bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of SR-BI Expression Leads to the Early Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions, Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E–Deficient Mice
Authors: Braun Anne , Trigatti Bernardo L. , Post Mark J. , Sato Kaori , Simons Michael , Edelberg Jay M. , Rosenberg Robert D. , Schrenzel Mark , Krieger Monty
Published: July 2002

Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.
Mutations of the Light Meromyosin Domain of the β-Myosin Heavy Chain Rod in Hypertrophic Cardiomyopathy
Authors: Blair Edward , Redwood Charles , de Jesus Oliveira Marisa , Moolman-Smook J.C. , Brink Paul , Corfield V.A. , Östman-Smith Ingegerd , Watkins Hugh
Published: July 2002

Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in 9 sarcomeric protein genes. The most commonly affected is β-myosin heavy chain (
MYH7
), where missense mutations cluster in the head and neck regions and directly affect motor function. Comparable mutations have not been described in the light meromyosin (LMM) region of the myosin rod, nor would these be expected to directly affect motor function. We studied 82 probands with HCM in whom no mutations had been found in
MYH7
exons encoding the head and neck regions of myosin nor in the other frequently implicated disease genes. Primers were designed to amplify exons 24 to 40 of
MYH7
. These amplimers were subjected to temperature modulated heteroduplex analysis by denaturing high-performance liquid chromatography. An Ala1379Thr missense mutation in exon 30 segregated with disease in three families and was not present in 200 normal chromosomes. The mutation occurred on two haplotypes, indicating that it was not a polymorphism linked with another disease-causing mutation. The position of this residue within the LMM region of myosin suggests that it may be important for thick filament assembly or for accessory protein binding. A further missense mutation in exon 37, Ser1776Gly, segregated with disease in a single family and was absent from 400 population-matched control chromosomes. Because the Ser1776 residue occupies a core position in the myosin rod at which the substitution of glycine is extremely energetically unfavorable, it is likely to disrupt the coiled-coil structure. We conclude that mutation of the LMM can cause HCM and that such mutations may act through novel mechanisms of disease pathogenesis involving myosin filament assembly or interaction with thick filament binding proteins.
Transient Receptor Potential Channels Regulate Myogenic Tone of Resistance Arteries
Authors: Welsh Donald G. , Morielli Anthony D. , Nelson Mark T. , Brayden Joseph E.
Published: July 2002

Elevation of intravascular pressure causes depolarization and constriction (myogenic tone) of small arteries and arterioles, and this response is a key element in blood flow regulation. However, the nature of pressure-induced depolarization has remained elusive. In the present study, we provide evidence that a transient receptor potential channel (TRPC6) homologue has a major role in this depolarizing response to pressure. Antisense oligodeoxynucleotides to TRPC6 decreased TRPC6 protein expression and greatly attenuated arterial smooth muscle depolarization and constriction caused by elevated pressure in intact cerebral arteries. Suppressing the expression of this channel protein also reduced the current density of a major cation current in resistance artery smooth muscle cells. We propose that TRPC6 channels play an essential role in regulation of myogenic tone.
Fabrication of Pulsatile Cardiac Tissue Grafts Using a Novel 3-Dimensional Cell Sheet Manipulation Technique and Temperature-Responsive Cell Culture Surfaces
Authors: Shimizu Tatsuya , Yamato Masayuki , Isoi Yuki , Akutsu Takumitsu , Setomaru Takeshi , Abe Kazuhiko , Kikuchi Akihiko , Umezu Mitsuo , Okano Teruo
Published: July 2002

Recent progress in cell transplantation therapy to repair impaired hearts has encouraged further attempts to bioengineer 3-dimensional (3-D) heart tissue from cultured cardiomyocytes. Cardiac tissue engineering is currently pursued utilizing conventional technology to fabricate 3-D biodegradable scaffolds as a temporary extracellular matrix. By contrast, new methods are now described to fabricate pulsatile cardiac grafts using new technology that layers cell sheets 3-dimensionally. We apply novel cell culture surfaces grafted with temperature-responsive polymer, poly(
N
-isopropylacrylamide) (PIPAAm), from which confluent cells detach as a cell sheet simply by reducing temperature without any enzymatic treatments. Neonatal rat cardiomyocyte sheets detached from PIPAAm-grafted surfaces were overlaid to construct cardiac grafts. Layered cell sheets began to pulse simultaneously and morphological communication via connexin43 was established between the sheets. When 4 sheets were layered, engineered constructs were macroscopically observed to pulse spontaneously. In vivo, layered cardiomyocyte sheets were transplanted into subcutaneous tissues of nude rats. Three weeks after transplantation, surface electrograms originating from transplanted grafts were detected and spontaneous beating was macroscopically observed. Histological studies showed characteristic structures of heart tissue and multiple neovascularization within contractile tissues. Constructs transplanted into 3-week-old rats exhibited more cardiomyocyte hypertrophy and less connective tissue than those placed into 8-week-old rats. Long-term survival of pulsatile cardiac grafts was confirmed up to 12 weeks. These results demonstrate that electrically communicative pulsatile 3-D cardiac constructs were achieved both in vitro and in vivo by layering cardiomyocyte sheets. Cardiac tissue engineering based on this technology may prove useful for heart model fabrication and cardiovascular tissue repair. The full text of this article is available at http://www.circresaha.org.
Estradiol Alters Nitric Oxide Production in the Mouse Aorta Through the α-, but not β-, Estrogen Receptor
Authors: Darblade B. , Pendaries C. , Krust A. , Dupont S. , Fouque M.-J. , Rami J. , Chambon P. , Bayard F. , Arnal J.-F.
Published: July 2002

