aortic arch (aOR 1.38;95% CI:1.00–1.91). ICA radius was smaller in women (2.3vs 2.5 mm, mean difference 0.22;95% CI:0.09–0.35) while M1 radius was essentially equal (1.6vs 1.7 mm, mean difference 0.09;95% CI:−0.02–0.21). Women had better collateral status (⩾50% filling in 62%vs 53% in men, aOR 1.48;95% CI:1.29–1.70). Finally, ASPECT scores were equal between women and men (median 9 in both sexes, IQR 8–10vs 9–10). Reperfusion rates were similar between women and men (acOR 0.94;95% CI:0.83–1.07). However, women less often reached functional independence than men (34%vs 46%, aOR 0.68;95% CI:0.53–0.86). Discussion and conclusion: On baseline imaging of this Dutch Registry, men and women with LVO mainly differ in vessel characteristics such as atherosclerotic burden, extracranial vessel tortuosity, and collateral status. These sex differences do not result in different reperfusion rates and are, therefore, not likely to explain the worse functional outcome in women after EVT.</p

A simplified mesoscale 3D model for characterizing fibrinolysis under flow conditions

One of the routine clinical treatments to eliminate ischemic stroke thrombi is injecting a biochemical product into the patient’s bloodstream, which breaks down the thrombi’s fibrin fibers: intravenous or intravascular thrombolysis. However, this procedure is not without risk for the patient; the worst circumstances can cause a brain hemorrhage or embolism that can be fatal. Improvement in patient management drastically reduced these risks, and patients who benefited from thrombolysis soon after the onset of the stroke have a significantly better 3-month prognosis, but treatment success is highly variable. The causes of this variability remain unclear, and it is likely that some fundamental aspects still require thorough investigations. For that reason, we conducted in vitro flow-driven fibrinolysis experiments to study pure fibrin thrombi breakdown in controlled conditions and observed that the lysis front evolved non-linearly in time. To understand these results, we developed an analytical 1D lysis model in which the thrombus is considered a porous medium. The lytic cascade is reduced to a second-order reaction involving fibrin and a surrogate pro-fibrinolytic agent. The model was able to reproduce the observed lysis evolution under the assumptions of constant fluid velocity and lysis occurring only at the front. For adding complexity, such as clot heterogeneity or complex flow conditions, we propose a 3-dimensional mesoscopic numerical model of blood flow and fibrinolysis, which validates the analytical model’s results. Such a numerical model could help us better understand the spatial evolution of the thrombi breakdown, extract the most relevant physiological parameters to lysis efficiency, and possibly explain the failure of the clinical treatment. These findings suggest that even though real-world fibrinolysis is a complex biological process, a simplified model can recover the main features of lysis evolution.</p

A Planning Tool for Left Ventricular Reconstruction in Patients with Severe Ischemic Cardiomyopathy

Surgical ventricular reconstruction aims to restore the ideal left ventricular geometry and function and is used as a treatment modality for patients with severe ischemic cardiomyopathy. This study addresses the clinical need for in-silico modelling to estimate the effect of left ventricular reconstruction through Revivent Myocardial Anchoring System on the function and geometry of the residual left ventricle. The planning tool developed in this study corrects for slice misalignment produced due to breathing motion and patient movement during Cardiac MR image acquisition. The extent and the location of the scar are identified on the contrast enhanced Cardiac MR images and subsequently used to classify the left ventricular short axis contour points into scarred and healthy segments. The reconstruction surgery is simulated by estimating each short axis contour of the residual LV as a circle obtained from the healthy segment. Functional analysis consisted of comparing the simulated residual left ventricular volumes at end-diastolic and end-systolic phase, stroke volume and ejection fraction with the baseline characteristics. Geometrical analysis consisted of quantifying the occlusion of the Right Ventricular Outflow Tract by the plicated scar and comparing the curvedness values of the residual LV with two geometrical models - Modified Simpson’s Model and Biplane Ellipsoid model. The required functional end-points are met for all four patients. A more localized approach is required for the geometrical analysis. The presented approach shows promising results but needs to be clinically validated by comparing with a larger database of post surgical scans to obtain higher accuracy and a more comprehensive understanding of the surgery.Biomedical Engineerin