XVII. European Stroke Conference
Nice, France
XVII. European Stroke Conference
Nice, France
Poster Session: Vascular biology
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Matrix metalloproteinases 3 plasma levels and 5-year stroke death in patients with brain infarction
F. Pico
J. Labreuche
M.-P.Jacob
J.-B.Michel
P. Amarenco
Versailles Hospital
FRANCE
Background: Matrix metalloproteinases (MMP) pathway influences the prognosis of patients with brain infarction (BI). Plasma levels of MMP 9 predict fatal vascular events or stroke in patients with carotid stenosis. Plasma MMP3 levels are associated with 3-month mortality in patients with intracerebral hemorrhage. We investigated trends in 5-year mortality (all-cause, stroke and non stroke vascular death) according to baseline matrix MMP 2, 3 and 9 plasma levels in patients with BI. Methods: Patients with BI (n=510) were consecutively recruited from 12 centers. MMP-2, MMP-3, and MMP-9 levels were determined in a single laboratory. Patients were followed for death incidence. All cause, stroke and non stroke vascular deaths were determined according to the French national registry of death certificates. Results: After a median of 5.3 years (range, 1.5 to 6.6), 167 patients died, and 22 were lost to follow-up after the third examination. There were 94 vascular deaths (including 57 strokes), 22 cancer deaths, 37 other nonvascular deaths. We found no significant difference across tertiles of MMP-2 and MMP-9 levels and 5-year all-cause, stroke and non stroke vascular death (Log-rank tests, p>0.30). For MMP-3 levels, we found a gradual increase in the risk of all-cause death (p for trend=0.01) and stroke deaths (p for trend=0.03) but not with non stroke vascular death (p=0.17). Using Cox proportional-hazard model adjusting for age, sex, current smoking and cardiovascular history, the HR for all-cause and stroke deaths per one SD increase in MMP-3 were 1.14 (95% CI: 0.96-1.34) and 1.39 (95%CI: 1.09-1.78) respectively. Discussion: In patients with brain infarction,MMP 3 could be a predictor of fatal stroke
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Retinal arteriolar branching angles do not differ between lacunar and cortical stroke.
R. de Haan
F.N.Doubal
T.J.MacGillivray
J.M.Wardlaw
University of Edinburgh, Western General Hospital, Division of Clinical Neurosciences
UNITED KINGDOM
Background: Lacunar stroke is associated with an intrinsic cerebral small vessel disorder of unknown cause. Possible mechanisms include endothelial dysfunction. Retinal and cerebral vessels are developmentally related and retinal abnormalities are common in stroke. Limited data suggest that arterial branching angles may vary with endothelial function and hypertension, both risk factors for lacunar stroke. We compared retinal branching angles in lacunar versus cortical stroke controls. Methods: We prospectively recruited patients with lacunar or cortical stroke, diagnosed and subtyped by an expert stroke physician clinically and with cerebral magnetic resonance imaging. All patients had bilateral 45° digital retinal photographs centred on the optic disc. Images were analysed with custom written software in Matlab. As branching angles do not differ between left and right eyes, we measured the 5 most proximal evaluable arterial branching angles in one randomly selected eye per patient. We calculated the deviation from a predicted optimum of 75° for each angle and took the median angle and median deviation for each patient. We analysed differences between stroke subtypes and the effect of age and hypertension on branching angles. Results: We recruited 205 patients, of whom 187 (94 lacunar, 93 cortical) were analysed (18 excluded as <3 angles were measurable). There was no difference in the mean of the median angles (lacunar 84.8°, cortical 83.6°, p=0.26) or in the mean of the median deviations from optimum (lacunar 11.5°, cortical 11.0°, p=0.61) between lacunar and cortical stroke. Neither hypertension (previous or current) nor increasing age were associated with branching angle sizes. Discussion: We found no difference in retinal arteriolar branching angles between lacunar and cortical stroke, or association with hypertension. Other features of retinal geometry may be altered by endothelial function and contribute to revealing the pathogenesis of lacunar stroke. Further studies are required to assess the role of branching angles in vascular disease.