Although estradiol (E
2
) has been recognized to exert several vasculoprotective effects in several species, its effects in mouse vasomotion are unknown, and consequently, so is the estrogen receptor subtype mediating these effects. We investigated the effect of E
2
(80 μg/kg/day for 15 days) on NO production in the thoracic aorta of ovariectomized C57Bl/6 mice compared with those given placebo. E
2
increased basal NO production. In contrast, the relaxation in response to ATP, to the calcium ionophore A23187, and to sodium nitroprusside was unaltered by E
2
, whereas acetylcholine-elicited relaxation was decreased. The abundance of NO synthase I, II, and III immunoreactive proteins (using Western blot) in thoracic aorta homogenates was unchanged by E
2
. To determine the estrogen receptor (ER) subtype involved in these effects, transgenic mice in which either the ERα or ERβ has been disrupted were ovariectomized and treated, or not, with E
2
. Basal NO production was increased and the sensitivity to acetylcholine decreased in ERβ knockout mice in response to E
2
, whereas this effect was abolished in ERα knockout mice. Finally, these effects of E
2
on vasomotion required long-term and/or in vivo exposure, as short-term incubation of aortic rings with 10 nmol/L E
2
in the isolated organ chamber did not elicit any vasoactive effects. In conclusion, this study demonstrates that ERα, but not ERβ, mediates the beneficial effect of E
2
on basal NO production.
Sp1 Transcription Factor as a Molecular Target for Nitric Oxide– and Cyclic Nucleotide–Mediated Suppression of cGMP-Dependent Protein Kinase-Iα Expression in Vascular Smooth Muscle Cells
Authors: Sellak Hassan , Yang Xiangli , Cao Xu , Cornwell Trudy , Soff Gerald A. , Lincoln Thomas
Published: July 2002

cGMP-dependent protein kinase (PKG) expression is highly variable and decreases in cultured vascular smooth muscle cells (VSMCs), exposure of cells to nitric oxide (NO), or in response to balloon catheter injury in vivo. In this study, the mechanisms of human type I PKG-α (PKG-Iα) gene expression were examined. Three structurally unrelated NO donors decreased PKG-Iα promoter activity after transfection of a promoter/luciferase construct in VSMCs. Promoter deletion analysis demonstrated that (1) a 120-bp promoter containing tandem Sp1 sites was sufficient to drive basal PKG-Iα promoter activity, and (2) NO was inhibitory at this site. Cyclic nucleotide analogues also suppressed PKG-Iα promoter activity with cAMP being more potent than cGMP. The effects of cyclic nucleotides to suppress PKG-Iα promoter activity were attenuated by a specific cAMP-dependent protein kinase (PKA) inhibitor. Single or double mutation of Sp1 binding sites abolished PKG-Iα expression. Moreover, Sp1 binding activity on the PKG-Iα promoter was detected in A7r5 cells, and this binding was inhibited by NO and cyclic nucleotides. These results indicate that PKG-Iα gene expression is driven by an Sp1 transcription mechanism, and that NO and cAMP inhibit Sp1-mediated PKG-Iα gene expression through separate mechanisms.
Adrenoceptor Hyporeactivity Is Responsible for
Escherichia coli
Endotoxin–Induced Acute Vascular Dysfunction in Humans
Authors: Pleiner Johannes , Heere-Ress Elisabeth , Langenberger Herbert , Sieder Anna E. , Bayerle-Eder Michaela , Mittermayer Fritz , Fuchsjäger-Mayrl Gabriele , Böhm Johannes , Jansen Burkhard , Wolzt Michael
Published: July 2002

Abstract
—

Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans.
Escherichia coli
endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and
N
G
-monomethyl-
l
-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (
P
<0.0005) and heart rate (
P
<0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by ≈50% (
P
<0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS.
Platelet Shape Changes and Adhesion Under High Shear Flow
Authors: Kuwahara Mitsuhiro , Sugimoto Mitsuhiko , Tsuji Shizuko , Matsui Hideto , Mizuno Tomohiro , Miyata Shigeki , Yoshioka Akira
Published: July 2002

Recent studies have revealed that the platelet adhesive process under flow is tightly regulated by multiple ligand-receptor interactions. However, platelet morphological changes during this process, particularly its physiological relevance, remain unknown under blood flow conditions. Using epifluorescence and scanning electron microscopy, we evaluated the real-time changes in platelet morphology during a platelet adhesive process on a von Willebrand factor-coated surface under physiological high shear flow in a perfusion chamber. Here, we show that dynamic platelet shape changes occurring during distinct phases of the adhesive process are precisely regulated by “inside-out” and “outside-in” integrin signals and are also a key regulatory element in successful platelet thrombogenesis opposing rapid blood flow in vivo.
Involvement of Rho-Kinase in Agonists-Induced Contractions of Arteriosclerotic Human Arteries
Authors: Kandabashi Tadashi , Shimokawa Hiroaki , Mukai Yasushi , Matoba Tetsuya , Kunihiro Ikuko , Morikawa Keiko , Ito Masaaki , Takahashi Shosuke , Kaibuchi Kozo , Takeshita Akira
Published: July 2002

Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart diseases. We have recently demonstrated that Rho-kinase plays a key role in the spasm in our porcine model. However, it remains to be elucidated whether Rho-kinase–mediated pathway also contributes to vasoconstriction of human arteries. From 15 patients who underwent coronary artery bypass operation, segments of isolated left internal thoracic arteries were obtained, and the endothelium was gently removed. Serotonin and histamine caused contractions, which were markedly inhibited by a specific Rho-kinase inhibitor, hydroxyfasudil. Western blot analysis showed that, during the serotonin-induced contractions, the extent of phosphorylation of myosin-binding subunit of myosin phosphatase (MBS, one of the major substrates of Rho-kinase) was significantly increased in the specimens. Hydroxyfasudil again significantly suppressed the serotonin-induced increase in MBS phosphorylation. There was a significant positive correlation between the extent of MBS phosphorylation and that of the serotonin-induced contractions and between hydroxyfasudil-sensitive components of the contractions and the extent of arteriosclerosis. These results indicate that Rho-kinase plays an important role in vascular smooth muscle contractions of arteriosclerotic human arteries, suggesting that Rho-kinase could be regarded as an important target for the treatment of arteriosclerotic vascular diseases in humans.
Lack of Plasminogen Activator Inhibitor-1 Promotes Growth and Abnormal Matrix Remodeling of Advanced Atherosclerotic Plaques in Apolipoprotein E–Deficient Mice
Authors: Luttun Aernout , Lupu Florea , Storkebaum Erik , Hoylaerts Marc F. , Moons Lieve , Crawley James , Bono Françoise , Poole A. Robin , Tipping Peter , Herbert Jean-Marc , Collen Désiré , Carmeliet Peter
Published: July 2002

Epidemiological studies suggest that elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) predispose an individual to ischemic heart disease or promote plaque progression by inhibiting fibrinolysis. In the present study, loss of PAI-1 in apolipoprotein E (apoE)-deficient (apoE
−/−
:PAI-1
−/−
) mice promoted the growth of advanced atherosclerotic plaques, which was due to enhanced extracellular matrix deposition. ApoE
−/−
:PAI-1
−/−
plaques also exhibited collagen fiber disorganization and degradation. Immunostaining and bone marrow transplantation revealed that smooth muscle cells, not macrophages, primarily expressed PAI-1 in plaques. Thus, although PAI-1 may promote plaque growth because of its antifibrinolytic properties, the present study reveals a protective role for PAI-1 by limiting plaque growth and preventing abnormal matrix remodeling.
Genetic Contribution to Circulating Levels of Hemostatic Factors in Healthy Families With Effects of Known Genetic Polymorphisms on Heritability
Authors: Freeman M. S. , Mansfield M. W. , Barrett J. H. , Grant P. J.
Published: July 2002

Levels of fibrinogen, factor VII (FVII), factor XIII (FXIII), plasminogen activator inhibitor (PAI)-1, and tissue plasminogen activator have been associated with coronary artery disease as have genetic polymorphisms. Quantitative genetic analyses allow determination of the genetic contribution to phenotypic variation. We investigated familial influences on these hemostatic factors in 537 adults from 89 randomly ascertained healthy families of white North European origin. We used maximum likelihood analysis to estimate the heritabilities of these factors and effects of covariates on the factors in these families. After adjustment for age and sex, the factors showed considerable heritability, varying from 26% (PAI-1) to 47% (FXIII complex). The influence of known polymorphisms was negligible for fibrinogen and contributed 2% to the variance of the FXIII complex and PAI-1 and 11% to the variance of FVII coagulant activity. Age, sex, body mass index, lifestyle, and metabolic covariates explained between 10% (FXIII) and 44% (PAI-1) of phenotypic variance. Childhood household influences significantly affected FVII (11%) and FXIII (18%). A significant degree of phenotypic variance of several hemostatic factors can be explained by additive genes and known covariates. The impact of certain well-characterized polymorphisms to the heritability is small in this population of healthy families, indicating the need to localize new genes influencing hemostatic factor levels.
Lipolytically Modified Triglyceride-Enriched HDLs Are Rapidly Cleared From the Circulation
Authors: Rashid Shirya , Barrett P. Hugh R. , Uffelman Kristine D. , Watanabe Takehiko , Adeli Khosrow , Lewis Gary F.
Published: July 2002

