bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiogenic Gene Therapy for Experimental Critical Limb Ischemia
Authors: Masaki Ichiro , Yonemitsu Yoshikazu , Yamashita Akihisa , Sata Shihoko , Tanii Mitsugu , Komori Kimihiro , Nakagawa Kazunori , Hou Xiaogang , Nagai Yoshiyuki , Hasegawa Mamoru , Sugimachi Keizo , Sueishi Katsuo
Published: July 2002

Recent studies suggest the possible therapeutic effect of intramuscular vascular endothelial growth factor (VEGF) gene transfer in individuals with critical limb ischemia. Little information, however, is available regarding (1) the required expression level of VEGF for therapeutic effect, (2) the related expression of endogenous angiogenic factors, including fibroblast growth factor-2 (FGF-2), and (3) the related adverse effects due to overexpression of VEGF. To address these issues, we tested effects of overexpression of VEGF165 using recombinant Sendai virus (SeV), as directly compared with FGF-2 gene transfer. Intramuscular injection of SeV strongly boosted FGF-2, resulting in significant therapeutic effects for limb salvage with increased blood perfusion associated with enhanced endogenous VEGF expression in murine models of critical limb ischemia. In contrast, VEGF165 overexpression, 5-times higher than that of baseline on day 1, also strongly evoked endogenous VEGF in muscles, resulting in an accelerated limb amputation without recovery of blood perfusion. Interestingly, viable skeletal muscles of either VEGF165- or FGF-2–treated ischemic limbs showed similar platelet-endothelial cell adhesion molecule-1–positive vessel densities. Maturation of newly formed vessels suggested by smooth muscle cell actin–positive cell lining, however, was significantly disturbed in muscles with VEGF. Further, therapeutic effects of FGF-2 were completely diminished by anti-VEGF neutralizing antibody in vivo, thus indicating that endogenous VEGF does contribute to the effect of FGF-2. These results suggest that VEGF is necessary, but should be delicately regulated to lower expression to treat ischemic limb. The therapeutic effect of FGF-2, associated with the harmonized angiogenic effects seen with endogenous VEGF, provides important insights into therapeutic angiogenesis.
Dominant-Negative Suppression of HCN1- and HCN2-Encoded Pacemaker Currents by an Engineered HCN1 Construct
Authors: Xue Tian , Marbán Eduardo , Li Ronald A.
Published: July 2002

I
f
, a diastolic depolarizing current activated by hyperpolarization, is a key player in cardiac pacing. Despite the fact that
I
f
has been known for over 20 years, the encoding genes, namely HCN1 to 4, have only recently been identified. Functional data imply that different HCN isoforms may coassemble to form heteromeric channel complexes, but little direct evidence is available. Subunit stoichiometry is also unknown. Although the pore region of HCN channels contains the
g
lycine-t
y
rosine-
g
lycine (GYG) signature motif found in K
+
-selective channels, they permeate both Na
+
and K
+
. In the present study, we probed the functional importance of the GYG selectivity motif in pacemaker channels by replacing this triplet in HCN1 with alanines (GYG
349–351
AAA or HCN1-AAA). HCN1-AAA did not yield functional currents; coexpression of HCN1-AAA with wild-type (WT) HCN1 suppressed normal channel activity in a dominant-negative manner (55.2±3.2%, 68.3±4.3%, 78.7±1.6%, 91.7±0.8%, and 97.9±0.2% current reduction at −140 mV for WT:AAA cRNA ratios of 4:1, 3:1, 2:1, 1:1, and 1:2, respectively) without affecting gating (steady-state activation, activation and deactivation kinetics) or permeation (reversal potential) properties. HCN1-AAA coexpression, however, did not alter the expressed current amplitudes of Kv1.4 and Kv2.1 channels, indicating that its suppressive effect was channel-specific. Statistical analysis reveals that a single HCN channel is composed of 4 monomeric subunits. Interestingly, HCN1-AAA also inhibited HCN2 in a dominant-negative manner with the same efficacy. We conclude that the GYG motif is a critical determinant of ion permeation for HCN channels, and that HCN1 and HCN2 readily coassemble to form heterotetrameric complexes.
Hypoxic Induction of the Hypoxia-Inducible Factor Is Mediated via the Adaptor Protein Shc in Endothelial Cells
Authors: Jung Frank , Haendeler Judith , Hoffmann Jörg , Reissner Agnes , Dernbach Elisabeth , Zeiher Andreas M. , Dimmeler Stefanie
Published: July 2002