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Comparison of Matrix-Metalloproteinase (MMP) expression in acute human stoke in relation to rt-PA treatment
M. Fatar
M. Stroick
B. Reuter
M. Griebe
A. Alonso
M.G.Hennerici
Faculty of Medicine Mannheim, University of Heidelberg
GERMANY
Background: Pre-treatment levels of MMP-9 predict intracranial haemorrhage after rt-PA in stroke and MMPs are accused to be responsible for blood-barrier breakdown. But if and how rt-PA treatment influences the MMP expression after acute stroke is unknown. We evaluated the potential interaction of rt-PA, MMP expression and their inhibitors (TIMP) in the first 7 days after stroke onset. Methods: rt-PA treated stroke patients (n=33) were compared with non-rt-PA treated, age, sex, type and aetiology of infarction and NIHSS on admission matched stroke controls (n=33) both recruited from our stroke unit. Participants were further classified by risk factors and Doppler sonography results. Blood samples were obtained on days 1, 2, 3 and 7 after symptom onset and serum levels of MMP-2, MMP-9, TIMP-1, TIMP-2, C-reactive protein (CRP) and neuron specific enolase (NSE) were measured by commercially available ELISA techniques. Results: MMP-2 (day 1: 199.3+/-88.2 vs. 214.8+/-70.37), MMP-9 (day 1: 911.4+/-375.2 vs. 810.2+/-407.6), TIMP-1 (day 1: 197.8+/-61.4 vs. 216.3+/-76.6) and TIMP-2 (day 1: 116.8+/-72.5 vs. 111.3+/-41.2) values did not differ significantly between the two groups on all measured time-points (days 1, 2, 3 and 7). Discussion: Our data demonstrate that after matching for age, sex, NIHSS and type of infarction no effects of rt-PA on measured matrix metabolites were observed. This makes a co-treatment with MMP inhibitors to prevent secondary haemorrhage irrespective from rt-PA treatment.
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Arterial stiffness among stroke subtypes
A. Kirkou
T. Pappa
J. Zafiriou
E. Manios
K. Xynos
C. Papamichael
K. Vemmos
University of Athens, Alexandra Hospital
GREECE
Background: Arterial stiffness has been associated with increased risk of coronary artery disease and stroke in healthy subjects. Due to the fact that stroke is a heterogeneous disease regarding aetiology, we investigated arterial stiffness among different stroke subtypes in ambulatory stroke patients. Methods: We prospectively studied 320 ambulatory stroke patients 1-3 months after ictus. Arterial stiffness was estimated by means of arterial pulse wave velocity (PWV). Pulse wave velocity was recorded simultaneously at the proximal common carotid artery and the distal femoral artery and expressed as m/s. Stroke subtypes were based on modified TOAST criteria. One-way ANOVA test was used for statistical analysis (Bonferroni test for multiple comparisons). Results: Our study population consisted of 223 men and 93 women with a mean age of 65.4±10.3. Stroke subtypes were: large vessel atherosclerotic (LVA) 82, cardioembolic 47, lacunar 102, cryptogenic 48 and intracerebral hemorrhage (ICH) 41 cases. The PWV (m/s) values were (mean, 95%CI): 12.0 (11.1-13.0) for LVA, 12.5 (11.7-13.4) for cardioembolic, 14.1 (13.2-15.0) for lacunar, 12.8 (11.8-13.8) for cryptogenic, and 11.8 (10.7-12.8) for the ICH cases. After adjustment for age, sex and history of hypertension, PWV values in lacunar stroke remained significantly higher than LVA stroke (p=0.005) and ICH cases (p=0.014). Conclusion: Arterial stiffness is different among stroke subtypes. Patients with lacunar stroke presented the highest arterial stiffness, fact that should be seriously considered in antihypertensive stroke treatment.
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Magnitude and time course of platelet inhibition with extended release dipyridamole with or without aspirin in healthy Japanese volunteers: The Japanese AGgrenox versus Aspirin Therapy Evaluation (JAGATE)
V.I.Serebruany
A.I.Malinin
D.F.Hanley
Johns Hopkins
USA
Background: Randomized trials showed greater stroke prevention with extended release dipyridamole in combination with low dose aspirin than either with aspirin or dipyridamole alone. However, most studies with this formulation (Aggrenox®) were done in Europe and North America. Considering potential inter-racial differences in drug response, we conducted a small randomized study in healthy Japanese volunteers to compare antiplatelet regimens with regard to the changes in the platelet biomarkers. Methods: Thirty healthy volunteers (18-40 years old, 15 male and 15 female) of Japanese descend were randomized to Aggrenox® (n=17) or aspirin 81 mg (n=13 volunteers) for 30 days. Platelet function was assessed at baseline, and days 15, and 30 by conventional aggregometry, whole blood flow cytometry, and cartridge-based analyzer. Results: Both Aggrenox® and aspirin provided sustained platelet inhibition at Day 15 and Day 30. Therapy with Aggrenox®, however, was associated with more prominent and significant inhibition of collagen-induced aggregation (p=0.08, Day 15), as well as prolongation of the closure time (p=0.001, Day 30); diminished expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) (p=0.02, Day 30), glycoprotein IIb (GPIIb) antigen (p=0.001 and 0.024 for Day 15 and Day 30), and GPIIb/IIIa activity by PAC-1 antibody (p = 0.014 and 0.03), CD62 (P-selectin) (p = 0.03 for Day 15 and Day 30), as well as inhibition of protease activated receptors (PAR-1) associated with intact WEDE-15 (p = 0.002 and 0.003) and SPAN-12 (p = 0.002 and 0.04) thrombin receptors when compared with aspirin. Conclusion: The magnitude and durability of platelet response after Aggrenox in healthy Japanese is similar to those effects observed in Caucasians and African-Americans. Larger study to assess drug efficacy and safety in the Japanese post-stroke patients is warranted.
