Search

Background and Purpose— There is debate over an optimal systolic blood pressure (SBP) in secondary stroke prevention of patients with symptomatic intracranial atherosclerotic stenosis (sICAS). We investigated whether translesional pressure gradient across sICAS would alter the relationship between SBP and risk of recurrent stroke in such patients. Methods— We recruited patients with sICAS (50%–99% stenosis) confirmed in computed tomography angiography. We simulated blood flow across sICAS with computed tomography angiography-based computational fluid dynamics models. Translesional pressure ratio (PR=Pressure post-stenotic /Pressure pre-stenotic ) was calculated in each case. Pressure ratio (PR) ≤ median was defined as low PR, indicating larger translesional pressure gradient across sICAS. All patients received optimal medical treatment. We investigated the interaction of translesional PR and mean SBP during follow-up (SBP FU ) in determining the risk of the primary outcome, recurrent ischemic stroke in the same territory within 1 year. Results— Among 157 patients with sICAS, the median PR was 0.93. Multivariate Cox regression revealed significant PR-SBP FU interaction on the primary outcome ( P =0.008): in patients with normal PR, risk of primary outcome significantly decreased with lower SBP FU (hazard ratio for 10 mm Hg decrement =0.46; P =0.018); however, in those with low PR, SBP FU ≤130 mm Hg was associated with significantly increased risk of primary outcome, compared with 130FU P =0.043). Conclusions— Low SBP level may be associated with increased risk of stroke recurrence in patients with sICAS with a large translesional pressure gradient. Translesional PR by computational fluid dynamics models may yield a promising indicator to guide more individualized blood pressure management in patients with sICAS, warranting future studies.

Background and Purpose— In patients with symptomatic intracranial atherosclerotic stenosis, identifying the underlying stroke mechanisms may inform secondary prevention. We aimed to propose reproducible classification criteria for stroke mechanisms based on routine neuroimaging in symptomatic intracranial atherosclerotic stenosis and explore their clinical implications. Methods— We recruited patients with acute ischemic stroke attributed to 50% to 99% intracranial atherosclerotic stenosis in anterior circulation from 2 centers. Two investigators independently classified probable stroke mechanisms as parent artery atherosclerosis occluding penetrating artery, artery-to-artery embolism, hypoperfusion, and mixed mechanisms, with prespecified criteria based on infarct topography and magnetic resonance/computed tomography angiography. These stroke mechanisms were correlated with features of the patients at baseline and recurrent ischemic stroke in the same territory or relevant transient ischemic attack within 1 year. Results— Among 153 patients recruited, the most common stroke mechanisms were isolated hypoperfusion (35.3%) and mixed mechanism of artery-to-artery embolism and hypoperfusion (37.3%) that was associated with higher incidence of dyslipidemia ( P =0.045) and hypertension ( P =0.033) than patients with other stroke mechanisms. The proposed criteria showed substantial to excellent intrarater and interrater reproducibilities (κ, 0.791–0.908). Overall, 31 patients received interventional treatment of the diseased intracranial artery; 122 received medical treatment, among whom a mixed mechanism of artery-to-artery embolism and hypoperfusion at baseline was associated with higher risk of ischemic stroke in the same territory within 1 year (24.4% versus 7.8%; hazard ratio, 3.40; 95% CI, 1.25–9.20; log-rank P =0.010) than other mechanisms combined. Conclusions— Artery-to-artery embolism and hypoperfusion commonly coexist in ischemic stroke attributed to intracranial atherosclerotic stenosis, which may be associated with higher risk of stroke relapse.

