bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Myocyte-Specific Excision of the β1 Integrin Gene Results in Myocardial Fibrosis and Cardiac Failure
Authors: Shai Shaw-Yung , Harpf Alice E. , Babbitt Christopher J. , Jordan Maria C. , Fishbein Michael C. , Chen Ju , Omura Michelle , Leil Tarek A. , Becker K. David , Jiang Meisheng , Smith Desmond J. , Cherry Simon R. , Loftus Joseph C. , Ross Robert S.
Published: July 2002

Integrins link the extracellular matrix to the cellular cytoskeleton and serve important roles in cell growth, differentiation, migration, and survival. Ablation of β1 integrin in all murine tissues results in peri-implantation embryonic lethality. To investigate the role of β1 integrin in the myocardium, we used Cre-LoxP technology to inactivate the β1 integrin gene exclusively in ventricular cardiac myocytes. Animals with homozygous ventricular myocyte β1 integrin gene excision were born in appropriate numbers and grew into adulthood. These animals had 18% of control levels of β1D integrin protein in the heart and displayed myocardial fibrosis. High-fidelity micromanometer-tipped catheterization of the intact 5-week-old β1 integrin knockout mice showed depressed left ventricular basal and dobutamine-stimulated contractility and relaxation (LV dP/dt
max
and LV dP/dt
min
) as compared with control groups (n=8 to 10 of each,
P
<0.01). Hemodynamic loading imposed by 7 days of transverse aortic constriction showed that the β1 integrin knockout mice were intolerant of this stress as they had 53% survival versus 88% in controls (n=15 each). By 6 months of age, mice with depressed ventricular expression of β1 integrin developed a dilated cardiomyopathy that was not evident in any control animals and had patchy decrease in glucose metabolism as determined by positron emission tomography. Myocyte membrane integrity as determined via Evan’s blue dye staining was disrupted in the β1 integrin knockout mice. This model provides strong evidence for the importance of β1 integrin in cardiac form and function and indicates that integrins can be linked to development of cardiomyopathies.
Retrovirally Mediated Overexpression of Versican V3 by Arterial Smooth Muscle Cells Induces Tropoelastin Synthesis and Elastic Fiber Formation In Vitro and In Neointima After Vascular Injury
Authors: Merrilees Mervyn J. , Lemire Joan M. , Fischer Jens W. , Kinsella Michael G. , Braun Kathleen R. , Clowes Alexander W. , Wight Thomas N.
Published: July 2002

Versican is an extracellular matrix (ECM) proteoglycan that is synthesized as multiple splice variants. In a recent study, we demonstrated that retroviral-mediated overexpression of the variant V3, which lacks chondroitin sulfate (CS) chains, altered arterial smooth muscle cell (ASMC) phenotype in short-term cell culture. We now report that V3-overexpressing ASMCs exhibit significantly increased expression of tropoelastin and increased formation of elastic fibers in long-term cell cultures. In addition, V3-overexpressing ASMCs seeded into ballooned rat carotid arteries continued to overexpress V3 and, at 4 weeks after seeding, produced a highly structured neointima significantly enriched in elastic fiber lamellae. In contrast to the hydrated, myxoid neointima produced by rounded or stellate vector-alone–transduced cells, V3-expressing cells produced a compact and highly ordered neointima, which contained elongated ASMCs that were arranged in parallel arrays and separated by densely packed collagen bundles and elastic fibers. These results indicate that a variant of versican is involved in elastic fiber assembly and may represent a novel therapeutic approach to facilitate the formation of elastic fibers.
Targeting CCR2 or CD18 Inhibits Experimental In-Stent Restenosis in Primates
Authors: Horvath Christopher , Welt Frederick G.P. , Nedelman Mark , Rao Patricia , Rogers Campbell
Published: July 2002

A central role for leukocytes in neointimal hyperplasia after arterial injury is suspected. However, the relative importance of neutrophils and monocytes in balloon or stent-induced injury are not well understood, and mechanistic targeting of leukocyte recruitment or function is crude. We determined the temporal and spatial distribution of different leukocytes after balloon and stent-induced injury in primate iliac arteries. Based on these data, we targeted neutrophil and monocyte recruitment selectively after angioplasty or stent implantation and demonstrated that monocyte-specific blockade achieved via blockade of the MCP-1 receptor CCR2, was effective at reducing neointimal hyperplasia after stenting. In contrast, combined neutrophil and monocyte blockade achieved by targeting the leukocyte β
2
-integrin β-subunit CD18 was required to reduce neointimal hyperplasia after balloon injury. Distinct patterns of leukocyte infiltration in balloon versus stent-injured arteries predict distinct mechanisms for antiinflammatory strategies targeting neutrophils or monocytes in primates and may assist design of effective clinical strategies for optimizing vascular interventions.
Relation of Apo(a) Size to Carotid Atherosclerosis in an Elderly Multiethnic Population
Authors: Paultre Furcy , Tuck Catherine H. , Boden-Albala Bernadette , Kargman Douglas E. , Todd Elizabeth , Jones Jeffrey , Paik Myunghee C. , Sacco Ralph L. , Berglund Lars
Published: July 2002

