Patients with symptomatic intracranial atherosclerosis (ICAS) of ≥ 70% luminal stenosis are at high risk of stroke recurrence. We aimed to evaluate the relationships between hemodynamics of ICAS ...revealed by computational fluid dynamics (CFD) models and risk of stroke recurrence in this patient subset.
Patients with a symptomatic ICAS lesion of 70-99% luminal stenosis were screened and enrolled in this study. CFD models were reconstructed based on baseline computed tomographic angiography (CTA) source images, to reveal hemodynamics of the qualifying symptomatic ICAS lesions. Change of pressures across a lesion was represented by the ratio of post- and pre-stenotic pressures. Change of shear strain rates (SSR) across a lesion was represented by the ratio of SSRs at the stenotic throat and proximal normal vessel segment, similar for the change of flow velocities. Patients were followed up for 1 year.
Overall, 32 patients (median age 65; 59.4% males) were recruited. The median pressure, SSR and velocity ratios for the ICAS lesions were 0.40 (-2.46-0.79), 4.5 (2.2-20.6), and 7.4 (5.2-12.5), respectively. SSR ratio (hazard ratio HR 1.027; 95% confidence interval CI, 1.004-1.051; P = 0.023) and velocity ratio (HR 1.029; 95% CI, 1.002-1.056; P = 0.035) were significantly related to recurrent territorial ischemic stroke within 1 year by univariate Cox regression, respectively with the c-statistics of 0.776 (95% CI, 0.594-0.903; P = 0.014) and 0.776 (95% CI, 0.594-0.903; P = 0.002) in receiver operating characteristic analysis.
Hemodynamics of ICAS on CFD models reconstructed from routinely obtained CTA images may predict subsequent stroke recurrence in patients with a symptomatic ICAS lesion of 70-99% luminal stenosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetic lesions that reduce telomerase activity inhibit stem cell replication and cause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF). Modalities to ...restore telomerase in stem cells throughout the body remain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstrate telomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomerase RNA component (TERC). We identified BCH001, a specific PAPD5 inhibitor that restored telomerase activity and telomere length in DC patient induced pluripotent stem cells. When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with a repurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3′ end maturation and telomere length. These findings pave the way for developing systemic telomere therapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-related diseases.
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•High-throughput screening identifies specific small-molecule PAPD5 inhibitor BCH001•BCH001 restores telomere length in iPSCs from patients with dyskeratosis congenita•Repurposed HBsAg suppressors, dihydroquinolizinones, increase TERC in stem cells•Oral PAPD5 inhibitors restore TERC and telomeres in human HSPCs in vivo
Nagpal et al. identify small-molecule inhibitors of PAPD5, a non-canonical polymerase, as regulators of the telomerase RNA component TERC. PAPD5 inhibitors restore telomere length in cells from patients with genetic “telomeropathies” and human blood stem cells xenotransplanted into mice, providing a therapeutic strategy to manipulate telomerase systemically.
Exacerbation of hepatitis B virus (HBV) is a serious cause of morbidity and mortality in hepatitis B surface antigen (HBsAg)-positive patients undergoing transplantation. Our aim was to evaluate the ...effectiveness of lamivudine to prevent hepatitis due to exacerbation of HBV in HBsAg-positive patients treated with allogeneic hematopoietic cell transplantation. We studied 20 consecutive HBsAg-positive recipients of allogeneic hematopoietic cell transplantation who received lamivudine 100 mg daily starting one week before transplantation until week 52 after transplantation (group 1). Serial serum alanine aminotransferase and HBV DNA levels were measured before and after transplantation at 4- to 8-week intervals for the first year and then 4- to 12-week intervals. Their virologic and clinical outcomes were compared with 20 case-matched recipients who did not receive any antiviral therapy to HBV (anti-HBV) before and after hematopoietic cell transplantation (group 2). After transplantation, 9 patients (45%) in group 2 and one patient (5%) in group 1 had hepatitis due to exacerbation of HBV (
P < .008), with 3 hepatic failures in group 2 and none in group 1. The one-year actuarial probability of survival without hepatitis due to exacerbation of HBV was higher in group 1 than group 2 (94.1% vs. 54.3%,
P = .002). By multivariate Cox analysis, preemptive use of lamivudine effectively reduced hepatitis due to exacerbation of HBV (adjusted hazards ratio, 0.09;
P = .021). In conclusion, preemptive lamivudine reduced HBV exacerbation. The use of lamivudine with other immunosuppressive regimens to prevent exacerbation of HBV should be further explored. H
EPATOLOGY 2002;36:702-709.)
