bluuebunny/crossref_metadata_2025 huggingface dataset:
Risks of Using Internal Thoracic Artery Grafts in Patients in Chronic Hemodialysis via Upper Extremity Arteriovenous Fistula
Authors: Gaudino Mario , Serricchio Michele , Luciani Nicola , Giungi Stefania , Salica Andrea , Pola Roberto , Pola Paolo , Luciani Giovanna , Possati Gianfederico
Published: May 2003

Background—

In patients in chronic hemodialysis via upper extremity arteriovenous fistula in whom ipsilateral internal thoracic artery graft was used for myocardial revascularization, hemodynamic interference between the fistula and the graft during dialysis can be hypothesized.

Methods and Results—

In 5 patients undergoing chronic hemodialysis via upper extremity arteriovenous fistula, ipsilateral to an internal thoracic to left anterior descending graft mammary flow was studied by means of transthoracic echo-color Doppler at baseline and during hemodialysis. Flow in the contralateral mammary artery was used as control. Transthoracic echocardiography was performed in concomitance with flow evaluation to assess eventual modifications of left ventricular segmental wall motion. Immediately after hemodialysis pump start there was a marked reduction of peak systolic and end-diastolic velocities and time average mean velocity and flow in the ITA ipsilateral to the fistula, whereas no substantial hemodynamic modification was evident in the contralateral artery. Dialysis-induced reduction of ipsilateral ITA flow was accompanied by evidence of hypokinesia of the anterior left ventricular wall. Three cases also experienced clinical angina.

Conclusions—

Hemodynamically evident flow steal and consequent myocardial ischemia develop during hemodialysis in patients with upper extremity arteriovenous fistula and ipsilateral internal thoracic artery to coronary graft. These data have major implications for patients’ management, both for nephrologists and cardiac surgeons.
Endothelin-1 and Vascular Tone in Subjects With Atherogenic Risk Factors
Authors: Nohria Anju , Garrett Leslie , Johnson Wendy , Kinlay Scott , Ganz Peter , Creager Mark A.
Published: May 2003

Endothelin-1 (ET-1) is a potent vasoconstrictor that increases vascular tone in the resistance vessels of subjects with hypertension. It is unclear whether endogenous ET-1 affects resistance-vessel function equally in patients with other cardiovascular risk factors. Vasoconstriction to ET-1 is mediated principally via the endothelin-A (ET
A
) receptor on vascular smooth muscle cells. Accordingly, we used an ET
A
-specific antagonist, BQ-123, to test the hypothesis that endogenous ET-1 increases vascular resistance selectively in subjects with hypertension compared with other risk factors. BQ-123 was infused at 100 nmol/min for 80 minutes into the brachial artery of 10 subjects with hypertension (mean±SEM arterial pressure, 106±5 mm Hg), 12 subjects with hypercholesterolemia (mean±SEM total cholesterol, 7.1±0.2 mmol/L), 10 active smokers (mean±SEM, 42±11 pack-years), and 11 healthy, age-matched individuals. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. BQ-123 dilated resistance arterioles in hypertensive subjects, with FBF’s increasing by 46±7% from baseline (
P
<0.001). BQ-123 increased FBF to a lesser extent in hypercholesterolemic (24±5%,
P
<0.001) and healthy (20±8%,
P
=0.007) individuals but did not affect FBF significantly in smokers (10±8%,
P
=0.185). The vasodilator response in hypertensive subjects, but not in hypercholesterolemic patients or smokers, was significantly greater than that in healthy individuals (
P
=0.012). Endogenous ET-1, acting via the ET
A
receptor, increases resistance-vessel tone in subjects with hypertension more than in subjects with hypercholesterolemia or in smokers. These results indicate that ET-1 contributes more to the pathophysiology of hypertension than of other risk factors in subjects without overt atherosclerosis.
Effects of the Dietary Approaches to Stop Hypertension (DASH) Diet on the Pressure-Natriuresis Relationship
Authors: Akita Sachie , Sacks Frank M. , Svetkey Laura P. , Conlin Paul R. , Kimura Genjiro
Published: May 2003

Blood pressure-lowering mechanisms of the Dietary Approaches to Stop Hypertension (DASH) diet, rich in fruits, vegetables, and low-fat dairy foods, were analyzed based on the pressure-natriuresis relationship. Participants (n=375) were randomly assigned to control or DASH diet groups by using a parallel-group design. They then ate their assigned diet for 3 consecutive 30-day intervention feeding periods, during which sodium intake varied among 3 levels by a randomly assigned sequence. Urinary sodium excretion rate and mean arterial pressure were measured at the end of each sodium intake level. Mean arterial pressure and urinary sodium excretion were plotted on
x
and
y
axes, respectively, for participants eating control and DASH diets and were modeled as linear relationships for simplicity to allow the estimation of the extrapolated x-intercept and slope of the relationships. The DASH diet steepened the slope of the relationship (29.5±3.4 vs 64.9±13.1 [mmol/d]/mm Hg,
P
=0.0002) without significantly shifting the x-intercept (94.1±0.5 vs 93.2±0.6 mm Hg, NS) of the relationship. These data suggest a natriuretic action of the DASH diet.
Effects of Pressure Overload on Extracellular Matrix Expression in the Heart of the Atrial Natriuretic Peptide–Null Mouse
Authors: Wang Dajun , Oparil Suzanne , Feng Ji An , Li Peng , Perry Gilbert , Chen Lan Bo , Dai Meiru , John Simon W.M. , Chen Yiu-Fai
Published: May 2003