The precise biochemical mechanisms underlying the reduction of HDL levels in hypertriglyceridemic states are currently not known. In humans, we showed that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, enhances the clearance of HDL-associated apolipoprotein A-I (apoA-I) from the circulation. In the New Zealand White rabbit (an animal model naturally deficient in hepatic lipase [HL]), however, TG enrichment of HDL is not sufficient to alter the clearance of either the protein or lipid moieties of HDL. In the present study, therefore, we determined in the New Zealand White rabbit the combined effects of ex vivo TG enrichment and lipolytic transformation of HDL by HL on the subsequent metabolic clearance of HDL apoA-I. Results of the in vivo kinetic studies (n=18 animals) showed that apoA-I associated with TG-enriched rabbit HDL modified ex vivo by catalytically active HL was cleared 22% more rapidly versus TG-enriched HDL incubated with heat-inactivated HL, and 26% more rapidly than fasting (TG-poor) HDL incubated with active HL (
P
<0.05 for both). Furthermore, a strong correlation was observed between the HDL TG content and apoA-I factional catabolic rate (0.59,
P
<0.05) in the combined active HL groups. These data establish that TG enrichment of HDL with subsequent lipolysis by HL enhances HDL apoA-I clearance, but neither TG enrichment of HDL without HL lipolysis nor HL lipolysis in the absence of previous TG enrichment of HDL is sufficient to enhance HDL clearance. These data further support the important interaction between HDL TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states.
Leukoaraiosis, Ischemic Stroke, and Normal White Matter on Diffusion-Weighted MRI
Authors: Helenius Johanna , Soinne Lauri , Salonen Oili , Kaste Markku , Tatlisumak Turgut
Published: July 2002

Background and Purpose

—

Leukoaraiosis is a radiological finding of uncertain pathogenesis with bilateral patchy or diffuse areas of hyperintensity of the cerebral white matter (WM) on T2-weighted MRI. Using diffusion-weighted MRI (DWI), we aimed to test (1) whether the average apparent diffusion coefficient (ADC
av
) values of the regions of leukoaraiosis vary according to the degree of the severity of leukoaraiosis and whether the regions of leukoaraiosis could be distinguished (2) from normal WM or (3) from ischemic strokes of various ages.

Methods

—

We compared 85 patients with leukoaraiosis, 22 healthy subjects with no leukoaraiosis on the conventional MR images, and 10 patients with ischemic strokes serially imaged <6 hours, 24 hours, 1 week, 1 month, and 3 months after stroke onset. All subjects were studied with DWI in 3 orthogonal directions with 2 b values (b=0 and b=1000 s/mm
2
) at 1.5 T. ADC
av
values were determined for the regions of leukoaraiosis, ischemic lesions, and normal WM.

Results

—

The more severe the leukoaraiosis was, the higher the ADC
av
values of the leukoaraiotic regions became. The ADC
av
values (in 10
−3
mm
2
/s) of the regions of leukoaraiosis (0.92 to 1.27) were significantly higher than that of the normal WM (0.69±0.04) and that of the ischemic strokes at 6 hours (0.38±0.07), 24 hours (0.36±0.10), and 1 week (0.51±0.09). One-month-old ischemic strokes (1.08±0.33) had ADC
av
values similar to those of leukoaraiotic regions, whereas 3-month-old infarcts (1.59±0.32) showed significantly higher ADC
av
values than the leukoaraiotic regions.

Conclusions

—

The regions of leukoaraiosis show characteristic changes in ADC
av
values, and DWI can be used to differentiate acute and chronic ischemic stroke lesions from leukoaraiosis.
Endovascular Treatment of Aneurysms in the Cavernous Sinus
Authors: van der Schaaf Irene C. , Brilstra Eva H. , Buskens Eric , Rinkel Gabriël J.E.
Published: July 2002

Background and Purpose

—

Balloon occlusion of the parent vessel and endosaccular coiling are both frequently used for treatment of intracavernous aneurysms of the carotid artery. We performed a systematic review of studies reporting on these two treatment modalities to assess the rate of complications, rate of successful aneurysm occlusion, and clinical condition after treatment.

Methods

—

We performed a
medline
search for studies published between January 1974 and May 1999 and hand-searched recent volumes of 21 journals. Two authors independently extracted data by means of a standardized data extraction form.

Results

—

We found 35 studies reporting on 316 patients. Only 9 of the 35 studies reported on more than 5 patients; in only 9 studies (totaling 85 patients), well-defined outcome measures were used. Twenty-five studies (with 78% of all patients included in the review) reported on balloon occlusion. Complications during or in the first 24 hours after the balloon occlusion occurred in 4 of 247 patients (1.6%; 95% CI, 0.01% to 3.2%) and late ischemic complications in 5 of 148 patients (3.4%; 95% CI, 0.43% to 6.4%). Clinical follow-up was performed in 21 of 25 studies on treatment by means of balloon occlusion (148 [60%] of the 247 patients). None of the 68 patients treated by embolization with coils had a complication (0%; 95% CI, 0% to 4.3%). Of 157 aneurysms treated by balloon occlusion, 153 were completely thrombosed (97.5%; 95% CI, 95% to 100%). After coiling, 52 of 65 aneurysms (80%; 95% CI, 70% to 90%) were occluded by >90%.

Conclusions

—

Many studies included in this review had methodological weaknesses. The available data suggest that both balloon occlusion and endosaccular coiling are reasonably safe and result in occlusion of the aneurysm in the majority of patients. However, long-term outcomes have not yet been reported.
Magnetic Resonance Imaging Detection of Microbleeds Before Thrombolysis
Authors: Kidwell Chelsea S. , Saver Jeffrey L. , Villablanca J. Pablo , Duckwiler Gary , Fredieu Andre , Gough Kristi , Leary Megan C. , Starkman Sidney , Gobin Y. Pierre , Jahan Reza , Vespa Paul , Liebeskind David S. , Alger Jeffry R. , Vinuela Fernando
Published: July 2002

Background

—

Hemorrhagic transformation (HT) is a major complication of thrombolytic treatment for acute ischemic stroke. Although a history of prior intracerebral hemorrhage diagnosed by head CT is a contraindication to thrombolysis, there are no guidelines or data regarding evidence of prior asymptomatic microbleeds visualized with T2*-weighted magnetic resonance imaging (MRI).