Tyrosine kinase cascades may play a role in the hypoxic regulation of hypoxia-inducible factor (HIF)-1. We investigated the role of tyrosine kinase phosphorylation and of the Shc/Ras cascade on hypoxic HIF-1 stabilization. Exposure of human umbilical vein endothelial cells to hypoxia results in HIF protein stabilization as early as 10 minutes, with a maximum at 3 hours, and also in Shc tyrosine phosphorylation, with a maximum at 10 minutes. To test whether Shc directly mediates hypoxia-induced HIF stabilization, human umbilical vein endothelial cells were transfected with a dominant-negative Shc mutant (dnShc), resulting in significantly reduced HIF protein levels compared with control. Similar results were obtained with cells transfected with dominant-negative Ras, a known downstream effector of Shc. Hypoxia-induced Ras activity was significantly reduced in cells transfected with dnShc compared with control levels, indicating that Ras indeed acts downstream from Shc. Moreover, cells pretreated with a specific Raf-1 kinase inhibitor, a known downstream effector of Ras, exhibited reduced HIF protein levels. To examine the functional consequences of Shc in hypoxic signaling, HIF-1 ubiquitination, protein stabilization, and endothelial cell migration were assessed. Overexpression of dnShc increased ubiquitination of HIF-1 and reduced the half-life of the protein. Moreover, dnShc, dominant-negative Ras, or the Raf-1 kinase inhibitor significantly inhibited migration under hypoxia. Thus, Shc in concert with Ras and Raf-1 contributes to hypoxia-induced HIF-1α protein stabilization and endothelial cell migration.
α
7
-Nicotinic Acetylcholine Receptors on Cerebral Perivascular Sympathetic Nerves Mediate Choline-Induced Nitrergic Neurogenic Vasodilation
Authors: Si Min-Liang , Lee Tony J.F.
Published: July 2002

It has been suggested in isolated porcine cerebral arteries that stimulation by nicotine of α
7
-nicotinic acetylcholine receptors (α
7
-nAChRs) on sympathetic nerves, but not direct stimulation of parasympathetic nitrergic nerves, caused nitrergic neurogenic dilation. Direct evidence supporting this hypothesis has not been presented. The present study, which used in vitro tissue bath and confocal microscopy techniques, was designed to determine whether choline, a selective agonist for α
7
-nAChRs, induced sympathetic-dependent nitrergic dilation of porcine basilar arterial rings. Choline and several nAChR agonists induced exclusive relaxation of basilar arterial rings without endothelium. The relaxation was blocked by tetrodotoxin, nitro-
l
-arginine, guanethidine, and β
2
-adrenoceptor antagonists. Furthermore, the relaxation was blocked by methyllycaconitine and α-bungarotoxin (preferential α
7
-nAChR antagonists) and mecamylamine but was not affected by dihydro-β-erythroidine (a preferential α
4
-nAChR antagonist). Confocal microscopic study demonstrated that choline and nicotine induced significant calcium influx in cultured porcine superior cervical ganglionic cells but failed to affect calcium influx in cultured sphenopalatine ganglionic cells, providing direct evidence that choline and nicotine did not act directly on the parasympathetic nitrergic neurons. The increased calcium influx in superior cervical ganglionic cells was attenuated by α-bungarotoxin and methyllycaconitine but not by dihydro-β-erythroidine. These results support our hypothesis that activation of α
7
-nAChRs on cerebral perivascular sympathetic nerves causes calcium influx and the release of norepinephrine, which then act on presynaptic β
2
-adrenoceptors located on the neighboring nitrergic nerve terminals, resulting in NO release and vasodilation. Endogenous choline may play an important role in regulating cerebral sympathetic activity and vascular tone.
1α,25-Dihydroxyvitamin D
3
Induces Vascular Smooth Muscle Cell Migration via Activation of Phosphatidylinositol 3-Kinase
Authors: Rebsamen Michela C. , Sun Jianxin , Norman Anthony W. , Liao James K.
Published: July 2002