ABSTRACT
BACKGROUND AND PURPOSE
Fractional flow may identify hemodynamic effects and ischemic risk beyond percent stenosis of an artery. We hypothesized that diminished TOF‐MRA signal intensity ...distal to an intracranial stenosis predicts stroke risk.
METHODS
TOF‐MRA was acquired prospectively in the SONIA‐WASID trials. The distal/proximal signal intensity ratio (SIR) was calculated from 3 mm regions of interest, blinded to outcome. Univariate and multivariate analyses included clinical variables, SIR, and invasive angiography measures to identify predictors for risk of stroke in the territory.
RESULTS
189 patients with 50‐99% symptomatic intracranial stenosis in SONIA‐WASID had TOF‐MRA available. In univariate analysis, the hazard ratio (HR) for stroke in the territory of the symptomatic artery with SIR < .9 was 5.2 (1.8, 15.3; P < .001) as compared to SIR ≥ .9. Multivariate analysis correcting for baseline systolic blood pressure, LDL, centrally measured percent stenosis, recency of symptoms, TICI and downstream collaterals, the HR for SIR < .9 was 10.9 (2.0, 58.9; P < .001). In those with <70% stenosis, a SIR < .9 maintained a significant association with recurrent stroke in the territory (P = .006), with a 2‐year event rate of 17.3%.
CONCLUSIONS
Fractional flow assessed by TOF‐MRA SIR may be a useful noninvasive tool to identify high‐risk intracranial lesions.
CLINICAL TRIAL REGISTRATION‐URL
This trial was not registered because enrollment began prior to July 1, 2005.
Advanced neuroimaging techniques may improve patient selection for endovascular stroke treatment but may also delay time to reperfusion. We studied the effect of advanced modality imaging with CT ...perfusion (CTP) or MRI compared with non-contrast CT (NCT) in a multicenter cohort.
This is a retrospective study of 10 stroke centers who select patients for endovascular treatment using institutional protocols. Approval was obtained from each institution's review board as only de-identified information was used. We collected demographic and radiographic data, selected time intervals, and outcome data. ANOVA was used to compare the groups (NCT vs CTP vs MRI). Binary logistic regression analysis was performed to determine factors associated with a good clinical outcome.
556 patients were analyzed. Mean age was 66 ± 15 years and median National Institutes of Health Stroke Scale score was 18 (IQR 14-22). NCT was used in 286 (51%) patients, CTP in 190 (34%) patients, and MRI in 80 (14%) patients. NCT patients had significantly lower median times to groin puncture (61 min, IQR (40-117)) compared with CTP (114 min, IQR (81-152)) or MRI (124 min, IQR (87-165)). There were no differences in clinical outcomes, hemorrhage rates, or final infarct volumes among the groups.
The current retrospective study shows that multimodal imaging may be associated with delays in treatment without reducing hemorrhage rates or improving clinical outcomes. This exploratory analysis suggests that prospective randomised studies are warranted to support the hypothesis that advanced modality imaging is superior to NCT in improving clinical outcomes.