Methods

—

Pretreatment T2*-weighted MRI sequences were retrospectively analyzed in all patients receiving intra-arterial thrombolytic therapy and undergoing a pretreatment MRI at our institution. The frequency and location of prior microbleeds was determined and compared with the frequency and location of secondary HT after therapy.

Results

—

Five of 41 patients undergoing MRI before receiving intra-arterial thrombolytic therapy demonstrated evidence of prior microbleeds on the pretreatment MRI studies. Major symptomatic hemorrhage occurred in 1 of 5 patients with microbleeds compared with 4 of 36 patients without. Only 1 patient in the entire 41-patient cohort experienced any HT outside the acute ischemic field. In this patient, the symptomatic hemorrhage occurred directly at the site of a prior microbleed, contralateral to the acute ischemic event.

Conclusions

—

Old silent microbleeds, visualized with T2*-weighted MRI sequences, may be a marker of increased risk of HT in patients receiving thrombolytic therapy for acute ischemic stroke. Pretreatment screening of thrombolytic candidates with these MRI sequences may be useful in the future to identify these patients.
Variability in Midlife Systolic Blood Pressure Is Related to Late-Life Brain White Matter Lesions
Authors: Havlik Richard J. , Foley Daniel J. , Sayer Bryan , Masaki Kamal , White Lon , Launer Lenore J.
Published: July 2002

Background and Purpose

—

Although white matter lesions (WMLs) on brain MRI in older persons are common, the mechanisms are unclear. Besides the associations with advanced age and high blood pressure (BP), variability in systolic BP (SBP) and the resulting changes in blood flow to the deep arteries of the brain may be contributing factors.

Methods

—

Japanese-American men in Hawaii have participated in a long-term study of cardiovascular disease, including midlife BP measurements at 3 clinical examinations in the period from 1965 to 1974. In the period from 1991 to 1993, dementia status was added to the fourth examination, and a brain MRI was completed in a fifth examination, which was from 1994 to 1996, on a subset of 575 men, who averaged 82 years. WMLs and ventricular atrophy were determined as the upper fifth in a standardized semiquantitative measure. Excess SBP variability was defined as greater than average increases in BP measurements from up to 3 examinations over 6 years. Logistic regression was used for the association of this variability with WMLs and atrophy, controlling for age, apolipoprotein E4 status, dementia diagnosis, and history of stroke.

Results

—

There were significant (2-fold) increased risks for WMLs among those with moderate and high SBP variability (third and fifth quintiles compared with the lowest quintile). Those in the highest SBP variability category (the fifth quintile) also had significantly more atrophy.

Conclusions

—

These SBP variability–MRI relationships suggest that variation in SBP in midlife may be a contributing factor to the development of WMLs and ventricular atrophy in late life.
Apolipoprotein E Genotype and Outcome in Aneurysmal Subarachnoid Hemorrhage
Authors: Leung Clarence H.S. , Poon W.S. , Yu L.M. , Wong George K.C. , Ng H.K.
Published: July 2002

Background and Purpose

—

Active management of ruptured intracranial aneurysm in subarachnoid hemorrhage is indicated in patients with favorable prognosis. Outcome prediction is based on patient characteristics and clinical and radiological factors. Current clinical grading scales are imprecise, with low interobserver reproducibility. Therefore, outcome prediction remains inconsistent and decision making becomes difficult, especially for patients with poor clinical grade.

Methods

—

The possible relationship between apolipoprotein E genotype and the outcome of patients suffering spontaneous subarachnoid hemorrhage was investigated. A prospective study was conducted on all patients with spontaneous aneurysmal subarachnoid hemorrhage admitted to our unit during a 2-year period. All patients were managed according to standard protocol, and treatments were given according to their clinical grading. Patient characteristics, clinical grade, radiological grade, and apolipoprotein E genotype were documented. The focus of the study was the 6-month neurological outcome for this group of patients after they were discharged.

Results

—

Seventy-two patients with aneurysmal subarachnoid hemorrhage were admitted to the Prince of Wales Hospital in Shatin, Hong Kong, China, from February 1998 to February 2000. Their ages ranged from 24 to 95 years of age, with a mean (SD) age of 58.3 (15.0) years. Apolipoprotein E ε4 was found in 15 patients (21%). At 6 months, Glasgow Outcome Scale score ≤3 was found in 29 patients (40%). Univariate analysis showed that older patients (odds ratio [OR], 1.03; 95% CI, 1.00 to 1.07;
P
=0.07) and patients with poor Fisher’s grade (OR, 4.5; 95% CI, 1.3 to 15.2;
P
=0.01), poor World Federation of Neurological Surgeons grade (OR, 5.8; 95% CI, 1.9 to 17.8;
P
=0.002), or apolipoprotein E ε4 (OR, 6.0; 95% CI, 1.7 to 21.3;
P
=0.006) were more likely to attain unfavorable outcome at 6 months. The additional effect of apolipoprotein E ε4 remained significant in the multiple logistic regression model (OR, 11.3; 95% CI, 2.2 to 57.0;
P
=0.003); the gain in predictive performance was not significant (
P
=0.26).