This study tested the hypothesis that atrial natriuretic peptide has direct antihypertrophic actions on the heart by modulating expression of genes involved in cardiac hypertrophy and extracellular matrix production. Hearts of male, atrial natriuretic peptide–null and control wild-type mice that had been subjected to pressure overload after transverse aortic constriction and control unoperated hearts were weighed and subjected to microarray, Northern blot, and immunohistochemical analyses. Microarray and Northern blot analyses were used to identify genes that are regulated differentially in response to stress in the presence and absence of atrial natriuretic peptide. Immunohistochemical analysis was used to identify and localize expression of the protein products of these genes. Atrial natriuretic peptide–null mice demonstrated cardiac hypertrophy at baseline and an exaggerated hypertrophic response to transverse aortic constriction associated with increased expression of the extracellular matrix molecules periostin, osteopontin, collagen I and III, and thrombospondin, as well as the extracellular matrix regulatory proteins, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3, and the novel growth factor pleiotrophin compared with wild-type controls. These results support the hypothesis that atrial natriuretic peptide protects against pressure overload–induced cardiac hypertrophy and remodeling by negative modulation of genes involved in extracellular matrix deposition.
Blood Pressure Indices and Cardiovascular Disease in the Asia Pacific Region
Authors:   Asia Pacific Cohort Studies Collaboration
Published: May 2003

This article aims to compare the importance of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) as risk factors for stroke and ischemic heart disease and to assess whether the patterns are consistent by age and gender. Cox proportional-hazards regression, adjusted for cholesterol and smoking, was used to assess the associations of the 4 BP indices with stroke and ischemic heart disease by age and gender. The relative importance of individual indices was assessed with a hazard ratios for a 1-SD change in BP and by likelihood-ratio χ
2
tests. The influence of >1 BP index in the Cox model was also estimated. The analyses demonstrated similar associations of SBP, DBP, and MAP with both fatal stroke and ischemic heart diseases, which were stronger than those of PP. Both SBP and MAP tended to be more important in the regression model than DBP or PP. In Cox models including DBP, addition of SBP improved the goodness of fit at all ages and for both genders. However, in Cox models including SBP, addition of DBP typically resulted in little incremental benefit over and above that of SBP alone. These data suggest that if time or resources are highly constrained, such as in much-needed epidemiologic surveys in developing countries, very little is lost from only measuring SBP.
Mild Renal Dysfunction and Subclinical Cardiovascular Damage in Primary Hypertension
Authors: Leoncini Giovanna , Viazzi Francesca , Parodi Denise , Vettoretti Simone , Ratto Elena , Ravera Maura , Tomolillo Cinzia , Del Sette Massimo , Bezante Gian Paolo , Deferrari Giacomo , Pontremoli Roberto
Published: May 2003

The presence of mild renal dysfunction is associated with high cardiovascular morbidity and mortality rates in patients with primary hypertension. The pathophysiological mechanisms underlying this association are currently unknown. We investigated the relation between mild renal dysfunction and subclinical cardiovascular organ damage in 358 never previously treated patients with primary hypertension. Mild renal dysfunction was defined as a creatinine clearance <60 mL/min and/or the presence of microalbuminuria. Left ventricular mass index and carotid intima-media thickness were assessed by ultrasound scan. The prevalence of mild renal dysfunction, left ventricular hypertrophy, and carotid plaque was 18%, 48%, and 28%, respectively. Mild renal dysfunction was related to the presence of several risk factors, such as older age, higher blood pressure levels and lipid status, and smoking habits. Patients with the highest left ventricular mass and carotid intima-media thickness (upper quartiles) showed a higher prevalence of mild renal dysfunction (
P
<0.0001). After adjusting for duration of hypertension, mean blood pressure, smoking habits, and age, we found that the risk of left ventricular hypertrophy and/or carotid atherosclerosis increased by 43% with each SD reduction in creatinine clearance, and by 89% with each SD increase in albuminuria. Mild renal dysfunction is associated with preclinical end-organ damage in patients with primary hypertension. These data may help explain the high cardiovascular mortality rates reported in patients with low glomerular filtration rate or with increased albuminuria. The evaluation of creatinine clearance and urinary albumin excretion could be useful for identifying subjects at higher cardiovascular risk.
Genetically Determined Heterogeneity in Hemoglobin Scavenging and Susceptibility to Diabetic Cardiovascular Disease
Authors: Asleh Rabea , Marsh Stuart , Shilkrut Mark , Binah Ofer , Guetta Julia , Lejbkowicz Flavio , Enav Ben , Shehadeh Naim , Kanter Yoram , Lache Orit , Cohen Osher , Levy Nina S. , Levy Andrew P.
Published: May 2003

A major function of haptoglobin (Hp) is to bind hemoglobin (Hb) to form a stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue damage. Clearance of the Hp-Hb complex can be mediated by the monocyte/macrophage scavenger receptor CD163. We recently demonstrated that diabetic individuals homozygous for the Hp 2 allele (Hp 2-2) were at 500% greater risk of cardiovascular disease (CVD) compared with diabetic individuals homozygous for the Hp 1 allele (Hp 1-1). No differences in risk by Hp type were seen in individuals without diabetes. To understand the relationship between the Hp polymorphism and diabetic CVD, we sought to identify differences in antioxidant and scavenging functions between the Hp types and to determine how these functions were modified in diabetes. The scavenging function of Hp was assessed using rhodamine-tagged and
125
I-Hp in cell lines stably transfected with CD163 and in macrophages expressing endogenous CD163. We found that the rate of clearance of Hp 1-1–Hb by CD163 is markedly greater than that of Hp 2-2–Hb. Diabetes is associated with an increase in the nonenzymatic glycosylation of serum proteins, including Hb. The antioxidant function of Hp was assessed with glycosylated and nonglycosylated Hb. We identified a severe impairment in the ability of Hp to prevent oxidation mediated by glycosylated Hb. We propose that the specific interaction between diabetes, CVD, and Hp genotype is the result of the heightened urgency of rapidly clearing glycosylated Hb-Hp complexes from the subendothelial space before they can oxidatively modify low-density lipoprotein to atherogenic oxidized low-density lipoprotein.
HFE Mutation and Dietary Iron Content Interact to Increase Ischemia/Reperfusion Injury of the Heart in Mice
Authors: Turoczi Tibor , Jun Li , Cordis Gerald , Morris James E. , Maulik Nilanjana , Stevens Richard G. , Das Dipak K.
Published: May 2003