Objective To investigate whether hemodynamic features of symptomatic intracranial atherosclerotic stenosis (sICAS) might correlate with the risk of stroke relapse, using a computational fluid dynamics (CFD) model. Methods In a cohort study, we recruited patients with acute ischemic stroke attributed to 50 to 99% ICAS confirmed by computed tomographic angiography (CTA). With CTA-based CFD models, translesional pressure ratio (PR = pressurepoststenotic /pressureprestenotic ) and translesional wall shear stress ratio (WSSR = WSSstenotic - throat /WSSprestenotic ) were obtained in each sICAS lesion. Translesional PR ≤ median was defined as low PR and WSSR ≥4th quartile as high WSSR. All patients received standard medical treatment. The primary outcome was recurrent ischemic stroke in the same territory (SIT) within 1 year. Results Overall, 245 patients (median age = 61 years, 63.7% males) were analyzed. Median translesional PR was 0.94 (interquartile range [IQR] = 0.87-0.97); median translesional WSSR was 13.3 (IQR = 7.0-26.7). SIT occurred in 20 (8.2%) patients, mostly with multiple infarcts in the border zone and/or cortical regions. In multivariate Cox regression, low PR (adjusted hazard ratio [HR] = 3.16, p = 0.026) and high WSSR (adjusted HR = 3.05, p = 0.014) were independently associated with SIT. Patients with both low PR and high WSSR had significantly higher risk of SIT than those with normal PR and WSSR (risk = 17.5% vs 3.0%, adjusted HR = 7.52, p = 0.004). Interpretation This work represents a step forward in utilizing computational flow simulation techniques in studying intracranial atherosclerotic disease. It reveals a hemodynamic pattern of sICAS that is more prone to stroke relapse, and supports hypoperfusion and artery-to-artery embolism as common mechanisms of ischemic stroke in such patients. Ann Neurol 2019;85:752-764.

Background: Artery-to-artery embolism (AAE) is a common stroke mechanism in patients with symptomatic intracranial atherosclerotic disease (ICAD), which might be associated with a higher risk of recurrent stroke than other stroke mechanisms. We aimed to investigate cerebral hemodynamic features associated with AAE in symptomatic ICAD patients. Methods: Patients with acute, anterior-circulation ischemic stroke attributed to ICAD (50-99% stenosis) confirmed in CT angiography (CTA) were recruited from two teaching hospitals. We classified probable stroke mechanisms as isolated parent artery atherosclerosis occluding penetrating artery (PAO), AAE, hypoperfusion, and mixed mechanisms, based on infarct topography in MRI and ICAD lesion features. CTA-based computational fluid dynamics (CFD) models were built to simulate blood flow across culprit ICAD lesions. Translesional pressure ratio (PR=Pressure post-stenotic /Pressure pre-stenotic ) and translesional wall shear stress ratio (WSSR=WSS stenotic-throat /WSS pre-stenotic ) were calculated, to reflect the relative change of the two hemodynamic metrics across an ICAD lesion. PR ≤ median was defined as low PR, indicating a larger pressure gradient across the lesion; and WSSR ≥ 4 th quartile as high WSSR, indicating elevated WSS upon the lesion. We associated PR and WSSR with presence of AAE as a probable stroke mechanism. Results: Among 99 symptomatic ICAD patients, 44 had AAE as a probable stroke mechanism, 13 with AAE alone and 31 with coexisting hypoperfusion; the remaining patients respectively had isolated PAO (n=18) and isolated hypoperfusion (n=37) as the probable stroke mechanisms. High WSSR was independently associated with AAE (adjusted OR 4.21; 95% CI 1.33-13.26; p=0.014). The significant, positive relationship between high WSSR and higher risk of AAE remained in those with a low PR (adjusted OR 4.01; 95% CI 1.03-15.46; p=0.044), but not in those with a normal PR (p=0.621). Conclusions: High WSS upon ICAD lesions may increase plaque vulnerability and lead to distal embolism, while sustained antegrade flow across the ICAD lesion (normal PR) may help clear the emboli. In secondary prevention of symptomatic ICAD with AAE, impaired cerebral perfusion may be a therapeutic target.