Conclusions

—

Apolipoprotein E ε4 genotype is related to poor outcome in patients with subarachnoid hemorrhage.
Stroke Awareness and Knowledge Retention in Children: The Brain Child Project
Authors: Dressman Laurie Atchity , Hunter John
Published: July 2002

Background and Purpose

—

Efforts at public education to improve adults’ response to stroke symptoms continue to be disappointing, and very little has been developed to improve the knowledge base of children regarding brain attacks. Children may be able to exert a positive influence on adult behavior and to learn positive healthcare habits, which will also influence their own health.

Methods

—

A total of 561 children enrolled in grades kindergarten through eighth (K-8), participated in The Brain Child Project, which included (1) assessment of their knowledge of stroke awareness (including initiation of the emergency medical system [EMS]) using a multiple-choice questionnaire, (2) attendance at a multimedia educational program designed to increase stroke knowledge, followed by (3) immediate administration of the same questionnaire, and (4) a final administration of the same questionnaire 10 days later to measure retention of acquired learning.

Results

—

The results showed that these children had a limited understanding of stroke, but with a brief educational program, all grades significantly increased their scores on the average from 64% to 82%. The loss of knowledge between the posttest and the retention test was negligible.

Conclusions

—

The results of this study indicate that through brief education, children show significant improvement in their knowledge of and response to brain attacks. Future efforts in this direction may positively affect stroke prevention, response and outcomes. A national program could be implemented in the school systems much like heart disease programs, with the ultimate goal of greater public awareness and prevention of stroke.
Physician Advice, Patient Actions, and Health-Related Quality of Life in Secondary Prevention of Stroke Through Diet and Exercise
Authors: Greenlund Kurt J. , Giles Wayne H. , Keenan Nora L. , Croft Janet B. , Mensah George A.
Published: July 2002

Background and Purpose

—

Healthy diet and exercise are recommended for secondary prevention in stroke patients. We examined the prevalence of persons with stroke who received physician advice for, and engaged in, dietary change and exercise, and we also sought to determine whether engaging in these actions was associated with differences in health-related quality of life (HRQOL).

Methods

—

Data are from 51 193 participants in the 1999 Behavioral Risk Factor Surveillance System, a state-based telephone survey. The participants noted whether they were advised to eat fewer high fat/high cholesterol foods and to exercise more and whether they engaged in these activities. HRQOL measures were the reported number of the preceding 30 days when physical health was not good, mental health was not good, usual activities were limited, and both physical and mental health were good (healthy days).

Results

—

Overall, 2.4% of the participants reported a history of stroke. Sixty-one percent of those who reported a history of stroke had been advised to eat fewer high fat/high cholesterol foods, and 85.4% of those who had received such advice reported a dietary change compared with 56.0% of those who did not receive such advice. Almost 64% of those who reported a stroke had been advised to exercise more, and 76.5% of those who received such advice reported exercising more versus 38.5% of those who did not receive such advice. Persons with stroke who reported exercising had fewer limited activity days and days when physical health was not good and more healthy days than did persons who did not exercise. Dietary actions were not associated with differences in HRQOL.

Conclusions

—

Results highlight the importance of provider advice for secondary prevention among persons with stroke.
Changes in Plasma Homocyst(e)ine in the Acute Phase After Stroke
Authors: Howard Virginia J. , Sides Elizabeth G. , Newman George C. , Cohen Stanley N. , Howard George , Malinow M. Rene , Toole James F.
Published: July 2002

Background and Purpose

—;

Elevated plasma homocyst(e)ine [H(e)] concentration has been associated with an increased risk of stroke. Although the literature suggests that H(e) increases from the acute to the convalescent phase after a stroke, it is not known whether H(e) changes within the acute period.

Methods

—;

A prospective, multicenter study was conducted to examine changes in H(e) during the 2 weeks after an incident stroke. Blood samples were collected at days 1, 3, 5, 7, and between 10 and 14 days after the stroke.

Results

—;

Seventy-six participants (51 men) were enrolled from 9 sites from February 1997 through June 1998. Mean age was 65.6 years, and subjects had at least two H(e) measurements. The estimated mean H(e) level at baseline was 11.3±0.5 μmol/L, which increased consistently to a mean of 12.0±0.05, 12.4±0.5, 13.3±0.5, and 13.7±0.7 μmol/L at days 3, 5, 7, and 10 to 14, respectively. The magnitude of the change in H(e) was not affected by age, sex, smoking status, alcohol use, history of hypertension or diabetes, or Rankin Scale Score.