The steroid hormone 1α,25-dihydroxyvitamin D
3
[1α, 25-(OH)
2
D
3
] promotes vascular smooth muscle cell (VSMC) growth and calcification, but the precise mechanism by which 1α, 25-(OH)
2
D
3
regulates VSMC migration is unknown. In rat aortic SMCs, we found that 1α, 25-(OH)
2
D
3
(0.1 to 100 nmol/L) induced a dose-dependent increase in VSMC migration. This response required the activation of phosphatidylinositol 3-kinase (PI3 kinase) because 1α, 25-(OH)
2
D
3
-induced migration was completely abolished by the PI3 kinase inhibitors, LY294002 (10 μmol/L) or wortmannin (30 nmol/L). Furthermore, the RNA polymerase inhibitor, 5,6-dichlorobenzimidazole riboside (50 μmol/L), did not affect 1α, 25-(OH)
2
D
3
-induced VSMC migration, suggesting that gene transcription is not involved in this rapid response. Using analogs of 1α, 25-(OH)
2
D
3
, which have been characterized for their abilities to induce either transcriptional or nontranscriptional responses of 1α, 25-(OH)
2
D
3
, we found that 1α,25-dihydroxylumisterol, which is a potent agonist of the rapid, nongenomic responses, was equipotent with 1α, 25-(OH)
2
D
3
in inducing PI3 kinase activity and VSMC migration. Moreover, 1β, 25-(OH)
2
D
3
, which specifically antagonizes the nongenomic actions of 1α, 25-(OH)
2
D
3
, abolished 1α, 25-(OH)
2
D
3
-induced PI3 kinase activity and VSMC migration, whereas the inhibitor of the genomic actions of vitamin D, (23S)-25-dehydro-1α-OH-D
3
-26,23-lactone, did not affect these responses. These results indicate that 1α, 25-(OH)
2
D
3
induces VSMC migration independent of gene transcription via PI3 kinase pathway, and suggest a possible mechanism by which 1α, 25-(OH)
2
D
3
may contribute to neointima formation in atherosclerosis and vascular remodeling.
Lack of Evidence for Pulmonary Venous Thrombosis in Cryptogenic Stroke
Authors: Grau Armin J. , Schoenberg Stefan O. , Lichy Christoph , Buggle Florian , Bock Michael , Hacke Werner
Published: July 2002

Background

—

Even after extensive evaluation, the etiology of ischemic stroke remains undefined in a considerable proportion of cases, suggesting that causes of stroke may exist that have not yet been established. We tested the hypothesis that pulmonary venous thrombosis (PVT) is a potential source of brain embolism in patients with cryptogenic stroke.

Summary of Report

—

Within 7 days after mild to moderately severe ischemic stroke or transient ischemic attack, 18 patients (9 women, 9 men; mean age, 48 years) were studied in whom the etiology remained undefined despite complete workup. All patients received high-resolution pulmonary venography with the use of multiple-bolus, multiphase, 3-dimensional, gadolinium-enhanced MR angiography (MRA). Overall quality of the MRA was good in 14 and insufficient in 4 patients, mainly as a result of breathing artifacts. Visualization of the main and segmental veins and evaluability of their patency were good for most right pulmonary veins but often inadequate for left pulmonary veins, particularly for those in the left lower lobe. There was no evidence for PVT in any of the sufficiently visualized pulmonary veins.

Conclusions

—

The results do not support the hypothesis of PVT as a contributor to the etiology of ischemic stroke. However, the study was limited regarding scan volume, spatial discrimination, patient selection, and delay between ischemia and MRA. Therefore, further investigations, including postmortem studies, are needed to resolve the question of whether PVT may contribute to ischemic stroke.
Large and Deep Brain Arteriovenous Malformations Are Associated With Risk of Future Hemorrhage
Authors: Stefani Marco A. , Porter Phillip J. , terBrugge Karel G. , Montanera Walter , Willinsky Robert A. , Wallace M. Christopher
Published: July 2002

Background and Purpose

—

The correlation between features present in brain arteriovenous malformations (AVMs) such as size, location, and angioarchitecture at presentation with subsequent risk of hemorrhage may be valuable in predicting the behavior of AVMs and therefore guiding management.

Methods

—

We prospectively followed up 390 patients with brain AVMs at the University of Toronto Vascular Malformation Study Group. Location, size, angioarchitecture details, blood supply, and clinical presentation were recorded at baseline. Intracranial hemorrhages during follow-up were recorded. Significant factors from univariate analyses were used to construct a multivariate model relating the above features to the occurrence of hemorrhage.

Results

—

Thirty-eight patients had bleeding caused by the AVM in a follow-up of 1205 patient-years (mean, 3.1 years per patient). In analyses adjusted for multiple AVM characteristics, large AVMs bled more frequently than small lesions (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.41 to 4.35;
P
<0.0001), and deep-seated AVMs had more bleeding in follow-up than those located at superficial sites (OR, 5.56; 95% CI, 2.63 to 12.5;
P
<0.0001).