Hereditary hemochromatosis is an inherited pathological condition characterized by iron overload in several vital organs including heart. To increase our understanding of the underlying pathogenic mechanisms of hereditary hemochromatosis, we used a HFE gene knockout mouse model that replicates hereditary hemochromatosis. A group of mice with no copies of HFE gene and corresponding wild-type mice were maintained either on low-iron (30 ppm) or high-iron (300 ppm) diet since birth. The results of our study revealed that HFE gene knockout mouse hearts were susceptible to ischemia-reperfusion injury as evidenced by increased postischemic ventricular dysfunction, increased myocardial infarct size and cardiomyocyte apoptosis compared with wild-type control hearts. The degree of injury increased in the hearts of the mice fed high-iron diet. The hearts of the HFE knockout mice showed increased iron deposition, increased content of reactive oxygen species (ROS) as evidenced by the increased formation of malondialdehyde, and reduced antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase. The results suggest that increased amount of ROS and reduced antioxidant reserve secondary to iron overloading may be instrumental for the susceptibility of the HFE gene knockout mice to cardiac injury.
Matrix Metalloproteinase-3 Genotype Contributes to Age-Related Aortic Stiffening Through Modulation of Gene and Protein Expression
Authors: Medley Tanya L. , Kingwell Bronwyn A. , Gatzka Christoph D. , Pillay Prakash , Cole Timothy J.
Published: May 2003

Matrix metalloproteinases (MMPs) include most major constituents of the arterial wall as substrates. A common promotor polymorphism (5A/6A) is associated with differences in MMP-3 (stromelysin-1) activity, and associations with certain forms of vascular disease have been shown. This study investigated whether the MMP-3 5A/6A promoter polymorphism contributes to age-related large artery stiffening. MMP-3 5A/6A genotype was determined in 203 (135 male) low cardiovascular risk, unmedicated individuals who were divided prospectively into two groups (30 to 60 years, n=126; ≥61 years, n=77). Noninvasive large artery stiffness was measured as ascending aortic input impedance from brachial blood pressure, carotid tonometry, and Doppler ascending aortic blood flow. In the older group, homozygotes had higher aortic input (
P
<0.01) and characteristic (
P
<0.01) impedance, ie, higher stiffness, than heterozygotes after correction for the effects of age, gender, and mean arterial pressure. There was no such difference in the younger group. Gene expression was subsequently investigated in dermal biopsies in randomly selected older men from the same cohort with real-time PCR (n=40). In 5A homozygotes, gene expression was 4-fold higher (
P
<0.05), and in 6A homozygotes, 2-fold lower (
P
<0.05) compared with the heterozygotes. Differences in gene expression were associated with corresponding significant changes in MMP-3 protein levels. Concordance between dermal and aortic gene and protein expression was shown in a separate cohort of postmortem aortic samples (n=7). We conclude that MMP-3 genotype may be an important determinant of vascular remodeling and age-related arterial stiffening, with the heterozygote having the optimal balance between matrix accumulation and deposition.
Persistent Stunning Induces Myocardial Hibernation and Protection
Authors: Kim Song-Jung , Peppas Athanasios , Hong Suk-Keun , Yang Guiping , Huang Yanhong , Diaz Gissela , Sadoshima Junichi , Vatner Dorothy E. , Vatner Stephen F.
Published: May 2003

To test the hypothesis that persistent myocardial stunning can lead to hibernating myocardium, 13 pigs were chronically instrumented, and persistent stunning was induced regionally by 6 repetitive episodes of 90-minute coronary stenosis (CS) (30% reduction in baseline coronary blood flow [CBF]) followed by full reperfusion every 12 hours. During the 1st CS, CBF fell from 43±2 to 31±2 mL/min, and anterior wall thickening (AWT) fell by 54±8%, but posterior WT did not change. AWT never recovered fully and remained depressed by 31±7% before the 6th CS, reflecting persistent myocardial stunning, but baseline CBF was not changed. Surprisingly, during the 6th CS, AWT did not fall further despite a similar reduction in CBF during CS, as occurred with the 1st episode. Regional MV̇
o
2
fell similarly during the 1st and 6th CS. During the 1st CS, plasma glucose uptake increased, whereas free fatty acid (FFA) uptake was reduced. Before the 6th CS, glucose uptake remained elevated, whereas FFA uptake remained reduced. Histology revealed enhanced glycogen deposition, which could be explained by decreased glycogen synthase kinase (GSK)-3β protein levels and activity. These results indicate that persistent stunning, even in the absence of chronic ischemia, can recapitulate the phenotype of myocardial hibernation. This results in a shift in the flow/function relationship where a 30% decrease in CBF is no longer accompanied by a fall in myocardial function, which could be explained, in part, by a shift in substrate utilization. These hemodynamic/metabolic adjustments could facilitate survival of hibernating myocardium.
Modification of GATA-2 Transcriptional Activity in Endothelial Cells by the SUMO E3 Ligase PIASy
Authors: Chun Tae-Hwa , Itoh Hiroshi , Subramanian Lalitha , Iñiguez-Lluhí Jorge A. , Nakao Kazuwa
Published: May 2003