Abstract only Background: Pressure gradients across an intracranial stenosis, or fractional flow (FF), may identify the hemodynamic significance of symptomatic lesions. Computational fluid dynamic ...(CFD) simulations on 3D morphology of such lesions can calculate these pressure gradients and model effects of systemic physiology interacting with these lesions, such as hypotension and induced hypertension. We studied SAMMPRIS angiography to calculate FF across symptomatic intracranial stenoses and modeled the downstream effect of systemic blood pressure (BP) fluctuations. Methods: Conventional angiography of symptomatic intracranial stenoses in the SAMMPRIS trial was converted from biplanar images to a 3D geometric mesh. CFD simulations were conducted with Ansys CFX on a Cray supercomputer to calculate FF derived from distal/proximal pressure gradients for each of 3 inflow conditions: normal BP (120/80 mm Hg), hypotension (90/60 mm Hg) and hypertension (180/120 mm Hg). Abnormal FF was defined as ≤ 0.8 during diastole to define hemodynamic significance of a stenosis. Results: 407 patients with 70-99% symptomatic stenosis had conventional angiography with biplanar views available for 3D reconstruction in 249, and CFD simulations in 188 (25 VA, 45 BA, 32 ICA, 86 MCA). Under simulated normal inflow conditions (120/80 mm Hg), only 76/188 (40%) cases had low FF. During simulated hypertension, FF improved to normal in 10/188 (5%) cases. Simulated hypotension caused FF to worsen from normal in 12/188 (6%) cases. Other hemodynamic parameters including shear stress could also be calculated and visually depicted in all cases. Conclusions: CFD and hemodynamic modeling of FF can be retrospectively performed after 3D conversion of biplanar angiogram views. FF estimates predict that only 40% of severe (70-99%) symptomatic intracranial stenoses are hemodynamically significant. Systemic BP fluctuations can be modeled during phases of the cardiac cycle to show downstream flow changes.
Abstract only Background: Intracranial stenosis carries a high risk of recurrent stroke, but there is no noninvasive method to identify high-risk lesions. Fractional flow, or the pressure gradient ...across a stenosis, may identify hemodynamic effects and ischemic risk beyond percent stenosis of an artery. TOF-MRA signal intensity correlates with blood flow and may serve as a useful, noninvasive risk marker. We hypothesized that diminished TOF-MRA signal intensity distal to an intracranial stenosis predicts stroke risk. Methods: TOF-MRA of the intracranial circulation acquired prospectively in the SONIA-WASID trials was digitized to enable measurement of relative signal intensity immediately distal and proximal to symptomatic intracranial stenoses. The distal/proximal signal intensity ratio (SIR) was calculated from 3 mm regions of interest distal and proximal to symptomatic stenoses, correcting for background intensity and blinded to outcome. Univariate and multivariate analyses included clinical variables, SIR, and invasive angiography measures (luminal stenosis, TICI, collateral grade) to identify predictors for risk of stroke in the territory in this SONIA-WASID cohort. Results: 189 patients with site-based 50-99% symptomatic intracranial stenosis in SONIA-WASID had TOF-MRA available. In a univariate analysis, the hazard ratio (HR) for stroke in the territory of the symptomatic artery with SIR < 0.9 (i.e. SIR below median) was 5.2 (1.8, 15.3; p=0.001) as compared to SIR ≥ 0.9. In a multivariate analysis correcting for baseline blood pressure, LDL, percent stenosis, recency of symptoms, TICI and downstream collaterals, the HR for SIR < 0.9 was 10.9 (2.0, 58.9; p=0.001). Only collaterals also had a significant independent association with stroke risk, HR 13.8 (3.4, 55.5; p<0.001). In the subset of patients with < 70% stenosis, a SIR < 0.9 maintained a significant association with recurrent stroke in the territory (p=0.006), with a two year event rate of 17.3%. Conclusions: Fractional flow assessed by TOF-MRA SIR may be a useful noninvasive tool to identify high-risk intracranial lesions, even in patients with moderate (< 70%) degrees of stenosis, and may be suitable for selection of high-risk patients for clinical trials or aggressive treatments.