Conclusions

—

Deep-seated and large AVMs were significantly more prone to hemorrhage during prospective follow-up. The distinction between factors associated with hemorrhagic presentation and the natural history risk of hemorrhage will be emphasized.
Magnetic Resonance Angiography in Childhood Arterial Brain Infarcts
Authors: Husson Béatrice , Rodesch Georges , Lasjaunias Pierre , Tardieu Marc , Sébire Guillaume
Published: July 2002

Background and Purpose

—

Contrast angiography (CA) is the reference examination for the diagnosis of cerebral arterial abnormality, but this procedure is invasive. In childhood, ischemic strokes are being increasingly investigated by means of MRI, including MR angiography (MRA). Very few data are available about the accuracy of MRA compared with CA in the specific context of acute pediatric stroke. We sought to compare the results of MRA with those of CA for the study of cerebral arteries in children with arterial infarction in an arterial distribution.

Methods

—

Twenty-four children presenting with 26 infarcts were studied. All were examined with cerebral MRI and MRA and with CA. The interval between CA and MRA was <3 days for most of the patients.

Results

—

Arterial lesions were detected in all but 2 children. They were located in the major cerebral arteries, predominantly in the anterior circulation (85% of cases). All lesions shown by CA were present on MRA (19 cases). Patients with no lesion on MRA had normal CA (2 cases). Associated distal vascular lesions and degree of arterial stenosis were more accurately detected with CA.

Conclusions

—

MRA is sensitive enough to provide an adequate initial evaluation of arterial brain disease in childhood.
Increased Circulating Immune Complexes in Acute Stroke
Authors: Tarnacka Beata , Gromadzka Gräyna , Członkowska Anna
Published: July 2002

Background and Purpose

—

The mechanisms of immune reaction involved in the pathogenesis and clinical course of acute vascular incidents are still not completely understood. The aim of this study was to examine the presence of immune complexes (IC) in the acute stroke setting and the first month thereafter and to characterize IC by analyzing the contents of chlamydial lipopolysaccharide and anti-cytomegalovirus (CMV) antibodies in IC.

Methods

—

Serum concentration of IC was investigated in 179 stroke patients, 122 “old” controls and 112 “young” controls, by the precipitation method. The presence of chlamydial lipopolisaccharyde and anti-CMV antibodies was investigated in some IC preparations by the ELISA method after earlier dissociation of IC into components by high pH treatment.

Results

—

Significantly increased serum IC concentration in stroke patients was noticed. Increased serum IC concentration was revealed as an independent strong stroke risk factor and was connected with significantly worse neurological status and increased 30-day mortality rate. A significantly larger proportion of stroke patients than controls had
Chlamydia pneumoniae
antigen and anti-CMV antibodies in IC.

Conclusions

—

This study provides the first evidence of an association between increased serum level of IC and the clinical course of cerebral ischemia and identifies a potentially important association of
C pneumoniae
and CMV-specific IC with stroke incidence.
Efficacy and Safety of Nicardipine Prolonged-Release Implants for Preventing Vasospasm in Humans
Authors: Kasuya Hidetoshi , Onda Hideaki , Takeshita Mikihiko , Okada Yoshikazu , Hori Tomokastu
Published: July 2002

Background and Purpose

—

Despite extensive investigative efforts, there are few treatments that can prevent vasospasm after subarachnoid hemorrhage. This study was conducted to examine the efficacy and safety of nicardipine prolonged-release implants (NPRI) for humans, which have already been proven in dogs.

Methods

—

Twenty consecutive subarachnoid hemorrhage patients with thick subarachnoid clot were treated with NPRI (a pellet of diameter 2 mm, length 10 mm, containing 4 mg of nicardipine) during surgery after clipping of their aneurysm. The number and location of pellets depended on the amount and site of subarachnoid clot on preoperative CT and on craniotomy.

Results

—

Two to 10 pellets were implanted in the cistern of the internal carotid, middle cerebral, and/or anterior cerebral artery, where thick clots existed and therefore vasospasm related to delayed ischemic neurological deficits was highly likely. Delayed ischemic neurological deficits and cerebral infarctions were seen in 1 patient. Angiography performed on days 7 to 12 revealed no vasospasm in any arteries near which NPRI were placed. No complications were experienced.

Conclusions

—

Vasospasm was completely prevented for the arteries in thick clot cisterns, when NPRI were placed adjacent to the arteries during surgery. This drug-delivery system offers a promising approach for preventing vasospasm.
Angioarchitectural Factors Present in Brain Arteriovenous Malformations Associated With Hemorrhagic Presentation
Authors: Stefani Marco A. , Porter Phillip J. , terBrugge Karel G. , Montanera Walter , Willinsky Robert A. , Wallace M. Christopher
Published: July 2002

Background and Purpose

—

Associations between clinical presentation of brain arteriovenous malformations (AVMs) and their angioarchitecture have been described. This study aims to identify significant factors related to the initial hemorrhagic event through multivariate statistical methodology.