GATA sequences are required for the optimal expression of endothelial cell–specific genes, including endothelin-1 (ET-1). We have identified PIASy in a search for new GATA-2 interacting proteins that can regulate GATA-2–mediated endothelial gene expression. Notably, among the cell populations comprising vascular walls, PIASy mRNA is selectively expressed in endothelial cells, and its expression can be regulated by angiogenic growth factors. We show that GATA-2 is covalently modified by small ubiquitin-like modifier (SUMO)-1 and -2 and that PIASy, through its E3 SUMO ligase activity, preferentially enhances the conjugation of SUMO-2 to GATA-2. Through a functional analysis, we demonstrate that PIASy potently suppresses the activity of the GATA-2–dependent human ET-1 promoter in endothelial cells. The suppressive effect of PIASy requires the GATA-binding site in the ET-1 promoter and depends on its interaction with GATA-2, which requires both N-terminal (amino acids 1-183) and C-terminal (amino acids 414-510) sequences in PIASy. We conclude that PIASy enhances the conjugation of SUMO-2 to GATA-2 and that the interaction of PIASy with GATA-2 can modulate GATA-mediated ET-1 transcription activity in endothelial cells through a RING-like domain-independent mechanism.
Mechanical Stretch Enhances mRNA Expression and Proenzyme Release of Matrix Metalloproteinase-2 (MMP-2) via NAD(P)H Oxidase–Derived Reactive Oxygen Species
Authors: Grote Karsten , Flach Inna , Luchtefeld Maren , Akin Elvan , Holland Steven M. , Drexler Helmut , Schieffer Bernhard
Published: May 2003

Mechanical stretch is a hallmark of arterial hypertension and leads to vessel wall remodeling, which involves matrix metalloproteinases (MMPs). Because mechanical stretch is further capable of inducing reactive oxygen species (ROS) formation via the NAD(P)H oxidase, we assessed whether mechanical stretch enhances MMP expression and activity in a NAD(P)H oxidase–dependent manner. Therefore, vascular smooth muscle cells (VSMCs) isolated from C57BL/6 mice were exposed to cyclic mechanical stretch. The impact of ROS was assessed using VSMCs isolated from p47

phox
−/−

mice, deficient for a NAD(P)H oxidase subunit responsible for ROS formation. Transcript levels were investigated by cDNA array and confirmed by RT-PCR. ROS formation was determined by DCF fluoroscopy and MMP-2 activity by zymography. Mechanical stretch of wild-type VSMCs resulted in a rapid ROS formation and p47

phox

membrane translocation that is followed by an increase in Nox-1 transcripts. ROS formation was completely abrogated in p47

phox
−/−

VSMCs. cDNA array further revealed an increase of MMP-2 mRNA in response to mechanical stretch, which was validated by RT-PCR. Using p47

phox
−/−

VSMCs, this increase in MMP-2 mRNA was completely blunted. mRNA expression of tissue inhibitor of MMP-2 TIMP-1 and TIMP-2 and membrane-type 1 MMP was unaffected by mechanical stretch. Gelatinolytic activity of pro-MMP-2 has been increased rapidly in wild-type VSMCs and was completely abolished in p47

phox
−/−

VSMCs. These results indicate that mechanical stretch induces ROS formation via the NAD(P)H oxidase and thereby enhances MMP-2 mRNA expression and pro-MMP-2 release. These results are consistent with the notion that in arterial hypertension, reactive oxygen species are involved in vascular remodeling via MMP activation. The full text of this article is available online at http://www.circresaha.org.
NFATc3 and NFATc4 Are Required for Cardiac Development and Mitochondrial Function
Authors: Bushdid Paul B. , Osinska Hanna , Waclaw Ronald R. , Molkentin Jeffery D. , Yutzey Katherine E.
Published: May 2003

Activation of the nuclear factor of activated T-cell (NFAT) family of transcription factors is associated with changes in gene expression and myocyte function in adult cardiac and skeletal muscle. However, the role of NFATs in normal embryonic heart development is not well characterized. In this report, the function of NFATc3 and NFATc4 in embryonic heart development was examined in mice with targeted disruption of both
nfatc3
and
nfatc4
genes. The
nfatc3
−/−
nfatc4
−/−
mice demonstrate embryonic lethality after embryonic day 10.5 and have thin ventricles, pericardial effusion, and a reduction in ventricular myocyte proliferation. Cardiac mitochondria are swollen with abnormal cristae, indicative of metabolic failure, but hallmarks of apoptosis are not evident. Furthermore, enzymatic activity of complex II and IV of the respiratory chain and mitochondrial oxidative activity are reduced in
nfatc3
−/−
nfatc4
−/−
cardiomyocytes. Cardiac-specific expression of constitutively active NFATc4 in
nfatc3
−/−
nfatc4
−/−
embryos prolongs embryonic viability to embryonic day 12 and preserves ventricular myocyte proliferation, compact zone density, and trabecular formation. The rescued embryos also maintain cardiac mitochondrial ultrastructure and complex II enzyme activity. Together, these data support the hypothesis that loss of NFAT activity in the heart results in a deficiency in mitochondrial energy metabolism required for cardiac morphogenesis and function.
Familial Intracranial Aneurysms
Authors: Wills Shannon , Ronkainen Antti , van der Voet Monique , Kuivaniemi Helena , Helin Katariina , Leinonen Eira , Frösen Juhana , Niemelä Mika , Jääskeläinen Juha , Hernesniemi Juha , Tromp Gerard
Published: May 2003

Background and Purpose—

Genetic risk factors are considered important in the development, growth, and rupture of intracranial aneurysms; however, few have been identified. We analyzed intracranial aneurysm families with at least 2 affected persons and determined relationships between affected persons and assessed the inheritance patterns of aneurysms.

