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.

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.

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.

Risk factors and neurological consequences of syncopes induced by internal carotid artery angioplasty.

BACKGROUND AND PURPOSE: Syncope and carotid sinus reactions (CSR) occur frequently in patients undergoing carotid angioplasty (CA). We investigated risk factors and the neurological consequences of carotid sinus syncope induced by CA. METHODS: We examined 359 consecutive patients. Patients underwent assessment of cerebrovascular reserve before CA and continuous electroencephalographical monitoring during the procedure. We examined the impact of vascular risk factors, cerebral hemodynamics, characteristics of plaque, and procedural modality on the incidence of CSR and syncope. The effect of syncopes on periprocedural complication rates was also investigated. RESULTS: CSR and syncope occurred in 62.7% and 18.0% of the procedures, respectively. The occurrence of CSR during angioplasty was significantly associated with the appearance of syncope. The incidence of syncope was significantly higher in longer plaques located in the carotid bifurcation, in the presence of contralateral carotid stenosis, or when protection devices were used. Although TIA during CA was more common in syncopal patients, stroke or death rates were similar in the 2 groups. CONCLUSIONS: Syncope occurs more frequently in patients with long plaques proximal to the carotid bifurcation, but it does not increase the periprocedural complications rate.

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.

Peripheral arterial disease in patients with stages IV and V chronic renal failure.

BACKGROUND: Cardiovascular disorders are frequently found among chronic renal failure (CRF) patients due to their higher susceptibility to develop atherosclerosis. However, peripheral arterial disease (PAD), that is associated with a high mortality rate, is not usually assessed in these patients. The aims of this study are to find out the prevalence of PAD affecting lower limbs in a population of CRF patients in stages IV/V, and to assess how much PAD determines the 5-year patient survival. METHODS: The study population (44 males and 29 females) was aged 58 +/- 15 years. They suffered from advanced CRF (18.6 +/- 6.1 ml/min creatinine clearance), but they were not on dialysis. These patients were sequentially referred initially to the predialysis unit over a period of 14 months. The vascular lesions were assessed by carotid and transcranial ultrasound, as well as by ankle-brachial index test (ABI). Routine 24 h blood and urine laboratory tests were performed for each patient. Cardiovascular morbidity and cardiovascular disease risk factors were evaluated through personal interview. RESULTS: Fourteen patients had an ABI index of less than 0.91 (PAD indicative), 11 of them also suffered from intermittent claudication. PAD affected significantly more males (P = 0.001) and diabetics (P = 0.001). Also, PAD prevalence was significantly higher in patients with a previous clinical record of coronary heart disease (P = 0.001), increased clinical record of cerebrovascular disease (P = 0.005), a thickness of the left ventricular posterior wall (P = 0.03) and lower cardiac ejection fraction (P = 0.02). PAD patients had a significantly different protein intake (P = 0.003), calcium-phosphorus product (P = 0.001), risk of coronary heart disease based on the Framingham score (P = 0.001) and 5-year survival rate (P = 0.004). There were no significant differences for PAD patients in terms of body mass index, creatinine clearance, lipid profile, Ca and P. Multivariate risk factor analysis revealed that a previous clinical record of coronary heart disease and diabetes increased the risk of developing PAD, as defined by ABI < 0.91. After 5 years, 21 patients (29%) had died: 64% of patients that suffered PAD (9/14) and 20% of the non-PAD population (12/59). The Cox proportional hazards model demonstrated that older age and a lower ABI increased the risk of death. CONCLUSIONS: The present study, conducted on CRF patients in stages IV and V not undergoing dialysis, showed; (a) that a high percentage of these patients developed PAD (19%) or other vascular pathologies; (b) that there was an associated high mortality rate (29%) after 5 years; (c) that the 5-year mortality rate was significantly higher (P = 0.004) in PAD patients (64 vs 20%).

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.

Internal carotid artery stenting in patients with symptomatic atheromatous pseudo-occlusion.

Angioplasty and stenting of the atheromatous internal carotid artery (ICA), besides in patients with a high surgical risk, may be indicated in specific cases such as contralateral occlusion, acute stroke clinical signs, or atherosclerotic pseudo-occlusion (APO). APO of the ICA is an underrecognized condition due to diagnostic difficulties both with noninvasive methods and even with angiography. Once recognized, there is usually the opportunity for successful revascularization with carotid endarterectomy. However, as the natural history of the APO is poorly characterized, the management of patients remains controversial. While some authors advocate a surgical approach, others consider that APO patients are not at high risk of stroke, making any interventional approach unnecessary. The perioperative risk of stroke in patients with APO is not appreciably greater than in patients with lesser degrees of stenosis and clear recommendation of surgery, although at 2 years that risk seems to be considerably much higher than in the latter patients. Looking for safer interventional procedures is worthwhile. Results of angioplasty and stenting in patients with ICA-APO have not been published yet. We report the results and complications associated with this procedure to address the issue of appropriate management of patients with ICA-APO.

Stroke mortality in Andalusia (Spain) from 1975 to 1999: effect of age, birth cohort and period of death.

The aim of this study was to analyze stroke mortality rates in Andalusia during the period from 1975 to 1999 by studying age, cohort and period effects. Deaths due to stroke along with the corresponding population figures were divided into 11 age groups and five 5-year periods. From this, age-specific mortality rates for 15 birth cohorts were then computed. These were plotted and fitted to Poisson regression models to assess age, period and cohort effects. An exponential age effect was present for both sexes regardless of cohort or period. The rates of stroke mortality decreased significantly among both sexes in Andalusia during the study period, although in recent years, this declining trend has started to slow down, primarily in males. Age- and period-adjusted stroke mortality was greater for earlier cohorts and lower for generations born at the beginning of the 20th century.