Intra-arterial bone marrow mononuclear cell transplantation correlates with GM-CSF, PDGF-BB, and MMP-2 serum levels in stroke patients: results from a clinical trial.

Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke through secretion of cytokines and growth factors (GFs), enhancing neoangiogenesis, and enhancing neuroplasticity. In this study, we tested whether BM-MNC transplantation in stroke patients induces changes in serum levels of cytokines and GFs. A phase I/II trial was conducted in middle cerebral artery (MCA) stroke patients with autologous intra-arterial BM-MNC transplantation between 5 and 9 days after stroke. Follow-up was done for up to 6 months. Eight cases and nine controls were included, and the serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), ß nerve growth factor (ß-NGF), and matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) were measured before and 4, 8, and 90 days after transplantation. The correlation of these serum levels with dose of cells and clinical outcomes was studied. A total of 1.59 × 10(8) (±1.21 × 10(8)) BM-MNCs were injected in cases; of them 3.38 × 10(6) (±2.33 × 10(6)) were CD34(+) cells. There was a positive correlation between total BM-MNCs injected and levels of GM-CSF and PDGF-BB at 90 days after transplantation (r = 0.929, p = 0.001 and r = 0.714, p = 0.047, respectively), and a negative correlation between total CD34(+) cells injected and MMP-2 levels at 4 days after transplantation (r = -0.786, p = 0.036). Lower plasma levels of MMP-2 at 4 days and higher levels of PDGF-BB at 90 days were associated with better functional outcomes during follow-up (p = 0.019 and p = 0.037, respectively). When administered intra-arterially in subacute MCA stroke patients, BM-MNCs seem to induce changes in serum levels of GM-CSF, PDGF-BB, and MMP-2, even 3 months after transplantation, which could be associated with better functional outcomes. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Antiplatelet effects of clopidogrel dose adjustment (75 mg/d vs 150 mg/d) after carotid stenting.

OBJECTIVE: Clopidogrel plays a central role in the treatment of patients undergoing carotid artery stenting (CAS). The objective was to evaluate the effect of clopidogrel (75 mg/d) on platelet reactivity in responders and nonresponders and the antiplatelet effect of different doses of clopidogrel in patients with high on-treatment reactivity (OTR) after CAS. METHODS: Patients with high OTR (defined by VerifyNow (Accumetrics, San Diego, Calif) assay as ≥230 P2Y12 reaction units [PRU]) were randomly assigned in a 1:1 ratio to group 1 (standard-dose clopidogrel therapy: 75 mg/d for 30 days) or group 2 (high-dose clopidogrel: 150 mg/d for 30 days). RESULTS: The study enrolled 214 patients. Of these, 115 (53.7%) were clopidogrel responders (group 0), and 99 (46.3%) had high OTR (clopidogrel nonresponders); of which, 50 were randomly assigned to group 1 and 49 to group 2. At baseline, the PRU value did not differ between group 1 (288.50 ± 46) and group 2 (295.45 ± 47.2; P = .308). Patients displayed reduced mean platelet reactivity levels at 30 days in group 1 (238.96 ± 72.25; P < .001) and group 2 (201.85 ± 77.8; P < .001). Although high-dose clopidogrel resulted in more intense platelet function inhibition, the differences between median 30-day PRU values (P = .483) and the percentage change of PRU (P = .442) for groups 1 and 2 were not significant. The incidences of transient ischemic attack, stroke, or death at up to 30 days after CAS in the high-OTR patients were similar between groups 1 and 2 (P = .481). CONCLUSIONS: Patients with high OTR undergoing CAS treated with standard-dose and double-dose clopidogrel had significantly reduced platelet reactivity after 30 days. The double dose did not result in statistically significantly greater reductions in reactivity compared with the standard dose.

Progressive changes in cerebral perfusion after carotid stenting: a dynamic susceptibility contrast perfusion weighted imaging study.

BACKGROUND: We aimed to assess baseline inter-hemispheric perfusion differences, before carotid artery stenting (CAS), of severe internal carotid artery (ICA) stenosis, and to evaluate perfusion changes over time after CAS by means of perfusion weighted imaging (PWI). METHODS: Dynamic susceptibility contrast PWI was performed in 33 patients with severe ICA stenosis 1 day before and 1 day after CAS, and repeated in 23 patients 30 days after CAS. Cerebral blood volume, cerebral blood flow, arrival time (T0), mean transit time, and time to peak (TTP) relative values comparing symptomatic and asymptomatic hemispheres before CAS were obtained. Pre- and post-CAS values were also compared in the treated hemisphere and middle cerebral artery (MCA) territories. The influence of collateral circulation and contralateral ICA stenosis were evaluated. RESULTS: Before CAS, TTP was significantly increased in the affected hemisphere and MCA territory in all patients (p=0.007 and p=0.021, respectively). After treatment, normalization was observed for TTP and T0 30 days after CAS in all patients, mainly in patients with any grade of contralateral stenosis and with one or both functioning communicating arteries (42.4% of patients had both, and 42.4% showed only one-anterior communicating artery=11 patients (78.6%) and posterior communicating artery=3 patients (21.4%)). CONCLUSIONS: Inter-hemispheric perfusion differences in patients with severe ICA stenosis normalize after CAS in the long term, up to 30 days after the procedure.