Lipoprotein(a) [Lp(a)] is a novel risk factor for atherosclerosis, whose role in multiracial populations has been debated. We recently demonstrated a significant association of elevated levels of Lp(a) carried in particles containing small apolipoprotein(a) [apo(a)] isoforms with coronary artery disease in African American and white men. To extend these findings, we investigated the associations between Lp(a) levels, apo(a) size, and maximum internal carotid artery plaque thickness (MPT) in a randomly selected elderly multiethnic population (173 men and 253 women, consisting of 135 African Americans, 146 Hispanics, and 145 whites; mean age 70.5±11.4 years). Lp(a) levels were not associated with MPT. Among white men, MPT was associated with a small apo(a) isoform size (
P
=0.03) as well as with the amount of Lp(a) carrying the small apo(a) size (
P
=0.04), and the latter showed a borderline association in African American men (
P
=0.07). Among white women, but not in Hispanic or African American women, MPT was associated with the amount of Lp(a) carrying a small apo(a) isoform size (
P
<0.01). For all patients, the amount of Lp(a) carrying the small apo(a) size was associated with carotid atherosclerosis when there was control for age, sex, ethnicity, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, diabetes mellitus, hypertension, waist-to-hip ratio, and current smoking status (
P
=0.03). This association was significant for all men (
P
=0.03) and for white women (
P
=0.007). The results suggest that molecular properties of apo(a) are important in determining the atherogenicity of Lp(a).
Shear Stress–Induced Endothelial Cell Migration Involves Integrin Signaling Via the Fibronectin Receptor Subunits α
5
and β
1
Authors: Urbich Carmen , Dernbach Elisabeth , Reissner Agnes , Vasa Mariuca , Zeiher Andreas M. , Dimmeler Stefanie
Published: July 2002

Endothelial cell (EC) migration is required for angiogenesis, neovascularization, and reendothelialization. Integrins, known as αβ-heterodimeric cell-surface receptors, regulate cell migration and are essential for mechanotransduction of hemodynamic forces. Therefore, we investigated the effect of shear stress on EC migration and the contribution of the integrins and integrin-dependent signaling pathways in a scratched-wound assay. Laminar shear stress–induced EC migration was significantly reduced by integrin-receptor blocking with RGD peptides or with neutralizing antibodies against integrin subunits α
5
and β
1
, whereas antibodies against α
v
β
3
or α
2
β
1
had no effect. Cell-surface levels of the integrin α
5
and β
1
were specifically upregulated in migrating ECs at the wound edges. Consistent with the important role of integrins for shear stress–increased cell migration, blockade of the integrin-associated adapter protein Shc by overexpression of dominant negative construct inhibited shear stress–stimulated EC migration. Moreover, pharmacological inhibition of the integrin downstream effector signaling molecules ERK1/2 or phosphatidyl-inositol-3-kinase prevented shear stress–induced EC migration. In contrast, inhibition of the NO synthase had no effect. Taken together, our results indicate that laminar shear stress enhances EC migration via the fibronectin receptor subunits α
5
and β
1
, which serve as central mechanotransducers in ECs. Shear stress–induced enhancement of EC migration might contribute importantly to accelerated reendothelialization of denuded arteries.
Oxidized Membrane Vesicles and Blebs From Apoptotic Cells Contain Biologically Active Oxidized Phospholipids That Induce Monocyte-Endothelial Interactions
Authors: Huber Joakim , Vales Anja , Mitulovic Goran , Blumer Michael , Schmid Rainer , Witztum Joseph L. , Binder Bernd R. , Leitinger Norbert
Published: July 2002

Abstract
—

Membrane vesicles (MVs) released from activated cells and blebs from apoptotic cells are increased in patients with vascular disease and in those with atherosclerotic lesions, and their contribution to inflammatory reactions has been suggested. At sites of inflammation, MVs could serve as rapidly available substrates for peroxidation, carry oxidized compounds to activate other cells, and amplify inflammation. Here, we show that MVs released from tert-butyl hydroperoxide–treated endothelial cells (ECs) and apoptotic blebs, but not MVs from Ca
2+
ionophore–treated ECs, stimulate monocyte adhesion to ECs, an important step in atherogenesis. We show that oxidized phospholipids, such as the previously identified 1-palmitoyl-2-(5-oxovaleroyl)-
sn
-glycero-3-phosphorylcholine (POVPC), are responsible for biological activity in MVs and apoptotic blebs. Natural antibodies from apolipoprotein E–null mice that recognize POVPC also recognize oxidized MVs, and pretreatment of MVs with these antibodies inhibits their ability to activate ECs. Furthermore, the biological activity of oxidized MVs is inhibited by platelet-activating factor receptor antagonists, which have been shown to inhibit the action of POVPC. Taken together, we show that oxidized MVs and apoptotic blebs stimulate ECs to specifically bind monocytes, with oxidized phospholipids (POVPC) being the active principle. In addition to oxidized lipoproteins, oxidized MVs and apoptotic blebs may play an important role in chronic inflammatory diseases, such as atherosclerosis.
Effects of Dominant-Negative c-Jun on Platelet-Derived Growth Factor–Induced Vascular Smooth Muscle Cell Proliferation
Authors: Zhan Yumei , Kim Shokei , Yasumoto Hideo , Namba Masashi , Miyazaki Hitoshi , Iwao Hiroshi
Published: July 2002