Background and Purpose: Understanding the mechanisms underlying progression/regression of symptomatic intracranial atherosclerotic stenosis (sICAS) will inform secondary prevention of the patients. Focal wall shear stress (WSS) may play an important role, which, however, had seldom been investigated. Methods: Patients with acute ischemic stroke or transient ischemic attack (TIA) attributed to 50% to 99% intracranial atherosclerotic stenosis were recruited. All patients underwent cerebral computed tomography angiography at baseline, and a computational fluid dynamics model was built based on computed tomography angiography to simulate blood flow and quantify WSS in the vicinity of the sICAS lesion. All patients received optimal medical treatment and a second computed tomography angiography at 1 year. The change in the luminal stenosis from baseline to 1 year in sICAS was defined as progression (increased >10%), quiescence (±10%), or regression (decreased >10%). Associations between baseline WSS metrics and sICAS regression were analyzed. Results: Among 39 patients (median age 62 years; 27 males), sICAS luminal stenosis progressed, remained quiescent and regressed in 6 (15.4%), 15 (38.5%), and 18 (46.2%) cases, respectively. A higher maximum WSS and larger high-WSS area, throughout the sICAS lesion or obtained separately in the proximal and distal parts of the lesion, were independently associated with regression of luminal stenosis in sICAS over 1 year. Conclusions: A majority of sICAS lesions regress or stay quiescent in the luminal stenosis over 1 year after stroke under optimal medical treatment, when higher focal WSS may facilitate stenosis regression. Further studies of the effects of hemodynamics including WSS in altering plaque vulnerability and stroke risks are needed.

Background: Tandem stenoses were widely observed in acute stroke cases. High pressure drop and low fractional flow (FF) indicate the risk of ischemia caused by intracranial atherosclerotic stenosis. Low wall shear stress (WSS) and high low-density lipoprotein (LDL) filtration rate indicate the risk of atherosclerotic plaque growth. High WSS is related to the risk of plaque rupture. The hemodynamic parameters (pressure drop, FF, WSS, and LDL filtration rate) could be estimated using computational fluid dynamics (CFD) simulation. Few studies have investigated the hemodynamics of intracranial tandem stenoses. This study aims to estimate the clinical risks of intracranial tandem stenoses using CFD simulation.Methods: With identical radius and length, 4 cylindrical tube models were developed with different stenoses (severity in area: 75% single, 75%-84% tandem, 75%-84%-89% tandem, and 89% single). The pressure drop and FF of each stenosis were derived from static CFD simulation and compared between models. A transient CFD simulation was performed on a patient-specific intracranial arterial model with three (56.2%, 51.3%, and 89.8%) tandem stenoses using boundary conditions derived from patient-specific measurements. For the three stenoses, pressure drop, FF, WSS, and LDL filtration rate were calculated and compared.Results: Independent from other stenoses, 89% single stenosis caused comparable pressure drops in four tube models (difference less than 10%), larger than those of 75%-84% tandem stenoses. 89% stenosis had the lowest FF (less than 0.85). In the patient-specific model, the 56.2% and 51.3% stenoses had pressure drops less than 2mmHg with FFs higher than 0.98, while the 89.8% stenosis caused a pressure drop more than 10mmHg with FF lower than 0.90, where a high WSS belt extended distally. Compared with low WSS (less than 0.5Pa), high LDL filtration rate appeared in smaller areas on arterial wall, with less temporal fluctuations.Conclusions: 1. Tandem stenoses are independent in pressure drop and FF. Pressure drop increases sharply with the severity of stenosis. 2. Compared with low WSS, high LDL filtration rate is more specific and stable in reflecting the risk of intracranial atherosclerotic plaque growth. 3. The risks of both plaque growth and rupture should be considered in severe stenoses.

