Stimulation of cell surface death receptors activates caspase-8, which targets a limited number of substrates including BAP31, an integral membrane protein of the endoplasmic reticulum (ER). ...Recently, we reported that a caspase-resistant BAP31 mutant inhibited several features of Fas-induced apoptosis, including the release of cytochrome c (cyt.c) from mitochondria, implicating ER-mitochondria crosstalk in this pathway. Here, we report that the p20 caspase cleavage fragment of BAP31 can direct pro-apoptotic signals between the ER and mitochondria. Adenoviral expression of p20 caused an early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and mitochondrial recruitment of Drp1, a dynamin-related protein that mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network. Inhibition of Drp1 or ER-mitochondrial Ca2+ signaling prevented p20-induced fission of mitochondria. p20 strongly sensitized mitochondria to caspase-8-induced cyt.c release, whereas prolonged expression of p20 on its own ultimately induced caspase activation and apoptosis through the mitochondrial apoptosome stress pathway. Therefore, caspase-8 cleavage of BAP31 at the ER stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cyt.c in response to this initiator caspase.
Background and Purpose- Hypoperfusion intensity ratio (HIR) is associated with collateral status in acute ischemic stroke patients with anterior circulation large vessel occlusion. We assessed ...whether HIR was correlated to patient eligibility for mechanical thrombectomy (MT). Methods- We performed a retrospective cohort study of consecutive acute ischemic stroke patients with a proximal middle cerebral artery or internal carotid artery occlusion who underwent MT triage with computed tomography or magnetic resonance perfusion imaging. Clinical data, ischemic core (mL), HIR (defined as time-to-maximum TMax >10 seconds/TMax >6 seconds), mismatch volume between core and penumbra, and MT details were assessed. Primary outcome was favorable HIR collateral score (HIR <0.4) between patients who underwent MT (MT+) and those who did not (MT-) according to American Heart Association guidelines both in the <6 hours and 6 to 24 hours windows. Secondary outcomes were favorable HIR score in MT- subgroups (National Institutes of Health Stroke Scale <6 versus core >70 mL) and core-penumbra mismatch volumes. Patients who did not meet guidelines were not included. Results- We included 197 patients (145 MT+ and 52 MT-). MT+ patients had a significantly lower median HIR compared with MT- patients (0.4 interquartile range, 0.2-0.5 versus 0.6 interquartile range, 0.5-0.8; P<0.001) and a higher mismatch volume (96 versus 27 mL, P<0.001). Among MT- patients, 43 had a core >70 mL, and 9 had a National Institutes of Health Stroke Scale <6. MT- patients with National Institutes of Health Stroke Scale <6 had a lower HIR than MT- patients with core >70 mL (0.2 interquartile range, 0.2-0.3 versus 0.7 interquartile range, 0.6-0.8, P<0.001) but their HIR was not significantly different that MT+ patients. Conclusions- Patients who meet American Heart Association guidelines for thrombectomy are more likely to have favorable collaterals (low HIR). HIR may be used as a marker of eligibility for MT triage.
To determine if intravoxel incoherent motion (IVIM) magnetic resonance perfusion can measure the quality of the collateral blood flow in the penumbra in hyperacute stroke.
A 6 b values IVIM MRI ...sequence was acquired in stroke patients with large vessel occlusion imaged <16 hours of last seen well. IVIM perfusion measures were evaluated in regions of interest drawn in the infarct core (D < 600 mm
/s), in the corresponding region in the contralateral hemisphere, and in the dynamic susceptibility contrast penumbra. In patients with a penumbra >15 mL, images were reviewed for the presence of a penumbra perfusion lesion on the IVIM f map, which was correlated with infarct size metrics. Statistical significance was tested using Student
test, Mann-Whitney
test, and Fisher exact test.
A total of 34 patients were included. In the stroke core, IVIM f was significantly lower (4.6 ± 3.3%) compared to the healthy contralateral region (6.3 ± 2.2%,
< 0.001). In the 25 patients with a penumbra >15 mL, 9 patients had an IVIM penumbra perfusion lesion (56 ± 76 mL), and 16 did not. Patients with an IVIM penumbra perfusion lesion had a larger infarct core (82 ± 84 mL) at baseline, a larger infarct growth (68 ± 40 mL), and a larger final infarct size (126 ± 81 mL) on follow-up images compared to the patients without (resp. 20 ± 17 mL,
< 0.05; 13 ± 19 mL,
< 0.01; 29 ± 24 mL,
< 0.05). All IVIM penumbra perfusion lesions progressed to infarction despite thrombectomy treatment.