Abstract only Background: Partial aortic occlusion may increase global cerebral blood volume (CBV) to enhance collateral perfusion in acute ischemic stroke. Therapeutic CBV changes in the ischemic ...territory may be difficult to detect with standard techniques if superimposed on global CBV alterations. We used CBV gradient maps to evaluate perfusion augmentation in the ischemic territory on serial MRI from baseline to 6 hours follow-up in subjects randomized to medical therapy with or without NeuroFlo treatment in the SENTIS trial. Methods: Perfusion MRI datasets in 54 subjects acquired at both baseline and 6 hours were prospectively collected at the core lab. Post-processing yielded CBV images and corresponding CBV gradient maps that depict regional variation of this perfusion parameter. Blinded imaging expert review was conducted to document presence, location, and other features of CBV gradients, with description of serial changes. Serial changes in CBV gradient maps were analyzed with respect to baseline demographics, medical history, treatment arm, and clinical outcomes (modified Rankin Scale, mRS) at day 90. Results: CBV gradient maps could be generated in 51 subjects with paired perfusion MRIs. CBV gradients were evident in 33/51 subjects (64.7%) at baseline, predominantly involving peripheral regions of the MCA territory. The presence of CBV gradients at baseline did not differ based on demographics, medical history, or treatment allocation. Overall, 12.1% revealed unchanged CBV gradients from baseline to 6 hours, with worsening in 18.2% and improvements in 69.7%. Alterations of CBV gradients on serial MRI were not related to baseline demographics or medical history in this cohort. Device therapy, however, was significantly associated with improvement of CBV gradients (p=0.005). Such early improvement in perfusion immediately post-procedure did not translate into statistically improved clinical outcomes (mRS 0-2) at day 90. Conclusions: CBV gradient maps can depict evolution of ischemia in acute stroke and therapeutic interventions such as perfusion augmentation. Treatment with the NeuroFlo device may improve perfusion in acute stroke, although other factors may subsequently influence clinical outcomes at day 90.
Abstract only Background: Current use of CT angiography (CTA) for intracranial atherosclerosis (ICAD) focuses solely on measurement of maximal degree in isolated stenosis, a parameter that poorly ...predicts subsequent stroke. Noninvasive modeling with computational fluid dynamics (CFD) measures hemodynamic impact of stenoses based on fractional flow. We tested a novel method to compare anatomy- and CFD-based hemodynamics. Methods: A geometric mesh of ICAD lesions was derived from CTA. Semi-automated seed placement and centerline calculation across stenotic segments was used to automatically identify luminal stenoses, tandem lesions, plaque length and associated volumes. Fractional flow, the pressure drop across lesions, was calculated and compared to CFD-derived values using Ansys CFX and CFD-post, with boundary conditions for laminar flow. Results: CTA of 73 patients (mean age 72.7 ± 10.2 years; 58% men) with recently symptomatic ICAD were analyzed by semi-automated anatomical measures and CFD. Lesions included 45 M1, 14 ICA, 11 Bas and 3 VA intracranial lesions with median stenosis of 62.0% (40-93). Median plaque length was 12.2 (2.9-29.9) mm. Total plaque volumes measured median 75.1 (19.2-325.3) mm 3 with focal stenoses accounting for 40.0 (6.3-168.5) mm 3 . Pressure drop across the lesion calculated anatomically based on maximal stenosis averaged 34.7% (IQR 18.1-76.9) and 12.7% (IQR 5.0-40.2), the latter accounting for plaque length. These correlated moderately with fractional flow measured by CFD (ρ=0.545 and ρ=0.561, respectively). Plaque volumes of the entire lesion or the focal stenosis, the presence of tandem lesions or irregular surface morphology did not correlate with CFD-derived fractional flow. Conclusions: Detailed anatomy of intracranial atherosclerotic lesions can be extracted by semi-automated techniques, revealing extensive heterogeneity. Clinical studies are needed to discern whether CTA anatomy or CFD-derived fractional flow measures predict recurrence of stroke in the territory.
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