We investigated whether intermittent theta burst stimulation (iTBS) can improve the spatial cognitive function of rats with hypertension-induced cerebral small vessel disease. To prove our hypothesis, stroke-prone renovascular hypertensive rats (RHRSPs) were treated with iTBS beginning at postoperative week 22. The Morris water maze was performed to assess spatial cognitive function. The expression of the N-methyl-d-aspartate receptor (NMDAR) subunits NR1, NR2A and NR2B, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), p-CaMKIIα and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) in the hippocampus were evaluated by western blot analysis. The distribution of GluR1, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBa-1) in the CA1 and CA3 regions and dentate gyrus (DG) of the hippocampus were evaluated by immunofluorescence analysis. Treatment with iTBS significantly improved the spatial cognitive function of RHRSPs, increased the expression of NR2B, p-CaMKIIα and GluR1 in the hippocampus, and decreased the proliferation of astrocytes and microglia. Our results showed that iTBS treatment had a beneficial effect on the cognitive impairments induced by cerebral small vessel disease, potentially through the activation of the NR2B-CaMKII pathway, an increase in GluR1 expression and the suppression of astrocyte and microglial activation.

Hypertensive white matter lesion (WML) is one of common causes of vascular cognitive impairment. In this study, we aimed to investigate the effect of rosuvastatin on cognitive impairment and its underlying mechanisms in chronic hypertensive rats. From the 8th week after establishment of stroke-prone renovascular hypertensive rats (RHRSPs), rosuvastatin (10 mg/kg) or saline as a control was administrated once daily for consecutive 12 weeks by gastric gavage. Cognitive function was assessed with the Morris water maze test and novel object recognition test. WML was observed by Luxol fast blue staining. Aβ deposits, Claudin-5, Occludin, and ZO-1 were determined by immunofluorescence. After rosuvastatin treatment, the escape latencies were decreased and the time of crossing the hidden platform was increased in the Morris water maze, compared with the vehicle-treated RHRSP group. In a novel object recognition test, the recognition index in the rosuvastatin-treated RHRSP group was significantly larger than that in the vehicle-treated RHRSP group. Rosuvastatin treatment presented with the effects of lower WML grades, higher expression of tight junction proteins Claudin-5, Occludin, and ZO-1 in the corpus callosum, and less Aβ deposits in the cortex and hippocampus. The data suggested that rosuvastatin improved the cognitive function of chronic hypertensive rats partly by attenuating WML and reducing Aβ burden.

We aimed to investigate the roles of antegrade residual flow and leptomeningeal collateral flow in sustaining cerebral perfusion distal to an intracranial atherosclerotic stenosis (ICAS). Patients with apparently normal cerebral perfusion distal to a symptomatic middle cerebral artery (MCA)-M1 stenosis were enrolled. Computational fluid dynamics models were built based on CT angiography to obtain a translesional pressure ratio (PR) to gauge the residual antegrade flow. Leptomeningeal collaterals (LMCs) were scaled on CT angiography. Cerebral perfusion metrics were obtained in CT perfusion maps. Among 83 patients, linear regression analyses revealed that both translesional PR and LMC scale were independently associated with relative ipsilesional mean transit time (rMTT). Subgroup analyses showed that ipsilesional rMTT was significantly associated with translesional PR ( p