Methods—

Families with ≥2 members with verified diagnoses of intracranial aneurysms were recruited from Kuopio and Helsinki, Finland. Families with a diagnosis of other heritable disorders that have associated intracranial aneurysms, such as autosomal dominant polycystic kidney disease, were excluded.

Results—

We identified 346 Finnish multiplex families with 160 (46.2%) male and 186 (53.8%) female index cases. There were a total of 937 aneurysm cases, with an average of 2.7 cases per family. The majority of the families had only 2 affected relatives (n=206; 59.5%), although there were families with up to 6 (n=10), 7 (n=1), 8 (n=1), or 10 (n=2) affected persons. The affected relatives of the index cases included 108 sisters, 116 brothers, 105 parents, 30 children, 15 grandparents, 102 aunts or uncles, and 64 cousins. Of the 937 affected persons, 569 (60.7%) were alive and available for genetic analysis. Inheritance patterns consistent with autosomal recessiveness were observed in 198 (57.2%), autosomal dominance in 126 (36.4%), and autosomal dominance with incomplete penetrance in 19 (5.5%) of the families.

Conclusions—

The collection is the most extensive published to date and extends previous observations of familial aggregation that are consistent with a major gene effect.
Recommendations for Advancing Development of Acute Stroke Therapies
Authors: Fisher Marc
Published: May 2003

Background—

The development of acute stroke therapy has proven to be a daunting task, with a few successful and many unsuccessful trials. New strategies need to be considered to enhance the chances for success in future trials.

Summary of Review—

The third Stroke Therapy Academic Industry Roundtable (STAIR) conference focused on issues related to increasing the percentage of acute stroke patients who might be included in acute stroke therapy trials and ultimately treated with drugs proven to be effective. A second focus was directed at the need for implementing multimodality stroke trials and potential ways to organize such trials in the near future. Finally, concepts for organizing and implementing acute stroke trials that incorporate current, state of the art trial methodology were discussed.

Conclusions—

It is hoped that these suggestions will enhance future stroke trials and the development of effective, new acute stroke treatments that are maximally effective and utilized.
Intracellular Pathways Involved in Upregulation of Vascular Endothelin Type B Receptors in Cerebral Arteries of the Rat
Authors: Henriksson Marie , Stenman Emelie , Edvinsson Lars
Published: May 2003

Background and Purpose—

Previous studies have shown that contractile endothelin type B (ET
B
) receptors are upregulated in cerebral arteries after experimental focal cerebral ischemia. The aim of this study was to examine the upregulation of contractile ET
B
receptors in cerebral arteries after organ culture and to elucidate the intracellular pathways involved.

Methods—

Rat middle cerebral arteries (MCAs) were incubated with or without inhibitors. The vessels were mounted in myographs, and the contractile responses to endothelin-1 (ET-1) (ET
A
and ET
B
receptor agonist) and sarafotoxin 6c (ET
B
receptor agonist) were measured. Levels of ET
B
receptor mRNA were measured with real-time polymerase chain reaction.

Results—

In fresh MCA, sarafotoxin 6c had no contractile effect. However, after organ culture, a strong concentration-dependent contraction was induced. ET-1 produced a strong contraction, in which the E
max
was unaffected by organ culture but the EC
50
was decreased with time. The sarafotoxin 6c–induced contraction after 24 hours of organ culture was attenuated by the transcriptional inhibitor actinomycin D and the translational inhibitor cycloheximide as well as the protein kinase C inhibitor Ro-31-8220. Real-time polymerase chain reaction revealed that the mRNA levels of the ET
B
receptor were increased after organ culture compared with fresh vessels. Actinomycin D and Ro-31-8220 diminished the enhanced mRNA levels considerably.

Conclusions—

The results suggest that, in fresh MCA, the ET
A
receptor is the most prominent subtype, while after organ culture ET
B
receptors also contribute to the contraction. This upregulation is due to de novo transcription of receptors. Protein kinase C is involved in the upregulation as Ro-31-8220 attenuates the contraction and the mRNA increase.
Cause of Stroke Recurrence Is Multifactorial
Authors: Hillen Thomas , Coshall Catherine , Tilling Kate , Rudd Anthony G. , McGovern Rory , Wolfe Charles D.A.
Published: May 2003

Background and Purpose—

This article examines stroke recurrence and whether the subtype of the initial stroke influences the risk and subtypes of further strokes. The proportion of recurrences attributable to conventional risk factors is quantified.

Methods—

From January 1995 to August 2000, all first-in-a-lifetime strokes (n=1626) were identified and prospectively followed up in a defined multiethnic inner city population of 234 533. Twelve overlapping referral sources and face-to-face follow-up at 3 months and 1 and 3 years were used to attain complete registration of stroke recurrence. Index and recurrent stroke were classified according to the Oxford Community Stroke Project classification.