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Cerebrovascular protection by pituitary adenylyl cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) after global cerebral ischemia in piglets
F. Bari
L. Lenti
A. Zimmermann
D. Kis
G. Tóth
F. Domoki
University of Szeged, Faculty of Medicine
HUNGARY
Impairment of cerebrovascular reactivity (CR) contributes to neuronal damage induced by ischemia/reperfusion (I/R). PACAP and VIP dilate cerebral vessels and are protective against ischemic brain damage, but the mechanisms of these actions have not been investigated in the newborn. In anesthetized, artificially ventilated 1-day old piglets (n= 62), we tested if PACAP isoforms (PACAP27 and 38) and VIP preserve CR to endothelium- or neuronal-dependent and I/R-sensitive vasodilator responses. Pial arteriolar diameters (baseline ~100 m) were determined via closed cranial window/intravital microscopy in response to hypercapnia (inhalation of 5 and 10% CO2 in air) which elicits endothelium dependent vasodilation or topical N-methyl-D aspartate (NMDA, 10-4 M) which activates the neurovascular axis before and 1 hr after I/R. Global cerebral ischemia (10 min) was induced by elevated intracranial pressure. Prior to I/R, non-vasoactive doses of PACAP27, 38 (10-8M, for 30 min), VIP (10-9M, for 20 min ) or vehicle were applied onto the cortex. I/R attenuated hypercapnia- and NMDA-induced vasodilation that was preserved both by PACAP27 and 38. For instance, postischemic CR to NMDA (vehicle vs. PACAP38; CR expressed as % of response before I/R, mean +/- SEM, n=6-8 in each group) was 30+/-12% vs. 86+/-6%, and CR to 10% CO2 was 45+/-9% vs. 90+/-7%. VIP preserved the endothelium-dependent response to hypercapnia, but not the neuronal-dependent reactivity to NMDA. In conclusion, PACAP- and VIP-induced neuroprotection are likely mediated in part by preservation of I/R-sensitive cerebrovascular mechanisms. Although the peptides are structurally related their action in cerebrovascular control and protection seems slightly different. Supported by the Hungarian Scientific Research Fund (OTKA K63401 and K68976) and the Hungarian Health Science Board (ETT 194042006).
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Butyrate Modulates Vascular Smooth Muscle Cells' Redox State: Implications for Atherosclerosis and Ischemic Strokes.
F.M.Yatsu
K. Ranganna
University of Texas Medical School at Houston
USA
Background: Atherosclerosis is the major contributor to global mortality and morbidity in being the primary cause of strokes and coronary heart diseases. Proliferation of vascular smooth muscle cells (VSMC) is a crucial factor in the pathogenesis of atherosclerosis, which is linked to alterations in redox-sensitive signaling pathways. We have established that butyrate, a product of dietary fiber and an inhibitor of histone deacetylase, is an inhibitor of VSMC proliferation. Molecular analysis of butyrate's antiproliferation action suggests involvement of glutathione- associated antioxidant enzyme system in butyrate-arrested VSMC proliferation. The goal of this study is to confirm the involvement of glutathione-associated antioxidant enzymes and to examine their association to the cellular redox state in butyrate-arrested VSMC. Methods: Effect of butyrate on the expression of members of glutathione-S-transferase (GST) family and glutathione peroxidase 4 (GPX4) was assessed by Western analysis and immunostaining. Intra-celluar glutathione and reactive oxygen species (ROS) levels were determined by a flourometric method and by using 2'7'-dichloroflourescin, respectively. Results: VSMC treated with butyrate exhibit upregulation of several members of GST family and GPX4. Additionally, analysis of intracellular glutathione levels reveals escalation of glutathione levels by butyrate. In contrast, butyrate treatment reduces ROS levels. Conclusions: Taken together, butyrate treatment-related increases in glutathione content, reduction in ROS levels, and upregulation of members of the GST family and GPX4 imply that butyrate's antiproliferative action involves modulation of cellular redox state suggesting a link between antioxidant action and antiproliferative effect of butyrate. This Work is supported by United States National Center for Research Resources/National Institutes of Health/RCMIG12RR0345 and C06RR012537-01 grants.