Although platelet-derived growth factor (PDGF)-BB is thought to participate in vascular disorders, the mechanism of PDGF-induced vascular smooth muscle cell (SMC) proliferation is not fully understood. This study was undertaken to examine the role of c-Jun in PDGF-BB–induced proliferation of rat aortic SMCs. PDGF-BB (10 ng/mL) significantly increased activator protein (AP)-1 DNA binding activity in SMCs, followed by the increase in [
3
H]thymidine incorporation and cell number. SMCs were infected with recombinant adenovirus containing TAM67, a dominant-negative c-Jun lacking the transactivation domain of wild c-Jun (Ad-DN-c-Jun), to inhibit endogenous AP-1. Ad-DN-c-Jun, which specifically blocked AP-1 transcriptional activity, significantly inhibited PDGF-BB–induced increases in [
3
H]thymidine incorporation or cell number. As shown by flow cytometric analysis, Ad-DN-c-Jun inhibited PDGF-BB–induced entrance of SMCs into S phase, leading to a G
1
arrest. Ad-DN-c-Jun attenuated PDGF-BB–induced downregulation of p27
Kip1
, as shown by Western blot analysis, and the prevented PDGF-BB–induced decrease in cyclin E/cyclin-dependent kinase 2 complex–associated p27
Kip1
, as shown by immunoprecipitation study. Furthermore, protein kinase assay showed that Ad-DN-c-Jun blocked PDGF-BB–induced activation of cyclin-dependent kinase 2. Our results provide the first evidence that dominant-negative c-Jun inhibits PDGF-BB–induced vascular SMC proliferation by preventing the downregulation of p27
Kip1
, thereby supporting the important role of c-Jun in vascular SMC proliferation.
Influence of Anatomical Location on Arterial Thrombosis
Authors: Karnicki Krzysztof , Komorowicz Erzsebet , Fass David N. , Owen Whyte G. , McBane Robert D.
Published: July 2002

Atherosclerosis manifests as a systemic disease with near global involvement of the named segments of the arterial tree. Acute thrombotic arterial occlusion, however, is not equally distributed. To evaluate intra-individual regional differences in arterial thrombogenicity, we compared
111
In-platelet deposition in porcine carotid and femoral arteries after a standardized crush injury. Within the unidirectional flow conditions of elastic carotid arteries, platelet deposition was more than 3-fold higher compared with predominantly muscular femoral arteries with triphasic arterial flow. To determine the influence of rheology on platelet deposition after crush injury, carotid arteries were transplanted into the femoral position and compared with the paired native carotid and femoral arteries. Similarly, femoral arteries transposed to the carotid position were compared with the paired native carotid artery. In each of these experiments, arterial transposition to a new anatomic location imparts a predilection for platelet deposition indigenous to the new location. In the controlled environment of two high-shear thrombin–independent and –dependent flow chambers, porcine carotid and femoral arterial substrates were indistinguishable from one another with respect to platelet deposition. Regional differences in arterial hemodynamics may account for substantial differences in thrombosis arising from deep arterial injury.
Aortic Constriction Exacerbates Atherosclerosis and Induces Cardiac Dysfunction in Mice Lacking Apolipoprotein E
Authors: Wu Jiao-Hui , Hagaman John , Kim Shinja , Reddick Robert L. , Maeda Nobuyo
Published: July 2002

Despite considerable evidence suggesting that hypertension contributes to the development and progression of atherosclerosis, the causative links remain unclear. We have tested the effects of chronic hypertension induced by suprarenal aortic constriction on the development of atherosclerosis in apolipoprotein E–deficient (
Apoe
−/−
) mice. Compared with a sham operation, narrowing the aortic luminal diameter by 33% increased blood pressure proximal to the constriction by ≈15 mm Hg, but the pressures distal to the constriction were unchanged. Kidney renin mRNA and plasma renin activity were also unaffected. Compared with plaque size after the sham operation, atherosclerotic plaque size in the aortic root 8 weeks after coarctation was increased to 245% and 152% in males and females, respectively. Aortic segments at the constriction were free of atherosclerotic deposits, but segments proximal to the constriction were dilated and had atherosclerotic lesions. Thrombi were present immediately below the constriction in
Apoe
−/−
and wild-type vessels. Surprisingly, compared with wild-type mice, the
Apoe
−/−
mice were more susceptible to the cardiac hypertrophy and dysfunction induced by pressure overload. Thus, aortic coarctation exacerbates atherosclerosis in vessels proximal to the constriction without a concomitant increase in the renin-angiotensin system. Our study also suggests that apolipoprotein E plays an important role in modulating cardiac hypertrophy.
Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour
Authors: Bostom Andrew G. , Jacques Paul F. , Liaugaudas Gintaras , Rogers Gail , Rosenberg Irwin H. , Selhub Jacob
Published: July 2002

The prevalence of deficient plasma folate status and elevated total plasma levels of homocysteine (tHcy), have been dramatically reduced after fortification of all enriched cereal grain flour products with folic acid at 140 μg/100 g flour. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid-based vitamin B supplementation among stable coronary artery disease (CAD) patients. Using a 2×2 factorial design, 131 stable CAD patients (mean age 60.1 years; 29.8% women) were randomly assigned to receive a combination of folic acid 2.5 mg/d, riboflavin 5 mg/d, + B
12
0.4 mg/d, or placebo, with or without vitamin B
6
50 mg/d, for 12 weeks of treatment. ANCOVA adjusted for baseline fasting tHcy levels revealed only very modest (ie, ≈1.0 μmol/L), albeit statistically significant (
P
<0.05), reductions in mean fasting tHcy levels afforded by the folic acid-containing treatments. Additional analyses indicated that none of the treatments provided a statistically significant reduction in the 2-hour post-methionine increase in tHcy levels, relative to placebo treatment. CAD patients exposed to cereal grain flour products fortified with folic acid who receive high-dose, folic acid-containing vitamin B regimens, experience only very modest reductions in their mean fasting plasma tHcy levels. These findings have important implications for the statistical power of clinical trials testing the hypothesis that tHcy-lowering treatment may reduce recurrent atherothrombotic event rates.
Accumulation of Biglycan and Perlecan, but Not Versican, in Lesions of Murine Models of Atherosclerosis
Authors: Kunjathoor Vidya V. , Chiu Diane S. , O’Brien Kevin D. , LeBoeuf Renée C.
Published: July 2002