Results—

In 2744 person-years of follow-up, 153 recurrences were observed. At 5 years, the cumulative risk of first stroke recurrence was 16.6% (95% CI, 13.5 to 20.4), and the combined risk of death or stroke recurrence was 65.3% (95% CI, 61.9 to 68.6). Ethnicity and subtype of index stroke were not associated with stroke recurrence. A change in subtype between index and recurrent stroke occurred in 45.5% (95% CI, 35.8 to 55.2) of cases and was most frequent among index lacunar strokes and primary intracerebral hemorrhages. In multivariable analyses, diabetes mellitus and atrial fibrillation were associated with both stroke recurrence and recurrence-free survival. In the stroke population, 9.1% (95% CI, −2.0 to 20.2) of recurrences were attributable to diabetes and 4.9% (95% CI, −7.3 to 17.2) to atrial fibrillation during the first year after the index stroke.

Conclusions—

The cause of stroke recurrence is multifactorial, and the subtypes of index and recurrent strokes are often not identical. Most recurrences remain unexplained by conventional risk factors.
Increase in Plasma Matrix Metalloproteinase-9 in Acute Stroke Patients With Thrombolysis Failure
Authors: Heo Ji Hoe , Kim Seo Hyun , Lee Kyung Yul , Kim Eun Hee , Chu Chong Kyu , Nam Jeong Mo
Published: May 2003

Background and Purpose—

Platelet-rich thrombi are resistant to thrombolytics. Matrix metalloproteinases (MMPs) may be involved in platelet aggregation and contribute to thrombolysis failure in stroke patients.

Methods—

Plasma samples from 23 stroke patients who had received thrombolytics and from 47 healthy volunteers were examined for MMP-2 and MMP-9 by both enzyme-linked immunosorbent assays and zymography.

Results—

The arteries were recanalized in 15 patients but not in the other 8. The MMP-9 plasma level was significantly higher in patients whose arteries were not recanalized.

Conclusions—

MMP-9 may be associated with the formation of a thrombolytics-resistant thrombus.
Impact of Establishing a Primary Stroke Center at a Community Hospital on the Use of Thrombolytic Therapy
Authors: Lattimore Susan Unipan , Chalela Julio , Davis Lisa , DeGraba Thomas , Ezzeddine Mustapha , Haymore Joseph , Nyquist Paul , Baird Alison E. , Hallenbeck John , Warach Steven
Published: May 2003

Background and Purpose—

To increase the proportion of ischemic stroke patients treated with thrombolytic therapy, the establishment of primary stroke centers in community hospitals has been advocated. We evaluated the use of thrombolytic therapy before and after institution of a primary stroke center in a community hospital.

Methods—

The availability of an on-call stroke emergency response team was the only significant additional resource required for this hospital. All eligible patients were treated with intravenous tissue plasminogen activator (tPA). The number of patients with cerebrovascular disease, number and proportion of patients treated with tPA, times to treatment, and patient outcomes were recorded during the first 2 years of the stroke center.

Results—

During the 12 months before institution of the stroke center, 3 ischemic stroke patients (1.5%) were treated with tPA. During the 2-year period of around-the-clock coverage, 44 of 420 ischemic stroke patients (10.5%) were treated with intravenous tPA, a significant increase in tPA use (
P
<0.0001).

Conclusions—

Establishment of a primary stroke center at a community hospital resulted in a substantial increase in the proportion of patients receiving thrombolytic therapy for ischemic stroke. If this experience is generalized, the beneficial impact of primary stroke centers on stroke outcomes and costs to the healthcare system may be substantial.
Stroke Development in Stroke-Prone Spontaneously Hypertensive Rats Alters the Ability of Cerebrovascular Muscle to Utilize Internal Ca
2+
to Elicit Constriction
Authors: Smeda John S.
Published: May 2003

Background and Purpose—

The ability of middle cerebral arteries (MCAs) to utilize intracellular smooth muscle (SM) Ca
2+
to produce constriction in response to pressure and agonists was assessed in relation to hemorrhagic stroke development in Wistar-Kyoto stroke-prone (SHRSP) and stroke-resistant (srSHR) spontaneously hypertensive rats.

Methods—

MCAs were studied with the use of a pressure myograph at 100 mm Hg.

Results—

MCAs from srSHR and prestroke SHRSP exhibited pressure-dependent constriction and constricted in response to vasopressin or serotonin in the presence of nifedipine or the absence of [Ca
2+
]
o
. MCAs from poststroke SHRSP lost the latter functions and could only constrict in response to vasopressin/serotonin in Krebs’ solution containing Ca
2+
in the absence of nifedipine. This indicated that the SM could not utilize internal Ca
2+
for constriction and maintained constriction by Ca
2+
entry through L-type channels. The MCAs of poststroke SHRSP could not constrict to [K
+
]
o
-induced depolarization, suggesting that the agonist-induced opening of the L-type channels occurred by mechanisms other than SM depolarization. Depletion of the sarcoplasmic SM Ca
2+
stores of MCAs from srSHR with cyclopiazonic acid did not prevent pressure-dependent constriction.

Conclusions—

Stroke in SHRSP produced a defect in the ability of MCAs to constrict in response to vasopressin or serotonin via the use of an intracellular source of Ca
2+
. This could be promoted by an inability of the SM to release intracellular Ca
2+
, by the depletion of internal Ca
2+
stores, or by a decrease in the contractile sensitivity to Ca
2+
released from the internal stores.
Alterations in Autoregulatory and Myogenic Function in the Cerebrovasculature of Dahl Salt-Sensitive Rats
Authors: Smeda John S. , Payne Geoffrey W.
Published: May 2003

Background and Purpose—

Dahl salt-sensitive rats fed an 8.7% NaCl diet exhibited hypertensive encephalopathy and developed seizures associated with areas of blood-brain barrier (BBB) disruption without brain ischemia. The incidence of hemorrhagic stroke was low (7/47). We tested the hypothesis that a defect in cerebral blood flow (CBF) autoregulation under hypertensive conditions preceded hypertensive encephalopathy.