Conclusions

—;

These data suggest that the clinical interpretation of H(e) after stroke and the eligibility for clinical trials assessing treatment for elevated H(e) levels require an adjustment in time since stroke to properly interpret the observed H(e) levels.
Flow Cytometric Analysis of Inflammatory Cells in Ischemic Rat Brain
Authors: Campanella Marilena , Sciorati Clara , Tarozzo Glauco , Beltramo Massimiliano
Published: July 2002

Background and Purpose

—

Inflammation plays a key role in cerebral ischemia through activation of microglia and infiltration by leukocytes. Flow cytometry is a well-established method for quantitative and qualitative analysis of inflammatory cells. However, this technique has not been applied to the study of cerebral ischemia inflammation. The aim of this study was to establish a flow cytometric method to measure inflammatory cells in ischemic brain.

Methods

—

To perform flow cytometry on brain tissue, we developed 2 cell-isolation methods based on different mechanical dissociation and Percoll gradient separation techniques. The methods were tested on a rat model of permanent middle cerebral artery occlusion. Morphological and immunophenotypic analyses, with the use of anti-CD11b, anti-CD45, and αβ T-cell receptor antibodies, were employed to identify and quantify inflammatory cells.

Results

—

Both methods gave consistent results in terms of yield and reproducibility. The cell suspension contained granulocytes, macrophages, lymphocytes, and neural cells. Morphological and immunophenotypic analyses enabled the identification of a cell-scatter gate (R1a) enriched in inflammatory cells. With both methods, a higher number of events in R1a were recorded in the ischemic hemisphere than in the nonischemic hemisphere (
P
≤0.001). CD11b, CD45, and αβ T-cell receptor staining confirmed that this augmentation was a reflection of the increase in the number of granulocytes, cells of the monocytic lineage, and lymphocytes.

Conclusions

—

Quantitative flow cytometric analysis of ischemic rat brain is feasible and provides a reliable and rapid assay to assess neuroinflammation in experimental models of brain ischemia.
Carotid Artery Intima-Media Thickness and Lacunar Versus Nonlacunar Infarcts
Authors: Cupini L.M. , Pasqualetti P. , Diomedi M. , Vernieri F. , Silvestrini M. , Rizzato B. , Ferrante F. , Bernardi G.
Published: July 2002

Background and Purpose

—

Increases in the thickness of the intima and media of the carotid artery have been associated with an increased risk of myocardial infarction and stroke in subjects without a history of cardiovascular disease. Lacunar infarcts, one of the most common subtype of ischemic stroke, show unique pathological and clinicoradiological characteristics. The present study examines the relationship between vascular risk factors, including carotid artery intima-media thickness (IMT), and lacunar versus nonlacunar infarcts.

Methods

—

We collected data from patients with acute ischemic stroke admitted to hospital. Patients and 129 control subjects underwent B-mode ultrasonographic measurements of IMT of the common carotid artery. We examined the association of lacunar and nonlacunar infarcts with age, sex, and potential vascular risk factors.

Results

—

Of 292 adult patients with an acute first-ever ischemic stroke, 96 were considered lacunar and 196 were considered nonlacunar strokes. We did not find a significantly different percentage of diabetes, smoking, hypertension, dyslipidemia, myocardial infarction, and previous transient ischemic attack between the 2 groups of patients. The multinomial logistic regression procedure selected carotid artery IMT and atrial fibrillation as the only independent factors able to discriminate between lacunar and nonlacunar patients. IMT values were significantly higher in patients with nonlacunar stroke versus both those with lacunar stroke and control subjects.

Conclusions

—

The present results indicate the usefulness of noninvasive measurement of IMT with ultrasonic techniques as a diagnostic tool that may help to identify different subtypes of ischemic stroke patients. The noninvasive measurements may have predictive power with respect to lacunar versus nonlacunar infarcts.
Role of the Endothelial Lining in Persistence of Residual Lesions and Growth of Recurrences After Endovascular Treatment of Experimental Aneurysms
Authors: Raymond Jean , Sauvageau Eric , Salazkin Igor , Ribourtout Edith , Gevry Guylaine , Desfaits Anne-Cécile
Published: July 2002

Background and Purpose

—

We sought to investigate the role of the endothelial lining in aneurysmal persistence and recurrence after endovascular treatment of aneurysms.

Methods

—

Bilateral venous pouch canine carotid aneurysms were studied by angiography and pathology 1, 2, and 3 weeks after intraoperative collagen sponge embolization, coated or not coated with fibrinogen (n=15). In 12 dogs the endothelial lining of one aneurysm was removed before embolization, and results were compared with a control aneurysm after bilateral sponge embolization. In 4 animals embolization with a sponge covered with endothelium was compared with treatment with a sponge covered with adventitia. In 4 animals an inverted venous pouch aneurysm embolized with an adventitia-covered sponge was compared with a normal aneurysm embolized with an endothelialized sponge. In 3 animals inverted venous pouch aneurysms were embolized with a sponge covered or not covered with endothelium. Control aneurysms (n=3 or 4 each) included untreated normal, inverted, and de-endothelialized venous pouch aneurysms. Angiographic results at 3 weeks were compared by Wilcoxon’s test.

Results

—

Endothelialization of the clot that forms on the sponge was complete at 1 week, forming clefts that developed into recurrences. Reversed or de-endothelialized aneurysms spontaneously thrombosed, while normal venous pouch aneurysms remained patent for at least 3 weeks. The addition of fibrinogen, endothelium, or adventitia to the sponges did not prevent recurrences, which occurred routinely after embolization of endothelialized aneurysm. De-endothelialization of the aneurysmal wall improved angiographic results at 3 weeks (
P
=0.02), while reversing the venous pouch before embolization led to complete healing (
P
=0.003).