Proteoglycan accumulation within the arterial intima has been implicated in lipoprotein retention and in atherosclerosis progression in humans. Two commonly studied murine models of atherosclerosis, the apolipoprotein E (apoE)-deficient (apoE−/−) mouse and the low density lipoprotein receptor–deficient (LDLR−/−) mouse, develop arterial lesions similar to those of human atherosclerosis. However, specific proteoglycan classes that accumulate in lesions of these mice and their relation to the retention of specific apolipoproteins have not been previously determined. In this report, we characterized the distribution of proteoglycans (versican, biglycan, and perlecan) and apolipoproteins (apoB, apoA-I, and apoE) in proximal aortic lesions of chow-fed apoE−/− and LDLR−/− mice at 10, 52, and 73 weeks of age. We observed that similar to the apoE−/− mice, the LDLR−/− mice develop intermediate and advanced plaques within 52 weeks of age. Perlecan and biglycan (both are proteoglycans) appeared early in lesion development with distinct expression patterns as the plaques advanced. Versican, a major proteoglycan detected in human plaques, was mostly absent in both strains. ApoA-I and apoB were detected in early through advanced lesions in regions of proteoglycan accumulation in both strains. Our results indicate that proteoglycans may contribute to the retention of lipoproteins at the earliest stage of atherosclerosis in murine models of atherosclerosis.
Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease
Authors: Mills Joseph D. , Mansfield Michael W. , Grant Peter J.
Published: July 2002

Elevated levels of tissue-type plasminogen activator antigen (tPA), fibrinogen, and fibrin D-dimer predict coronary artery disease (CAD) events and stroke. These factors, possibly in association with insulin resistance, may be important in families in which CAD has become clinically apparent at a premature age. From 125 patients with angiographically confirmed, premature CAD, 175 healthy male relatives (age ≤65 years) were identified. One hundred seventy-five healthy volunteers of similar age and without any family history of CAD were recruited. There were no differences between relatives and controls in terms of conventional CAD risk factors, cigarette smoking, alcohol consumption, or cardiorespiratory fitness. Estimated insulin resistance and plasminogen activator inhibitor 1 levels were not increased in relatives. Fibrin D-dimer, tPA, and fibrinogen levels were elevated in relatives compared with controls, 55 (52 to 58) ng/mL versus 49 (45 to 53) ng/mL,
P
<0.01, for D-dimer; 8.0 (7.5 to 8.6) ng/mL versus 5.6 (5.2 to 6.1) ng/mL,
P
<0.001, for tPA; and 3.0 (2.9 to 3.1) g/L versus 2.8 (2.7 to 2.9) g/L,
P
<0.05, for fibrinogen. These differences remained after adjustment for correlates, including fibrinogen, age for D-dimer, and features of the insulin resistance syndrome for tPA. tPA and D-dimer levels are elevated in the healthy, male, first-degree relatives of patients with premature CAD. This association is independent of potential confounding factors.
Altered Hemodynamic Responses in Patients After Subcortical Stroke Measured by Functional MRI
Authors: Pineiro R. , Pendlebury S. , Johansen-Berg H. , Matthews P.M.
Published: July 2002

Background and Purpose

—

Blood oxygenation level–dependent (BOLD) functional MRI (fMRI) is a promising method for defining brain recovery after stroke quantitatively. Applications thus far have assumed that the BOLD hemodynamic response in patients after stroke is identical to that in healthy controls. However, because of local vascular compromise or more diffuse vascular disease predisposing to infarction, this assumption may not be justified after stroke. We sought to test whether patients who have suffered a lacunar stroke show BOLD fMRI response characteristics identical to those of healthy controls.

Methods

—

We measured the BOLD fMRI signal time course in the sensorimotor cortex contralateral to the affected hand with finger- or hand-tapping tasks for minimally or mildly impaired right-handed patients (n=12) after lacunar strokes causing limb weakness and for healthy controls (n=20).

Results

—

With a right-handed sequential finger-tapping task, the rate of rise and maximum increase of the BOLD signal in the contralateral sensorimotor cortex were >30% lower (
P
≤0.01) in the stroke patients. Similar relative decreases were found for the same task performed with the left hand. These changes were found in patients both in the hemisphere affected by stroke and in the unaffected hemisphere, suggesting that the BOLD fMRI time course differences observed arise from a diffuse functional pathology. The difference between patients and controls is not a result of age alone, since differences were not found between the younger (n=10; aged 22 to 38 years) and the older (n=10; aged 56 to 83 years) healthy controls. The effect also does not seem to be dependent on the specific hand movement task used.

Conclusions

—

The magnitude of the BOLD fMRI response can be reduced in stroke patients even if infarcts do not involve the cortex. This may be a consequence of the stroke, but the observation that the BOLD signal time course is similar in the affected and unaffected hemispheres suggests that it also could result from preexisting pathophysiological changes in the cerebral microvasculature.
Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke
Authors: Madonna Pasquale , de Stefano Valentino , Coppola Antonio , Cirillo Ferdinando , Cerbone Anna Maria , Orefice Giuseppe , Di Minno Giovanni
Published: July 2002

Background and Purpose

—

The mechanisms of ischemic stroke in young adults are poorly understood. During the last years, several studies suggested a role for genetic factors predisposing to thrombophilia and for moderate hyperhomocysteinemia in this setting.

Methods

—

We evaluated in 132 consecutive patients (66 males, 66 females; mean±SD age, 38.4±11.7 years; mean±SD age at first event, 34.8±10.9 years; range, 6 months to 50 years) referred to our center between January 1997 and December 1999 for a history of young adult ischemic stroke (age at first event, <51 years) the prevalence of factor V (FV) Leiden, prothrombin (FII) G20210A, and C677T and 5,10-methylenetetrahydrofolate reductase (MTHFR) gene mutations and fasting serum total homocysteine levels. Two hundred sixty-two apparently healthy subjects (117 males, 145 females; mean±SD age, 36±13.2 years) served as controls.