Methods—

Brain ischemia and BBB disruption were assessed with the use of tetrazolium red staining and Evans blue dye extravasation, respectively. Myogenic constriction to pressure was measured in isolated middle cerebral arteries (MCAs) with a pressure myograph. CBF autoregulation was assessed with the use of laser-Doppler techniques.

Results—

Asymptomatic rats fed 8.7% NaCl had MCAs that developed an age-related attenuation in their ability to constrict to pressure, which was amplified in rats exhibiting hypertensive encephalopathy. The MCAs of rats with hemorrhagic stroke lost this function and developed large degrees of basal tone. The majority (4/6) of asymptomatic rats fed high salt for longer than 3 weeks exhibited a linear relationship between CBF and blood pressure. The characteristics of CBF regulation were consistent with the possible absence of autoregulation coupled with cerebrovascular vasoconstriction.

Conclusions—

Both MCA pressure-dependent constriction and CBF autoregulation in the MCA perfusion domain were lost before the development of hypertensive encephalopathy or hemorrhagic stroke. These defects could contribute to the development of BBB disruption during hypertension. Cerebrovascular vasoconstriction in the absence of CBF autoregulation may protect the brain from excessive overperfusion during hypertension and could account for the low incidence of cerebral hemorrhage in this model.
Neurological Dysfunctions Versus Regional Infarction Volume After Focal Ischemia in Mongolian Gerbils
Authors: Ishibashi Satoru , Kuroiwa Toshihiko , Endo Shu , Okeda Riki , Mizusawa Hidehiro
Published: May 2003

Background and Purpose—

With advances in the therapy of stroke at the postacute phase, the use of animal models for chronological and region-specific evaluation of neurological function has become increasingly important. Our aim was to test long-term behavioral dysfunction in gerbils after focal ischemia and to correlate the results with the regional distribution of infarction in the coordinating cortical regions.

Methods—

Repetitive unilateral hemispheric ischemia (two 10-minute occlusions, 5-hour interval) was induced in Mongolian gerbils. The elevated body swing test (EBST), bilateral asymmetry test (BAT), and T-maze test were performed to assess asymmetrical motor behavior, somatosensory deficit, and spatial cognitive dysfunction during 4 weeks after ischemia. The results were correlated against the regional infarction volume of the primary motor, somatosensory, and primary visual cortices at 4 weeks after ischemia.

Results—

In all postischemic gerbils, persistent sensorimotor and cognitive dysfunctions were detectable throughout the postischemic period. Histological examination revealed that a cortical zone of infarction surrounded the selective neuronal death in the ipsilateral cerebral hemisphere. The regional infarction volumes of the primary motor, somatosensory, and visual cortices were significantly correlated with the scores of the EBST, BAT, and T-maze test, respectively. These combinations had the highest regression coefficient of all pairs.

Conclusions—

Postischemic motor and somatosensory functions were significantly correlated with regional infarction volumes in the corresponding cortical regions. In gerbils, visual abnormality could be independently detected by the T-maze test. Such regional analyses of ischemic lesions would be useful for investigating the functional outcomes of stroke therapy.
Homocysteine and Cerebral Infarction in Finnish Male Smokers
Authors: Fallon Una B. , Virtamo Jarmo , Young Ian , McMaster Dorothy , Ben-Shlomo Yoav , Wood Nigel , Whitehead Alexander S. , Smith George Davey
Published: May 2003

Background and Purpose—

Homocysteine is associated with stroke, but it is not clear whether this relationship is causal. We examined the association between total serum homocysteine concentration (tHcy) and cerebral infarction in a cohort of Finnish male smokers.

Methods—

This is a matched case-control study of 201 cases of cerebral infarction and 201 concurrently sampled age-matched controls nested in a cohort of 13 840 male smokers free of cardiovascular disease at the completion of the Alpha-Tocopherol and Beta-Carotene (ATBC) Cancer Prevention study. Conditional logistic regression was used to calculate odds ratios (ORs) and to adjust for confounding variables. An unmatched analysis was also performed.

Results—

The geometric mean tHcy was 13.3 μmol/L (95% CI, 12.6 to 13.9) in cases and 12.6 μmol/L (95% CI, 12.0 to 13.2) in controls (
P
=0.09). There was a graded increase in the OR of cerebral infarction per quartile increase in tHcy (OR, 1.0, 1.7, 1.9, 2.1; trend
P
=0.02; 201 case-control pairs) when adjusted for traditional risk factors. There was a similar trend in a subgroup of 120 case-control pairs for which further adjustment for lifestyle factors was possible (OR, 1.0, 1.9, 2.5, 2.2; trend
P
=0.07 in the matched analyses; OR, 1.0, 1.2, 1.9, 2.0; trend
P
=0.02 in the unmatched analyses). The adjusted OR per 1-SD increase in log-transformed tHcy (equivalent to 4.7 μmol) was 1.4 (95% CI, 1.1 to 1.7;
P
=0.01).

Conclusions—

tHcy appears to predict cerebral infarction in Finnish male smokers.
Acute Focal Neurological Deficits in Aneurysmal Subarachnoid Hemorrhage
Authors: Sarrafzadeh Asita , Haux Daniel , Sakowitz Oliver , Benndorf Goetz , Herzog Harry , Kuechler Ingeborg , Unterberg Andreas
Published: May 2003

Background and Purpose—

We sought (1) to identify early metabolic markers for the development of (ir)reversible neurological deficits and cerebral infarction in subarachnoid hemorrhage (SAH) patients by using the microdialysis technique and (2) to evaluate the influence of intracerebral hemorrhage (ICH) on microdialysis parameters.