IVIM is a promising tool to assess the quality of the collateral blood flow in hyperacute stroke. IVIM penumbra perfusion lesion may be a marker of nonsalvageable tissue despite treatment with thrombectomy, suggesting that the IVIM penumbra perfusion lesion might be counted to the stroke core, together with the DWI lesion.
Purpose
Intravoxel incoherent motion is a diffusion-weighted imaging magnetic resonance imaging technique that measures microvascular perfusion from a multi-b value sequence. Intravoxel incoherent ...motion microvascular perfusion has not been directly compared to conventional dynamic susceptibility contrast perfusion-weighted imaging in the context of acute ischemic stroke. We determined the degree of correlation between perfusion-weighted imaging and intravoxel incoherent motion parameter maps in patients with acute ischemic stroke.
Methods
We performed a retrospective cohort study of acute ischemic stroke patients undergoing thrombectomy treatment triage by magnetic resonance imaging. Intravoxel incoherent motion perfusion fraction maps were derived using two-step voxel-by-voxel post-processing. Ischemic core, penumbra, non-ischemia, and contralateral hemisphere were delineated based upon diffusion-weighted imaging and perfusion-weighted imaging using a Tmax >6 s threshold. Signal intensity within different brain compartments were measured on intravoxel incoherent motion (IVIM f, IVIM D*, IVIM fD*) parametric maps and compared the differences using one-way ANOVA. Ischemic volumes were measured on perfusion-weighted imaging and intravoxel incoherent motion parametric maps. Bland–Altman analysis and voxel-based volumetric comparison were used to determine the agreements among ischemic volumes of perfusion-weighted imaging and intravoxel incoherent motion perfusion parameters. Inter-rater reliability on intravoxel incoherent motion maps was also assessed. Significance level was set at α < 0.05.
Results
Twenty patients (11 males, 55%; mean age 67.1 ± 13.8 years) were included. Vessel occlusions involved the internal carotid artery (6 patients, 30%) and M1 segment of the middle cerebral artery (14, 70%). Mean pre-treatment core infarct volume was 19.07 ± 23.56 ml. Mean pre-treatment ischemic volumes on perfusion-weighted imaging were 10.90 ± 13.33 ml (CBV), 24.83 ± 23.08 ml (CBF), 58.87 ± 37.85 ml (MTT), and 47.53 ± 26.78 ml (Tmax). Mean pre-treatment ischemic volumes on corresponding IVIM parameters were 23.20 ± 25.63 ml (IVIM f), 14.01 ± 16.81 ml (IVIM D*), and 27.41 ± 40.01 ml (IVIM fD*). IVIM f, D, and fD* demonstrated significant differences (P < 0.001). The best agreement in term of ischemic volumes and voxel-based overlap was between IVIM fD* and CBF with mean volume difference of 0.5 ml and mean dice similarity coefficient (DSC) of 0.630 ± 0.136.
Conclusion
There are moderate differences in brain perfusion assessment between intravoxel incoherent motion and perfusion-weighted imaging parametric maps, and IVIM fD* and perfusion-weighted imaging CBF show excellent agreement. Intravoxel incoherent motion is promising for cerebral perfusion assessment in acute ischemic stroke patients.
The susceptibility-vessel-sign (SVS) allows thrombus visualization, length estimation and composition, and it may impact reperfusion during mechanical thrombectomy (MT). SVS can also describe ...thrombus shape in the occluded artery: in the straight M1-segment (S-shaped), or in an angulated/traversing a bifurcation segment (A-shaped). We determined whether SVS clot shape influenced reperfusion and outcomes after MT for proximal middle-cerebral-artery (M1) occlusions.
Between May 2015 and March 2018, consecutive patients who underwent MT at one comprehensive stroke center and who had a baseline MRI with a T2
sequence were included. Clinical, procedural and radiographic data, including clot shape on SVS angulated/bifurcation (A-SVS) vs. straight (S-SVS) and length were assessed. Primary outcome was successful reperfusion (TICI 2b-3). Secondary outcome were MT complication rates, MT reperfusion time, and clinical outcome at 90-days. Predictors of outcome were assessed with univariate and multivariate analyses.
A total of 62 patients were included. 56% (35/62) had an A-SVS. Clots were significantly longer in the A-SVS group (19 mm vs. 8 mm
= 0.0002). Groups were otherwise well-matched with regard to baseline characteristics. There was a significantly lower rate of successful reperfusion in the A-SVS cohort (83%) compared to the S-SVS cohort (96%) in multivariable analysis OR 0.04 (95% CI, 0.002-0.58),
= 0.02. There was no significant difference in long term clinical outcome between groups.