Results

—

Total homocysteine levels differed significantly (
P
=0.004,
t
test) between patients and controls: 13.03±18.61 versus 10.75±6.24 μmol/L (mean±SD), respectively. In contrast, homozygosity for the
TT
mutation of the MTHFR gene was 30 of 132 (22.7%) in patients and 45 of 262 (17.2%) in controls; this difference was not statistically significant (
P
>0.05, χ
2
test). However, when we stratified the whole population according to genotype, fasting serum homocysteine levels were significantly higher in
TT
patients than in
TT
controls (25.3±36.8 versus 15±11.6 μmol/L;
P
=0.02,
t
test). Mutations of FV Leiden and of FII G20210A gene are currently reported to be associated with a tendency toward ischemic stroke. Their frequencies were not statistically significantly different between patients and controls in this setting: 7 of 132 (5.3%) versus 17 of 262 (6.5%) for FV Leiden and 10 of 132 (7.6%) versus 16 of 262 (6.1%) for FII G20210A, respectively (all
P
>0.05, χ
2
test).

Conclusions

—

In the present cohort of patients, moderate hyperhomocysteinemia is the only variable that helps to identify young adults with a history of ischemic stroke.
Effects of Hypothermia on Excitatory Amino Acids and Metabolism in Stroke Patients
Authors: Berger Christian , Schäbitz Wolf-Rüdiger , Georgiadis Dimitrios , Steiner Thorsten , Aschoff Alfred , Schwab Stefan
Published: July 2002

Background and Purpose

—

The objective of this study was to assess the effect of therapeutic moderate hypothermia on excitatory amino acids and metabolism by applying cerebral microdialysis in patients suffering from space-occupying middle cerebral artery infarction.

Methods

—

This was an open, prospective, observational study of 12 patients undergoing moderate hypothermia (33°C) as rescue therapy for large, life-threatening middle cerebral artery infarction. Microdialysis probes were placed concomitantly with intracranial pressure (ICP) measuring devices in the frontal lobe of the infarcted and/or noninfarcted hemisphere. Using the CMA 600 Microdialysis Autoanalyzer, we analyzed glutamate, glycerol, pyruvate, and lactate.

Results

—

According to follow-up cranial CT scans, 3 different compartments of microdialysis measurements could be defined. First, noninfarcted brain tissue had stable dialysate concentrations but a significant effect of hypothermia on glutamate (2.6 versus 3.6 μmol/L), lactate (1.8 versus 3 mmol/L), and pyruvate (50 versus 95.8 μmol/L). Second, measurements from peri-infarct tissue had a significant effect of hypothermia on glutamate (4.8 versus 12.6 μmol/L), glycerol (58 versus 82 μmol/L), lactate (0.7 versus 1.3 mmol/L), and pyruvate (13.3 versus 36.8 μmol/L). Third, dialysate concentrations obtained from irreversibly damaged tissue were excessive for glutamate (453 μmol/L), glycerol (1187 μmol/L), lactate (12 μmol/L), and pyruvate (4 μmol/L). In this extreme compartment, no effect of hypothermia was observed.

Conclusions

—

Cerebral microdialysis is a safe and feasible bedside method for neurochemical monitoring indicating normal brain tissue, potentially salvageable brain tissue, and irreversibly damaged areas in stroke. We could demonstrate that hypothermia decreases glutamate, glycerol, lactate, and pyruvate in the “tissue at risk” area of the infarct but not within the infarct core. Thus, future treatment strategies for life-threatening stroke should be guided by close neurochemical monitoring.
Predictors of Cognitive Dysfunction After Subarachnoid Hemorrhage
Authors: Kreiter Kurt T. , Copeland Daphne , Bernardini Gary L. , Bates Joseph E. , Peery Shelley , Claassen Jan , Du Y. Evelyn , Stern Yaakov , Connolly E. Sander , Mayer Stephan A.
Published: July 2002

Background

—

Cognitive dysfunction is a common and disabling sequela of subarachnoid hemorrhage (SAH). Although several clinical and radiographic findings have been implicated in the pathogenesis of cognitive dysfunction after SAH, few prospective studies have comprehensively and simultaneously evaluated these risk factors.

Methods

—

Between July 1996 and March 2000, we prospectively evaluated 113 of 248 consecutively admitted nontraumatic SAH patients alive at 3 months with a comprehensive neuropsychological evaluation. Summary scores for 8 cognitive domains were calculated to express test performance relative to the entire study population. Clinical and radiographic variables associated with domain-specific cognitive dysfunction were identified with forward stepwise multiple regression, with control for the influence of demographic factors.

Results

—

The study participants were younger (
P
=0.005), less often white (
P
=0.006), and had better 3-month modified Rankin scores (
P
=0.001) than those who did not undergo neuropsychological testing. The proportion of subjects who scored in the impaired range (>2 SD below the normative mean) on each neuropsychological test ranged from 10% to 50%. Predictors of cognitive dysfunction in 2 or more domains in the multivariate analysis included global cerebral edema (4 domains), left-sided infarction (3 domains), and lack of a posterior circulation aneurysm (2 domains). Other variables consistently associated with cognitive dysfunction in the univariate analysis included admission Hunt-Hess grade >2 and thick SAH in the anterior interhemispheric and sylvian fissures.

Conclusions

—

Global cerebral edema and left-sided infarction are important risk factors for cognitive dysfunction after SAH. Treatment strategies aimed at reducing neurological injury related to generalized brain swelling, infarction, and clot-related hemotoxicity hold the best promise for improving cognitive outcomes after SAH.
Cooling-Induced Carotid Artery Dilatation
Authors: Mustafa Seham , Thulesius Olav
Published: July 2002

Background and Purpose

—

Clinical and experimental studies seem to indicate that hypothermia may improve outcome in stroke victims and reduce experimental brain injury. The current interpretation is that cooling has a neuroprotective effect by reducing brain metabolism. The objective of our study was to test the hypothesis that hypothermia induces arterial vasodilatation and thereby increases cerebral blood flow.