Methods—

We performed a prospective study of 44 SAH patients with acute focal neurological deficits (AFND) occurring acutely with SAH (due to ICH) or directly after surgery (due to clip stenosis, thromboembolism, or early edema). Fifty-one nonischemic SAH patients served as a control group. A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. The microdialysates were analyzed hourly for extracellular glucose, lactate, lactate/pyruvate ratio, glutamate, and glycerol with a bedside analyzer. Microdialysis-related CT findings were evaluated for the presence of ICH and cerebral infarction. Reversibility of neurological symptoms after 4 weeks and 6- and 12-month outcomes were assessed.

Results—

In patients with AFND, cerebral metabolism was severely disturbed when microdialysis started compared with controls (
P
<0.005). Infarction on CT was associated with pathological microdialysis parameters (
P
<0.002) and development of a fixed deficit (
P
<0.003), while the presence of ICH alone was not. A secondary neurological deterioration of AFND patients (n=11) was reflected by preceding (0 to 20 hours) changes of microdialysate concentrations.

Conclusions—

In the presence of ICH, pathological microdialysis values may indicate reversible tissue damage. Extreme microdialysis values and pathological microdialysis concentrations that further deteriorate 2-fold are highly indicative of the development of cerebral infarction and permanent neurological deficits. Therefore, the analysis of relative changes of microdialysis parameters is crucial for the detection of ischemia in SAH patients.
Poor Nutritional Status on Admission Predicts Poor Outcomes After Stroke
Authors:   FOOD Trial Collaboration
Published: May 2003

Background and Purpose—

Previous studies suggest that undernourished patients with acute stroke do badly. The data, however, are not robust. We aimed to reliably assess the importance of baseline nutritional status as an independent predictor of long-term outcome after stroke in a large prospective cohort enrolled in the Feed Or Ordinary Diet (FOOD) trial, a multicenter randomized trial evaluating various feeding policies.

Methods—

Patients admitted to hospital with a recent stroke were enrolled in the FOOD trial. Data on nutritional status and other clinical predictors of outcome were collected at trial entry. At 6 months, the coordinating center collected data on survival and functional status (modified Rankin Scale). Outcome assessment was done by researchers blinded to baseline assessments and treatment allocation.

Results—

Between November 1996 and November 2001, 3012 patients were enrolled, and 2955 (98%) were followed up. Of the 275 undernourished patients, 102 (37%) were dead by final follow-up compared with only 445 (20%) of 2194 patients of normal nutritional status (odds ratio [OR], 2.32; 95% CI, 1.78 to 3.02). After adjustment for age, prestroke functional state, and stroke severity, this relationship, although weakened, still held (OR, 1.82; 95% CI, 1.34 to 2.47). Undernourished patients were more likely to develop pneumonia, other infections, and gastrointestinal bleeding during their hospital admission than other patients.

Conclusions—

These data provide reliable evidence that nutritional status early after stroke is independently associated with long-term outcome. It supports the rationale for the FOOD trial, which continues to recruit and aims to estimate the effect of different feeding regimes on outcome after stroke and thus determine whether the association observed in this study is likely to be causal.
Trends in Stroke Incidence and 10-Year Survival in Söderhamn, Sweden, 1975-2001
Authors: Terént Andreas
Published: May 2003

Background and Purpose—

Stroke mortality rates have declined in many countries. Stroke incidence rates have also declined, but not to the same extent and not always in parallel with stroke mortality. The aim of the present study was to investigate trends in stroke incidence and long-term survival in a Swedish population.

Methods—

A population-based survey of the incidence of first-ever stroke was performed prospectively in the periods 1975 to 1977, 1983 to 1986, and 1987 to 1990. Case fatality ratios and survival rates were followed to 2001.

Results—

Crude incidence rates increased between 1975 to 1977 and 1983 to 1986, but age- and sex-adjusted incidence rates were stable during the whole period of 1975 to 1990. The incidence of intracerebral hemorrhage decreased by approximately two thirds, whereas the incidence of mild brain infarction almost doubled. The case fatality ratio at 28 days did not change, but the 10-year survival ratio increased from 13% to 35%. Mean survival time increased significantly among patients with intracerebral hemorrhage and brain infarction but not among patients with subarachnoidal hemorrhage or stroke of undetermined origin.

Conclusions—

Stroke incidence and short-term case fatality did not change between 1975 and 1990 in the Söderhamn population. Long-term survival after stroke, on the other hand, has continued to improve to 2001. The implication of these changes is that the burden of stroke is likely to increase unless strokes are becoming less severe.
A Taxonomy for Spatiotemporal Connectionist Networks Revisited: The Unsupervised Case
Authors: Barreto Guilherme de A. , Araújo Aluizio F. R. , Kremer Stefan C.
Published: May 2003

Spatiotemporal connectionist networks (STCNs) comprise an important class of neural models that can deal with patterns distributed in both time and space. In this article, we widen the application domain of the taxonomy for supervised STCNs recently proposed by Kremer (2001) to the unsupervised case. This is possible through a reinterpretation of the state vector as a vector of latent (hidden) variables, as proposed by Meinicke (2000). The goal of this generalized taxonomy is then to provide a nonlinear generative framework for describing unsupervised spatiotemporal networks, making it easier to compare and contrast their representational and operational characteristics. Computational properties, representational issues, and learning are also discussed, and a number of references to the relevant source publications are provided. It is argued that the proposed approach is simple and more powerful than the previous attempts from a descriptive and predictive viewpoint. We also discuss the relation of this taxonomy with automata theory and state-space modeling and suggest directions for further work.