Clot shape as determined on T2
imaging, in patients presenting with M1 occlusion appears to be a predictor of successful reperfusion after MT. Angulated and bifurcating clots are associated with poorer rates of successful reperfusion.
Background
Acute ischemic stroke patients with a large-vessel occlusion but mild symptoms (NIHSS ≤ 6) pose a treatment dilemma between medical management and endovascular thrombectomy.
Aims
To ...evaluate the differences in clinical outcomes of endovascular thrombectomy-eligible patients with target-mismatch perfusion profiles who undergo either medical management or endovascular thrombectomy.
Methods
Forty-seven patients with acute ischemic stroke due to large-vessel occlusion, NIHSS ≤ 6, and a target-mismatch perfusion imaging profile were included. Patients underwent medical management or endovascular thrombectomy following treating neurointerventionalist and neurologist consensus. The primary outcome measure was NIHSS shift. Secondary outcome measures were symptomatic intracranial hemorrhage, in-hospital mortality, and 90-day mRS scores. The primary intention-to-treat and as-treated analyses were compared to determine the impact of crossover patient allocation on study outcome measures.
Results
Forty-seven patients were included. Thirty underwent medical management (64%) and 17 underwent endovascular thrombectomy (36%). Three medical management patients underwent endovascular thrombectomy due to early clinical deterioration. Presentation NIHSS (P = 0.82), NIHSS shift (P = 0.62), and 90-day functional independence (mRS 0–2; P = 0.25) were similar between groups. Endovascular thrombectomy patients demonstrated an increased overall rate of intracranial hemorrhage (35.3% vs. 10.0%; P = 0.04), but symptomatic intracranial hemorrhage was similar between groups (P = 0.25). In-hospital mortality was similar between groups (P = 0.46), though all two deaths in the medical management group occurred among crossover patients. Endovascular thrombectomy patients demonstrated a longer length of stay (7.6 ± 7.2 vs. 4.3 ± 3.9 days; P = 0.04) and a higher frequency of unfavorable discharge to a skilled-nursing facility (P = 0.03) rather than home (P = 0.05).
Conclusions
Endovascular thrombectomy may pose an unfavorable risk-benefit profile over medical management for endovascular thrombectomy-eligible acute ischemic stroke patients with mild symptoms, which warrants a randomized trial in this subpopulation.
Baseline-core-infarct volume is a critical factor in patient selection and outcome in acute ischemic stroke (AIS) before mechanical thrombectomy (MT). We determined whether oxygen extraction ...efficiency and arterial collaterals, two different physiologic components of the cerebral ischemic cascade, interacted to modulate baseline-core-infarct volume in patients with AIS-LVO undergoing MT triage.
Between January 2015 and March 2018, consecutive patients with an AIS and M1 occlusion considered for MT with a baseline MRI and perfusion-imaging were included. Variables such as baseline-core-infarct volume mL, arterial collaterals (HIR: TMax > 10 s volume/TMax > 6 s), high oxygen extraction (HOE, presence of the brush-sign on T2
) were assessed. A linear-regression was used to test the interaction of HOE and HIR with baseline-core-infarct volume, after including potential confounding variables.
We included 103 patients. Median age was 70 (58-78), and 63% were female. Median baseline-core-infarct volume was 32 ml (IQR 8-74.5). Seventy six patients (74%) had HOE. In a multivariate analysis both favorable HIR collaterals (
= 0.02) and HOE (
= 0.038) were associated with lower baseline-core-infarct volume. However, HOE significantly interacted with HIR (
= 0.01) to predict baseline-core-infarct volume, favorable collaterals (low HIR) with HOE was associated with small baseline-core-infarct whereas patients with poor collaterals (high HIR) and HOE had large baseline-core-infarct.
While HOE under effective collateral blood-flow has the lowest baseline-core-infarct volume of all patients, the protective effect of HOE reverses under poor collateral blood-flow and may be a maladaptive response to ischemic stroke as measured by core infarctions in AIS-LVO patients undergoing MT triage.
Background
International dose reference levels are lacking for mechanical thrombectomy in acute ischemic stroke patients with large vessel occlusions. We studied whether radiation dose-reduction ...systems (RDS) could effectively reduce exposure and propose achievable levels.