Reoclusión arterial recurrente tras recanalización endovascular en un paciente con déficit de proteína S / Recurring arterial reocclusion following endovascular recanalisation in a patient with protein S deficiency

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[Recurring arterial reocclusion following endovascular recanalisation in a patient with protein S deficiency]. / Reoclusion arterial recurrente tras recanalizacion endovascular en un paciente con deficit de proteina S.

TITLE: Reoclusion arterial recurrente tras recanalizacion endovascular en un paciente con deficit de proteina S.

Carotid plaque characterization by virtual histology intravascular ultrasound related to the timing of carotid intervention.

PURPOSE: To determine the incidence of vulnerable plaques characterized by virtual histology intravascular ultrasound (VH IVUS) in patients with severe internal carotid artery (ICA) stenosis and its relationship to the timing of protected carotid artery stenting (CAS). METHODS: The study included 141 patients (119 men; mean age 66.9 ± 9 years) with severe ICA stenosis undergoing CAS with cerebral protection. Patients were classified in 3 groups: 39 symptomatic early CAS (<14 days from clinical symptoms); 58 symptomatic delayed CAS (range 15-180 days), and 44 asymptomatic CAS. Culprit plaque component was evaluated by VH IVUS. A vulnerable plaque was defined by a thin-cap fibroatheroma and/or calcified thin-cap fibroatheroma. RESULTS: The composite disabling stroke/mortality was 2.1%. The incidence of vulnerable plaques was significantly higher in the symptomatic early CAS group (25/39, 64.1%) than in the symptomatic delayed CAS group (26/58, 44.8%; p=0.048) or the asymptomatic CAS group (14/44, 31.8%; p=0.003). Symptomatic patients showed a significantly higher incidence of vulnerable plaques (52.6%) than asymptomatic patients (31.8%, p=0.022). There were no significant differences between the symptomatic delayed and asymptomatic groups (p=0.129). By clinical subgroup, a vulnerable plaque was observed in 29 (52.7%) of the patients with 55 transient ischemic attacks, 22 (52.4%) of the 42 minor stroke patients, and 14 (31.8%) of the 44 asymptomatic patients (p=0.152). CONCLUSION: The incidence of vulnerable plaques was significantly higher in symptomatic patients, increasing as the intravascular study was performed closer to the index ischemic episode.

Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial.

BACKGROUND AND PURPOSE: Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke. We aimed to assess the safety, feasibility, and biological effects of autologous BM-MNC transplantation in patients with stroke. METHODS: A single-blind (outcomes assessor) controlled Phase I/II trial was conducted in patients with middle cerebral artery stroke. Autologous BM-MNCs were injected intra-arterially between 5 and 9 days after stroke. Follow-up was done for up to 6 months and blood samples were collected for biological markers. The primary outcome was safety and feasibility of the procedure. The secondary outcome was improvement in neurological function. RESULTS: Ten cases (BM-MNC-treated) and 10 control subjects (BM-MNC-nontreated) were consecutively included. Mean National Institutes of Health Stroke Scale before the procedure was 15.6. Mean BM-MNCs injected were 1.59×10(8). There was no death, stroke recurrence, or tumor formation during follow-up, although 2 cases had an isolate partial seizure at 3 months. After transplantation, higher plasma levels of beta nerve growth factor (ß-nerve growth factor) were found compared with control subjects (P=0.02). There were no significant differences in neurological function at 180 days. A trend to positive correlation between number of CD34+ cells injected and Barthel Index was found (r=0.56, P=0.09). CONCLUSIONS: Intra-arterial BM-MNC transplantation in subacute ischemic stroke is feasible and seems to be safe. Larger randomized trials are needed to confirm the safety and elucidate the efficacy of BM-MNC transplantation. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT00761982.

Mechanical thrombectomy with snare in patients with acute ischemic stroke.