Background: Intracranial arterial stenosis (ICAS) is a predominant cause of ischemic stroke in Asia. Changes in the signal intensities (SIs) across ICAS lesions on time-of-flight magnetic resonance angiography (TOF-MRA) have been indicated to partially reflect the hemodynamic significance of the lesions, which we aimed to verify by correlating it with cerebral perfusion features provided by CT perfusion (CTP) imaging. Methods: Ischemic stroke or transient ischemic attack patients with unilateral symptomatic stenosis (≥50%) of intracranial internal carotid artery or middle cerebral artery (MCA) were included in this study. Change of SIs across an ICAS lesion on TOF-MRA was calculated by the distal and proximal SI ratio (SIR). Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) within the MCA territory of ipsilateral and contralateral hemispheres were evaluated on the CTP images at the basal ganglia level. Relative CBV, CBF and MTT were defined as ratios of the values obtained from ipsilateral and contralateral hemispheres. The relationships between SIR and CTP parameters were analyzed. Results: Fifty subjects (74% male, mean age 62) were recruited. Overall, the mean SIR was 0.77 ± 0.17. SIR of ICAS was significantly, linearly and negatively correlated with ipsilateral CBV (r = -0.335, p = 0.017), ipsilateral MTT (r = -0.301, p = 0.034), and ipsilateral/contralateral MTT ratio (r = -0.443, p = 0.001). Conclusions: Diminished SIs distal to ICAS on TOF-MRA might be associated with delayed ipsilateral cerebral perfusion. Changes of the SIs across ICAS lesions on TOF-MRA may be a simple marker to reflect cerebral perfusion changes in patients with symptomatic ICAS.

Background Intracranial arterial stenosis (ICAS) is the dominant cause for ischemic stroke worldwide, with hemodynamic compromise as a crucial contributor. Prolonged perfusion is commonly observed in ICAS patients on CT perfusion (CTP) maps, while the clinical significance of this perfusion pattern has not been elucidated. Method Patients having symptomatic ICAS of 50-99% stenosis with sustained downstream cerebral blood flow (CBF) were enrolled in this study. Prolonged perfusion was defined as increased mean transit time (MTT) in vascular territories of the target ICAS on CTP maps. The primary clinical outcome was recurrence of ipsilateral ischemic stroke, and secondary outcome was any ipsilateral ischemic events at 2 years follow-up. Results Of the 95 patients (median age 61y; 70% males) with symptomatic ICAS, 29 patients (30.5%) had prolonged perfusion. Such delayed perfusion was persistent in a majority of patients according to the 1-year imaging follow-up. The prolongation of cerebral perfusion was associated with subsequent risk for ipsilateral ischemic stroke (HR 7.01; 95% CI 1.86-26.46; p = 0.004), but not for any ipsilateral ischemic events (HR 1.52; 95% CI 0.63-3.68; p = 0.348). Further comparison of perfusion measures showed lower CBF (p = 0.034) and higher MTT (p = 0.064) in patients with recurrent ischemic stroke, but not in those with recurrent transient ischemic attack (TIA). Among patients with recurrent stroke, a majority had multiple infarcts along the borderzone regions. Conclusion In patients with symptomatic ICAS, persistent prolonged cerebral perfusion might contribute to the relapse of ischemic stroke, but not TIA.

Summary Aims Cerebrovascular white matter lesion (WML) is a major subtype of cerebral small vessel disease. Clinical drugs are not available for WML. We investigated whether peroxisome proliferator-activated receptor-γ agonist pioglitazone, with properties of vascular protection and antiinflammation, exerts beneficial effect in hypertensive WML rats. Methods Stroke-prone renovascular hypertensive rats (RHRSP) were treated with pioglitazone for 12 weeks. Morris water maze experiment was conducted to assess cognition. WML was observed by Luxol fast blue staining. Smooth muscle actin-alpha, collagen I, collagen IV, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule-1 were evaluated by immunohistochemistry. Interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in brain and soluble intercellular adhesion molecule-1 (sICAM-1) in serum were detected. Results Pioglitazone significantly attenuated WML in corpus callosum, caudate putamen, external capsule, and internal capsule. Cognitive impairment in RHRSP was ameliorated by pioglitazone. Pioglitazone attenuated arteriolar remodeling and reduced sICAM-1 level in serum. Pioglitazone decreased the proliferation of microglia and astrocyte and lowered the expression of proinflammatory cytokines IL-1β and TNF-α in the white matter. Conclusions Long-term treatment of pioglitazone has beneficial effect on hypertension-induced WML and cognition decline, which may partly through its effect on attenuation of arteriolar remodeling, endothelial activation, and brain inflammation.