Materials and methods
We retrospectively included consecutive patients treated with thrombectomy on a biplane angiography system (BP) in five international, high-volume centers between January 2014 and May 2017. Institutional Review Board approvals were obtained. Technical, procedural, and clinical characteristics were assessed. Efficacy, safety, radiation dose, and contrast load were compared between angiography systems with and without RDS. Multivariate analyses were adjusted according to Bonferroni’s correction. Proposed international achievable cutoff levels were set at the 75th percentile.
Results
Out of the 1096 thrombectomized patients, 520 (47%) were treated on a BP equipped with RDS. After multivariate analysis, RDS significantly reduced dose–area product (DAP) (91 vs 140 Gy cm
2
, relative effect 0.74 (CI 0.66; 0.83), 35% decrease,
p
< 0.001) and air kerma (0.46 vs 0.97 Gy, relative effect 0.63 (CI 0.56; 0.71), 53% decrease,
p
< 0.001) with 75th percentile levels of 148 Gy cm
2
and 0.73 Gy, respectively. There was no difference in contrast load, rates of successful recanalization, complications, or clinical outcome.
Conclusion
Radiation dose-reduction systems can reduce DAP and air kerma by a third and a half, respectively, without affecting thrombectomy efficacy or safety. The respective thresholds of 148 Gy cm
2
and 0.73 Gy represent achievable levels that may serve to optimize current and future radiation exposure in the setting of acute ischemic stroke treatment. As technology evolves, we expect these values to decrease.
Key Points
• Internationally validated achievable levels may help caregivers and health authorities better assess and reduce radiation exposure of both ischemic stroke patients and treating staff during thrombectomy procedures.
• Radiation dose-reduction systems can reduce DAP and air kerma by a third and a half, respectively, without affecting thrombectomy efficacy or safety in the setting of acute ischemic stroke due to large vessel occlusion.
Purpose
To determine the optimal combination of low b‑values to generate perfusion information from intravoxel incoherent motion (IVIM) in patients with acute ischemic stroke (AIS) considering the ...time constraints for these patients.
Methods
A retrospective cohort study of AIS patients with IVIM MRI was performed. A two-step voxel-by-voxel postprocessing was used to derive IVIM perfusion fraction maps with different combinations of b values. Signal values within regions of ischemic core, non-infarcted ischemic hemisphere, and contralateral hemisphere were measured on IVIM (
f
, D
*
,
f
D
*
, D) parameter maps. Bland-Altman analysis and the Dice similarity coefficient were used to determine quantitative and spatial agreements between the reference standard IVIM (IVIM with 6 b values of 0, 50, 100, 150, 200, 1000 s/mm
2
) and other combinations of b values. Significance level was set at
p
< 0.05.
Results
There were 58 patients (36 males, 61.3%; mean age 70.2 ± 13.4 years) included. Considering all IVIM parameters, the combination of b values of 0, 50, 200, 1000 was the most consistent with our reference standard on Bland-Altman analysis. The best voxel-based overlaps of ischemic regions were on IVIM D, while there were good voxel-based overlaps on IVIM
f.
Conclusion
The IVIM with these four b values collects diffusion and perfusion information from a single short MRI sequence, which may have important implications for the imaging of AIS patients.
An increasing number of centers not necessarily equipped with biplane (BP) angiosuites are performing mechanical thrombectomy (MT) in acute ischemic stroke patients. We assessed whether MT performed ...on single-plane (SP) is equivalent in terms of safety, effectiveness, radiation and contrast agent exposure. Consecutive patients treated by MT in four high volume centers between January 2014 and May 2017 were included. Demographic and MT characteristics were assessed and compared between SP and BP. Of 906 patients treated by MT, 576 (64%) were handled on a BP system. After multivariate analysis, contrast load and fluoroscopy duration were significantly lower in the BP group 100vs200mL, relative effect 0.85 (CI: 0.79-0.92), p = 0.0002; 22 vs 27 min, relative effect 0.84 (CI: 0.76-0.93), p = 0.0008, respectively. There was no difference in recanalization (modified Thrombolysis-In-Cerebral-Infarction 2b-3), good clinical outcome (modified Rankin Scale 0-2), complications rates, procedure duration or radiation exposure. A three-vessel diagnostic angiogram performed prior to MT led to a significant increase in procedure duration (15% increase, p = 0.05), radiation exposure (33% increase, p < 0.0001) and contrast load (125% increase, p < 0.0001). Mechanical neuro-thrombectomy seems equally safe and effective on a single or biplane angiography system despite increased contrast load and fluoroscopy duration on the former.
PDF