Methods

—

We recorded isometric tension in rabbit carotid artery strips in organ baths during stepwise cooling. The cooling responses were tested at basal tone, in noradrenaline-precontracted vessels, and after electric field stimulation.

Results

—

Stepwise cooling from 37°C to 4°C induced reproducible graded relaxation, inversely proportional to temperature. The responses could be elicited at basal tone and in precontracted vessels. Cooling decreased the contractile responses to norepinephrine and potassium chloride. Cooling at 20°C decreased the contractile responses to electric field stimulation, while at 10°C these were totally abolished. Cooling-induced vasodilatation is not dependent on an endothelial mechanism.

Conclusions

—

Cooling of carotid artery preparations induced a reversible graded vasodilatation and decreased or abolished the effect of vasocontractile neurotransmitters. The effect of local hypothermia could increase cerebral blood flow and may constitute a positive therapeutic modality in stroke patients.
Changes of Neural Activity Correlate With the Severity of Cortical Ischemia in Patients With Unilateral Major Cerebral Artery Occlusion
Authors: Bundo Masahiko , Inao Suguru , Nakamura Akinori , Kato Takashi , Ito Kengo , Tadokoro Masanori , Kabeya Ryusuke , Sugimoto Toru , Kajita Yasukazu , Yoshida Jun
Published: July 2002

Background and Purpose

—

In major cerebral arterial steno-occlusive diseases, there can be remarkably decreased hemodynamic reserve without marked neurological impairments. In such settings, it is not known whether the neural activity is well maintained or disturbed according to the severity of cerebral ischemia. The present study was therefore undertaken to examine the neural activity under mild cerebral ischemia resulting from major cerebral arterial occlusion.

Methods

—

Seven patients with minor neurological impairment as well as either unilateral internal carotid artery or middle cerebral artery occlusion were studied. The severity of the cortical ischemia was assessed by measuring regional cerebral blood flow (rCBF) with positron emission tomography. The change in neural activity in the ischemic brain was then evaluated by means of somatosensory evoked magnetic field with magnetoencephalography.

Results

—

The rCBF in the primary sensory area and the strength of the initial component of somatosensory evoked magnetic field (N20 m) were significantly reduced (
P
<0.01) and the second component (P30 m) was significantly augmented (
P
<0.05) in the lesioned cerebral hemisphere as compared with the nonlesioned hemisphere. The asymmetry indexes for N20 m were positively correlated (
r
=0.78) and those for P30 m were inversely correlated (
r
=−0.92) with asymmetry indexes for rCBF.

Conclusions

—

In patients with either unilateral internal carotid artery or middle cerebral artery occlusion and minor neural impairments, there was a reduction of afferent signal and an augmentation of the secondary response of the neurons in the primary sensory area. This showed correlation with the severity of cortical ischemia.
Incidence of Aneurysmal Subarachnoid Hemorrhage in Shimokita, Japan, From 1989 to 1998
Authors: Ohkuma Hiroki , Fujita Seiichiroh , Suzuki Shigeharu
Published: July 2002

Background and Purpose

—

The incidence of subarachnoid hemorrhage (SAH) has been investigated in many studies. A recent study in Izumo, Japan, indicates that the incidence of SAH is as high as that in Finland. The purpose of this study was to confirm the high incidence of SAH in Japan.

Methods

—

The incidence rate of SAH was investigated from 1989 through 1998 in the Shimokita peninsula, which is a clearly defined closed-boundary area in northern Japan with a population of 89 991. The registration was based on the complete referral system of SAH patients. All cases suspected of SAH underwent CT scan, and the images were referred to stroke specialists. The moribund cases and dead-on-arrival cases suspected of SAH also underwent CT scan.

Results

—

From 1989 through 1998, 198 cases were diagnosed as having aneurysmal SAH. Out of these, 26 cases were moribund or dead when the initial CT scan was performed. The age-adjusted annual incidence of SAH was 21 per 100 000 person-years. The age and sex distribution of the cases indicated that the incidence plateaued after age 45 in men and the incidence increased after age 45 and reached the peak after 75 years in women.

Conclusions

—

The high incidence of SAH in Japan is confirmed. The incidence of SAH obtained in this study is near to that of the Izumo study, of which the size of the geographic region and denominator and diagnostic criteria were similar to this study.
Clinical and Sonographic Patterns of Tandem Internal Carotid Artery/Middle Cerebral Artery Occlusion in Tissue Plasminogen Activator–Treated Patients
Authors: El-Mitwalli Ashraf , Saad Mohamed , Christou Ioannis , Malkoff Marc , Alexandrov Andrei V.
Published: July 2002

Background and Purpose

—

The National Institutes of Health Stroke Scale (NIHSS) is predictive of thrombus presence but has limited ability to identify occlusion location in the anterior circulation. We describe clinical and sonographic patterns that are associated with tandem internal carotid artery (ICA) and middle cerebral artery (MCA) occlusions.

Methods

—

Consecutive acute ischemic stroke patients receiving intravenous tissue plasminogen activator (TPA) were studied. Pretreatment NIHSS scores and bedside transcranial Doppler (TCD) were obtained for all patients.