INTRODUCTION: We evaluated the efficacy and safety of thrombus extraction using a microsnare in patients with acute ischemic stroke (AIS). METHODS: This was a prospective, observational, cohort study in which consecutive patients with AIS (<6 hours of ischemia for anterior circulation and <24 hours for posterior circulation) who had been previously excluded from intravenous tissue plasminogen activator (tPA) thrombolysis were included and followed-up for 3 months. Mechanical embolectomy with a microsnare of 2-4 mm was undertaken as the first treatment. Low-dose intraarterial thrombolysis or angioplasty was used if needed. TIMI grade and modified Rankin stroke scale (mRSS) score were used to evaluate vessel recanalization and clinical efficacy, respectively. RESULTS: Nine patients (mean age 55 years, range 17-69 years) were included. Their basal mean NIHSS score was 16 (range 12-24). In seven out of the nine patients (77.8%) the clot was removed, giving a TIMI grade of 3 in four patients and TIMI grade 2 in three patients. Occlusion sites were: middle cerebral artery (four), basilar artery (two) and anterior cerebral artery plus middle cerebral artery (one). The mean time for recanalization from the start of the procedure was 50 min (range 50-75 min). At 3 months, the mRSS score was 0 in two patients and 3-4 in three patients (two patients died). CONCLUSION: According to our results, the microsnare is a safe procedure for mechanical thrombectomy with a good recanalization rate. Further studies are required to determine the role of the microsnare in the treatment of AIS.

Safety and security of carotid artery stenting for severe stenosis with contralateral occlusion.

BACKGROUND: Despite advances in the surgical treatment of patients with severe internal carotid stenosis (ICA), there are selective groups of patients who, due to several reasons, are not good candidates for surgery. Patients with contralateral occlusion are one of these subgroups. Thereby, other therapeutic alternatives, such as angioplasty may be of value. So far, there has been little published data about carotid angioplasty (CA) or stenting (CAS) in those patients. The objective of this study was to evaluate the efficacy and safety of angioplasty and stenting in patients with severe internal carotid stenosis and contralateral occlusion. METHODS: Between 1991 and June 2004, 519 consecutive patients who underwent CA or CAS for severe stenosis of the ICA were registered in our prospective CA Data Bank. Of them, we identified 96 with contralateral occlusion (18.5%), who formed the basis of the present analysis. RESULTS: Mean age was 64 +/- 9 (range 40-80), 85 (88.5%) were men, and 61 (63.5%) were symptomatic. Thirty-two patients (33.3%) did not meet the criteria to be included in the NASCET. CA was done in 25 patients (26%) and CAS in 71 (74%). Distal protection was used in 38 patients (39.6%). Asymptomatic stenosis was treated in cases of progression (>85%), exhausted vasoreactivity, positive microemboli detection in transcranial Doppler, and/or asymptomatic lesions in CT/MRI. Transient hemodynamic effects were frequent: hypotension (54.5%), bradycardia (61.5%), asystole (33.3%), and syncope (33.3%). TIA occurred in 1 patient (1%), minor stroke in 1 (1%), and disabling stroke in 2 patients (2.1%). Mortality was 0%. Morbidity was 0% in cases done with distal protection. CONCLUSION: In our experience, CA/CAS performed in patients with severe carotid stenosis and contralateral occlusion compared favorably with the results obtained with carotid endarterectomy (CEA), to the extent that if randomized series comparing CEA and CA/CAS are done, CA/CAS might be considered as the treatment of choice in this subgroup of patients.

Silent cerebral ischemic lesions after carotid artery stenting with distal cerebral protection.

OBJECTIVE: To evaluate by MR diffusion weighted image (DWI-MR) the presence of new ischemic cerebral lesions after carotid artery stenting (CAS) and distal cerebral protection, in patients with internal carotid artery (ICA) stenosis >70. METHODS: Sixty-seven CAS were performed under cerebral protection with a distal filter. Mean age of the patients was 68.3 years (range 37-86) and 42 patients (62.7%) were symptomatic. An EZ filter device was used in all cases. The mean length of the procedure was 22.2 minutes (range 8-110). All patients had a cerebral MRI done in the 3 days before CAS and a DW-MR (eco planar single shot, b=1000 mm2/seconds) was done the day after. RESULTS: As a consequence of the CAS, three transient ischemic attacks were observed. There was one minor stroke (1.5%) on day 21, but no major stroke, death or myocardial infarction in a 30-day period. DW-MRI after CAS showed 26 new silent ischemic lesions in 11 asymptomatic patients (16.4%). In six, they were multiple (range 2-5). Lesions were mainly seen in the ipsilateral medial cerebral artery (21); four in the posterior fossa, and one in the contralateral medial cerebral artery. DISCUSSION: Although the use of distal cerebral protection was safe, new cerebral ischemic lesions, supposedly embolic, were observed in 16.4% of the patients. Although without clinical consequences in our series, their moderate high incidence should promote the investigation of safer techniques and devices.