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Modified C-reactive protein is predominantly expressed in the neovessels of complicated atherosclerotic plaques and is potently angiogenic in vitro.
M. Slevin
M.M.Turu
I. Badimon
I.A.Potempa
Y. Wu
N. Mitsios
S. Matou
A. Luque
J. Krupinski
Manchester Metropolitan University
UNITED KINGDOM
Background and purpose: Cardiovascular disease is forecast in the 21st century to remain as the primary cause of death in the world. Understanding the molecular mechanisms responsible for cellular activation will help to explain the relationships between inflammation, angiogenesis and the instability of atherosclerotic plaques leading to thrombosis. Inflammatory biomarkers, such as C reactive protein (CRP), may be useful in prediction of the risk of vascular disease. CRP is a pentameric oligoprotein composed of identical 23 KDa subunits which can be irreversibly dissociated to form free subunits or mCRP. mCRP has a reduced aqueous solubility and a tendency to aggregate into matrix-like lattices in various tissues, in particular, blood vessel walls. Methods: We have used immunohistochemistry, in vitro angiogenesis assays and Western blotting to identify intra-cellular cell signalling pathways elicited by mCRP. Results: Our studies showed that this modified form of CRP, mCRP was expressed predominantly in intimal neovessels of complicated carotid plaques and also induced an increase in vascular endothelial cell (EC) proliferation, migration and tube formation in matrigel, with a much higher potency than native CRP and a similar potency to that of fibroblast growth factor. mCRP also induced phosphorylation of intracellular signalling proteins associated with mitogenesis including ERK1/2. Discussion: Knowledge of the molecular mechanisms through which mCRP promotes angiogenesis may contribute to the design of novel therapeutic treatment aimed at blocking neovessel formation in atherosclerotic plaques.
Session:
Poster Session II
Date:
Thursday 15 May 2008
Time:
12:30 - 14:00
Room:
Agora 2
Correlation between white matter lesion burden and endothelial dysfunction measured by pulse wave analysis in patients with a recent ischaemic stroke
R.L.Soiza
G.E.Hoyle
A.D.Murray
D. Prasad
D.G.Seymour
D.J.Williams
Department of Medicine & Therapeutics, University of Aberdeen
UNITED KINGDOM
Introduction White matter lesions (WML) are more common in frail individuals. Their cause is unclear, but may be related to vascular disease. Endothelial dysfunction can be measured using pulse wave analysis by the degree of attenuation in the fall in augmentation index (AIx) after inhaling salbutamol (an endothelium-dependent vasodilator), relative to sublingual glyceryl trinitrate (GTN, which is endothelium-independent). We hypothesised that WML burden would be associated with endothelial dysfunction. Methods Two radiologists independently scored WML burden on the CT brain scans of volunteers enrolled in a study of endothelial dysfunction in acute ischaemic stroke. Pulse wave analysis was performed before and after administration of 400mcg inhaled salbutamol via spacer, followed one hour later by 400mcg sublingual GTN. Results Twenty-five scans were reviewed (16 (64%) males, median age 70yrs). Inter-observer agreement for WML burden was low (kappa<.5) except for parieto-occipital WML burden (kappa (SE)= .57 (.12)). Higher mean parieto-occipital WML burden was associated with an attenuated drop in augmentation index after inhaled salbutamol (Spearman’s rho=-.41, p=.04), consistent with endothelial dysfunction. However, the correlation with the ratio of the change in AIx after salbutamol relative to GTN was non-significant (rho=-.11, p=.60). Conclusion Parieto-occipital WML burden was associated with an attenuated fall in Aix after inhaled salbutamol, but was not statistically significantly associated with the ratio of the fall in Aix after salbutamol/GTN. A larger study (with improved inter-observer agreement) is required to prove any association between endothelial dysfunction and WML.