Results

—

A total of 95 patients treated with intravenous TPA at 132±60 minutes from stroke onset were studied. On TCD, 48 had isolated MCA occlusion (mean NIHSS 16.8±5.8, median 17, range 5 to 28); and 16 had tandem ICA/MCA occlusion (mean NIHSS 18.8±5.8, median 22, range 8 to 29;
P
=NS). In the MCA occlusion and tandem ICA/MCA occlusion groups, 19% and 11%, respectively, had NIHSS scores <12 points. Compared with the NIHSS scores in patients with hemiplegia, forced gaze deviation, and complete neglect, the lower NIHSS scores were attributable to partial arm and/or leg paresis, gaze preference, and partial neglect. In those patients, TCD showed ≥2 major collateral channels and low-resistance flow at the M1 origin, suggesting perfusion of perforating arteries. Although TCD cannot differentiate between high-grade ICA stenosis or occlusion, collateral flow patterns and stenotic signals at the terminal ICA differentiated tandem lesions from isolated MCA occlusion (
P
<0.01).

Conclusions

—

Tandem ICA/MCA occlusion was found on TCD in 17% of TPA-treated patients. NIHSS scores were similar in patients with isolated MCA and tandem occlusions. Lower NIHSS scores were seen in patients with a higher number of major collateral flow channels and higher Thrombolysis in Brain Ischemia (TIBI) flow grades at the MCA origin.
Combined Endothelial Nitric Oxide Synthase Upregulation and Caveolin-1 Downregulation Decrease Leukocyte Adhesion in Pial Venules of Ovariectomized Female Rats
Authors: Santizo Roberto A. , Xu Hao-Liang , Galea Elena , Muyskens Steve , Baughman Verna L. , Pelligrino Dale A.
Published: July 2002

Background and Purpose

—

We recently found that chronic estrogen depletion enhances leukocyte adhesion in pial venules in the female rat, while estrogen repletion decreases it. Estrogen-associated repression of inflammation may be due to upregulation of the endothelial isoform of nitric oxide synthase (eNOS) and concomitant downregulation of the endogenous inhibitor of eNOS, caveolin-1 (CAV-1). In this study we examined the effects of estrogen-independent eNOS upregulation (via simvastatin) and/or CAV-1 downregulation (antisense) on pial venular leukocyte adhesion in ovariectomized (OVX) rats.

Methods

—

Intact and OVX rats were prepared with closed cranial windows. Adherent rhodamine 6G–labeled leukocytes were viewed by intravital microscopy. To demonstrate the importance of pial venular eNOS in the resistance to leukocyte adhesion, intact female rats were treated with a nonselective (
N
G
-nitro-
l
-arginine) or a neuronal NOS–selective (7-nitroindazole) inhibitor. In OVX females, leukocyte adhesion was compared in the following groups: (1) untreated; (2) treated with simvastatin; (3) treated with simvastatin plus CAV-1 antisense; (4) treated with simvastatin plus CAV-1 missense; (5) treated with CAV-1 antisense; and (6) treated with CAV-1 missense.

Results

—

In intact females, pial venular leukocyte adhesion was increased when total NOS activity, but not neuronal NOS activity alone, was blocked. In OVX rats, basal leukocyte adhesion, measured as the percentage of venular area occupied by adherent leukocytes, was attenuated (by ≈60%) only in the presence of combined simvastatin plus CAV-1 antisense treatment.

Conclusions

—

Present findings demonstrate that eNOS-derived NO plays an important role in limiting cerebral venular leukocyte adhesion in female rats. These data also suggest that simvastatin-induced upregulation of eNOS expression in OVX rats will not restore eNOS function, as measured by decreased leukocyte adhesion, unless CAV-1 levels are reduced as well.
Randomized Controlled Study of Stroke Unit Care Versus Stroke Team Care in Different Stroke Subtypes
Authors: Evans Andrew , Harraf Farzaneh , Donaldson Nora , Kalra Lalit
Published: July 2002

Background and Purpose

—

The benefits of stroke unit management may vary according to stroke subtype. A post hoc analysis of the influence of stroke subtype on stroke unit effectiveness was undertaken by using prospective data collected in a randomized controlled trial.

Methods

—

Two hundred sixty-seven patients with moderately severe ischemic stroke (164 with large-vessel infarcts and 103 with lacunar infarcts) were randomly allocated to treatment in stroke units or in general medical wards with specialist stroke team support. Mortality, institutionalization, neurological, functional, and quality-of-life scores and resource use were assessed at 3 and again at 12 months after stroke onset. An intention-to-treat analysis was undertaken, and logistic regression was used to evaluate the independent effect of stroke unit intervention.

Results

—

Stroke team–supported management was associated with higher mortality (odds ratio [OR] 4.9, 95% CI 1.3 to 18.6) and higher mortality or institutionalization (OR 2.9, 95% CI 1.1 to 7.4) at 3 months (OR 3.6, 95% CI 1.5 to 8.7) and at 1 year (OR 2.8, 95% CI 1.3 to 6.2) in patients with large-vessel infarcts. In contrast, there were no significant differences in outcome in patients with lacunar strokes managed in the stroke unit or by the stroke team. In patients with lacunar strokes, stroke unit care was associated with a longer length of hospital stay (18 versus 13.5 days for stroke unit care versus stroke team care, respectively;
P
<0.01) and significantly greater use of therapy.

Conclusions

—

Stroke units improve the outcome in patients with large-vessel infarcts but not in those with lacunar syndromes. For lacunar strokes, stroke unit management may be associated with higher initial health costs for equivalent benefit.
Effects of Body Position on Intracranial Pressure and Cerebral Perfusion in Patients With Large Hemispheric Stroke
Authors: Schwarz Stefan , Georgiadis Dimitrios , Aschoff Alfred , Schwab Stefan
Published: July 2002

Background and Purpose

—

The purpose of this study was to prospectively evaluate the effects of body position in patients with large supratentorial stroke.