Conclusions

—

The endothelial lining is essential to the persistence of residual lesions. Early endothelial invasion of the clot leads to recanalization and recurrences after embolization of aneurysms. This observation provides new opportunities to improve results of endovascular treatment of aneurysms.
Old Microbleeds Are a Potential Risk Factor for Cerebral Bleeding After Ischemic Stroke
Authors: Nighoghossian N. , Hermier M. , Adeleine P. , Blanc-Lasserre K. , Derex L. , Honnorat J. , Philippeau F. , Dugor J.F. , Froment J.C. , Trouillas P.
Published: July 2002

Background and Purpose
—

T2*-weighted gradient-echo MRI is known to detect old microbleeds (MBs), considered indicative of microangiopathy. MBs might be a potential risk factor for early cerebral bleeding (CB) after ischemic stroke. Therefore, we assessed the impact of MBs on the occurrence of CB after cerebral infarction.

Methods
—

We included prospectively stroke patients who had documented ischemic damage. The imaging protocol involved baseline CT scan, T2*-weighted gradient-echo MRI, diffusion-weighted imaging, T2-weighted imaging, and magnetic resonance angiography and had to be performed within 24 hours after symptom onset. The assessment of CB with T2*-weighted gradient-echo sequence necessitated a focal area of signal loss either within the ischemic area revealed by diffusion-weighted imaging or remote from it. Old MBs were defined on T2*-weighted images as homogeneous rounded areas of signal loss without surrounding edema. CT scan was systematically repeated within the first week to verify CB as diagnosed by the T2* weighted sequence.

Results
—

One hundred patients (mean age, 60±13 years; range, 19 to 83 years; 58 men, 42 women) met the inclusion criteria. MBs were seen in 20 patients on T2*-weighted imaging. Multivariate logistic regression analysis revealed that age, diabetes, previous use of antithrombotic drugs, evidence of an atherothrombotic source of stroke, and lacunar infarct were significantly associated with MBs (
P
<0.0001). CB was diagnosed in 26 patients: at the acute stage by T2*-gradient echo sequence in 18 patients and with CT scan performed within the first week in 8 patients. Multivariate logistic regression analysis showed that baseline National Institutes of Health Stroke Scale score, diabetes, and MBs were considered significant and independent predictors of CB (
P
<0.001).

Conclusions
—

Although the pathogenesis of CB after ischemic stroke is multifactorial, the increased observation of CB in patients with MBs suggests that the associated vascular vulnerability contributes to CB.
Emergent Use of Anticoagulation for Treatment of Patients With Ischemic Stroke
Authors: Adams Harold P.
Published: July 2002

Background

—

Several clinical trials have tested the potential utility of emergent anticoagulation for acute ischemic stroke.

Summary of Review

—

Rather than performing a meta-analysis that combines the data from several trials, this review focuses on individual studies. Although these trials do have inherent limitations, they demonstrate that emergent use of an anticoagulant is associated with a modest but significantly increased risk of hemorrhagic transformation of the ischemic stroke or serious nonneurological bleeding. The trials do not demonstrate a benefit from emergent anticoagulation in improving outcome, reducing mortality, and preventing early recurrent stroke.

Conclusions

—

These results suggest that most patients with acute stroke should not be treated with unfractionated heparin or other rapidly acting anticoagulants after stroke. Prevention of deep vein thrombosis and pulmonary embolism among bedridden patients is the only established indication for early anticoagulation after acute ischemic stroke.
Alcohol Consumption and Risk of Ischemic Stroke
Authors: Djoussé Luc , Ellison R. Curtis , Beiser Alexa , Scaramucci Amy , D’Agostino Ralph B. , Wolf Philip A.
Published: July 2002

Background and Purpose

—

Stroke is a major cause of death in the United States. The association between alcohol consumption and ischemic stroke (IS) remains controversial.

Methods

—

We used data collected on participants in the Framingham Study to assess the association between total alcohol intake and type of alcoholic beverage and development of IS, overall and according to age.

Results

—

A total of 196 men and 245 women developed IS during three 10-year follow-up periods. In the categories of never drinkers, drinkers of 0.1 to 11, 12 to 23, and ≥24 g/d of ethanol (a “typical drink” is ≈12 g of ethanol), and former drinkers of 0.1 to 11 and ≥12 g/d, crude incidence rates of IS were 6.5, 5.9, 4.9, 5.0, 6.7, and 17.8 cases per 1000 person-years, respectively, for men and 5.9, 4.1, 4.1, 4.3, 8.3, and 7.1, respectively, for women. Overall, compared with never drinkers in a multivariate Cox regression, current alcohol consumption was not related significantly to IS in either sex. Former drinking of ≥12 g/d of alcohol was associated with a 2.4 times higher risk of IS among men but not among women. When stratified by age, alcohol intake was associated with lower risk of IS among subjects aged 60 to 69 years. In beverage-specific analysis, only wine consumption was related to a decreased risk of IS.

Conclusions

—

Our data showed no significant association between total alcohol and IS overall but showed a protective effect of alcohol among subjects aged 60 to 69 years.