Methods

—

We performed 43 monitoring sessions in 18 patients with acute complete or subtotal middle cerebral artery (MCA) territory stroke. Intracranial pressure (ICP) was monitored with a parenchymal probe. Mean arterial blood pressure, ICP, and MCA peak mean flow velocity (V
m
MCA) were continuously recorded. Patients with acute ICP crises were excluded. After baseline values at a 0° supine position were attained, the backrest was elevated in 2 steps of 5 minutes each to 15° and 30° and then returned to 0°.

Results

—

Baseline mean arterial pressure was 90.0±1.6 mm Hg and fell to 82.7±1.7 mm Hg at 15° and 76.1±1.6 mm Hg at 30° backrest elevation (
P
<0.0001). ICP decreased from 13.0±0.9 to 12.0±0.9 mm Hg at 15° and 11.4±0.9 mm Hg at 30° backrest elevation (
P
<0.0001). As a result, cerebral perfusion pressure decreased from a baseline value of 77.0±1.8 to 70.0±1.8 mm Hg at 15° and 64.7±1.7 mm Hg at 30° backrest elevation (
P
<0.0001). V
m
MCA was already higher on the affected side during baseline measurements. V
m
MCA decreased from 72.8±11.3 cm/s at 0° to 67.2±9.7 cm/s at 15° and 61.2±8.9 cm/s at 30° on the affected and from 49.9±3.7 cm/s at 0° to 47.7±3.6 cm/s at 15° and 46.2±2.2 cm/s at 30° on the contralateral side (
P
<0.0001).

Conclusions

—

In patients with large hemispheric stroke without an acute ICP crisis, cerebral perfusion pressure was maximal in the horizontal position although ICP was usually at its highest point. If adequate cerebral perfusion pressure is considered more desirable than the absolute level of ICP, the horizontal position is optimal for these patients.
Cost of Identifying Patients for Carotid Endarterectomy
Authors: Benade Marikie M. , Warlow Charles P.
Published: July 2002

Background and Purpose

—

The cost of carotid endarterectomy (CEA) usually considers only the cost of the preoperative investigations and the procedure for the individual patient but ignores the cost incurred in selecting a patient from a referred “pool” of potential candidates or the “total direct program cost.” The aim of this study was to estimate the total direct program cost (workup and procedure) of CEA in a large major teaching hospital in Edinburgh, Scotland using a retrospective study design.

Methods

—

Participants were patients with transient ischemic attacks and mild strokes referred to the neurovascular clinics for assessment, investigation, and possible CEA. The “workup” was defined as the clinical consultation, carotid duplex, 1 follow-up visit, and a catheter angiogram where indicated. We used data routinely collected from the neurovascular clinics during a 1-year period to estimate the workup cost of patients who might be suitable for CEA. The CEA procedure cost was estimated prospectively in a concurrent study. Estimated costs were applied to the proportions assessed at the different levels of investigation to determine the total direct program cost of CEA.

Results

—

A total of 790 new patients with symptoms suggestive of transient ischemic attacks and mild strokes were identified. Four hundred one (51%) patients were referred for carotid duplex. Duplex identified 78 (10%) with carotid stenosis of ≥70%. Of the total of 790 patients, 26 (3.3%) had catheter angiogram and 18 (2.3%) had CEA. The total direct program cost to investigate this cohort was about £207 000, with 68% (£140 000) of the cost incurred before any surgery was performed.

Conclusion

—

The cost of identifying suitable patients for carotid surgery is quite high, with more than 30% of the cost attributed to the initial consultation at the neurovascular clinics. The cost of preventing 1 stroke by CEA is in the region of £100 000 at 1997/1998 prices if all the costs incurred in the workup of a cohort for potential CEA are included.
Safety of Intraventricular Sodium Nitroprusside and Thiosulfate for the Treatment of Cerebral Vasospasm in the Intensive Care Unit Setting
Authors: Thomas Jeffrey E. , McGinnis Gerri
Published: July 2002

Background and Purpose

—

We have recently reported the safety of intraventricular sodium nitroprusside for the treatment of cerebral ischemia from vasospasm. Treatments have been accompanied previously by cerebral angiography to gauge treatment effect on established vasospasm. We presently report the safe coadministration of intraventricular sodium nitroprusside and thiosulfate in 10 patients with secured ruptured cerebral aneurysms in the intensive care unit, without the use of cerebral angiography for vasospasm treatment.

Methods

—

Patients were considered eligible for treatment on the basis of subarachnoid hemorrhage grade or manifestation of cerebral vasospasm by either transcranial Doppler ultrasonography (TCD) or neurological examination criteria. The route of administration was intraventricular, by way of ventriculostomy. Two separate protocols differing in dosage frequency were used, depending on the presence or absence of a new neurological deficit. Response to treatment was measured by TCD and neurological criteria.

Results

—

Good outcome was observed in 7 of 8 vasospasm patients presenting with clinical subarachnoid hemorrhage grade ≥3. Four patients demonstrated reversal of well-defined neurological deficits (hemiparesis, paraparesis) in the setting of treatment. Seven patients demonstrated a decrease in TCD velocities within 1 hour of treatment. Two patients died: 1 from intractable vasospasm despite maximal medical management and angioplasty and 1 from pulmonary causes. One episode of hypotension occurred in the setting of a high dose of medication. This responded promptly to medical management. Prolonged intracranial hypertension did not occur; modest elevations of both intracranial pressure and mean arterial blood pressure were observed when nausea and vomiting were associated with treatment, which occurred commonly in awake subjects.

Conclusions

—

Intraventricular sodium nitroprusside with thiosulfate may be safely administered in the intensive care unit setting without the requirement of cerebral angiography to guide the effects of therapy.