Methods

—

The authors studied the initial clinical presentation of 390 consecutive patients with brain AVMs at the University of Toronto Vascular Malformation Study Group. Angiographic features present at that time, such as location, size, and blood supply, were recorded following a standard protocol and associated, through multivariate analysis techniques, with type of presentation.

Results

—

Patients had hemorrhagic presentation in 146 cases (37.4%). Hemorrhage was the initial presentation in 59.5% of the deep-seated AVMs (odds ratio [OR]=3.26; 95% CI=1.15 to 9.2;
P
=0.03). A single draining vein was associated with bleeding at presentation in 57.6% AVMs (OR=1.78; 95% CI=1.12 to 2.82;
P
=0.01), and 72.8% of the patients with venous ectasia had bleeding as initial evidence (OR=3.9; 95% CI=1.63 to 9.28;
P
=0.002). Hemorrhage was the initial presentation in 47.6% (111/233) of AVMs <3 cm, 22.5% (32/142) in sizes between 3 and 6 cm, and 20% in malformations >6 cm (3/15), but these differences were not significant in multivariate analyses.

Conclusions

—

For initial hemorrhagic presentation, a small number of draining veins, deep location, and the presence of venous ectasias were significant associated factors. In contrast with many previous reports, AVM size was not associated with hemorrhage at presentation in adjusted analyses.
The Stroke Patient Who Woke Up
Authors: Fink John N. , Kumar Sandeep , Horkan Clare , Linfante Italo , Selim Magdy H. , Caplan Louis R. , Schlaug Gottfried
Published: July 2002

Background and Purpose

—

Time of stroke onset is uncertain for patients who wake from sleep with stroke. Functional imaging techniques may allow estimation of benefit and risk of acute stroke therapy. We compared the clinical and multimodal MRI findings of patients with uncertain stroke onset with those with known onset time.

Methods

—

Patients imaged within 24 hours of ischemic stroke onset between January 1997 and June 2000 were identified from a prospective stroke registry. Clinical and imaging data from patients with known stroke onset (group I) were compared with those who woke with stroke (group II).

Results

—

A total of 364 patients were identified, of whom 100 (27%) woke from sleep with stroke. Group I and group II did not differ in age, gender, National Institutes of Health Stroke Scale, or TOAST (Trial of Org 10172 in Acute Stroke Treatment) diagnoses. Time from stroke onset was shorter in group I (mean 6.0 versus 13.3 hours,
P
<0.001); time from detection did not differ between groups (6.0 versus 5.9 hours). Within 3 hours, diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes were similar in both groups; DWI-PWI mismatch was present in 82% of group I and 73% of group II patients. Mean apparent diffusion coefficient of water (ADC) of group I patients was negatively associated with DWI volume (β=−0.324,
P
=0.004) and time from stroke onset (β=−0.238,
P
=0.031) in multivariate analysis. The mean ADC of group II patients was lower than that of group I patients within 3 hours of stroke detection (mean 556
versus
665 μm
2
/s,
P
<0.01), but individual group II patients had ADC values as high as 742 μm
2
/s, in addition to a DWI-PWI mismatch pattern.

Conclusions

—

Onset time is uncertain in over one quarter of acute ischemic stroke patients. Clinical features of these patients do not differ significantly from those with known onset time. Some patients who wake with stroke seem to have favorable imaging characteristics for acute stroke therapy. Further study is needed to determine whether criteria for therapy based on imaging parameters can safely be applied to these patients.
Acute Stroke Care in Illinois
Authors: Ruland Sean , Gorelick Philip B. , Schneck Michael , Kim Duk , Moore Charity G. , Leurgans Sue
Published: July 2002

Background and Purpose

—

To define areas for quality improvement in acute stroke care, a statewide assessment of preparedness for acute stroke diagnosis and treatment was carried out among 202 acute receiving hospitals in Illinois.

Methods

—

Medical directors or their designees completed a 1-page survey form that addressed availability of personnel, diagnostic technology, and organized programs for the treatment of acute stroke patients at their facility. In the analysis, acute care receiving hospitals in the Greater Chicago Metropolitan Area (GCMA) (Cook, Dupage, Lake, Will, and Kane counties) were compared with those in the remainder of the state.

Results

—

Of the acute care receiving hospitals, 91% responded to the survey. Overall, 99% had an emergency room receiving facility, 98.3% had a CT scanner, and slightly >70% had a recombinant tissue plasminogen activator (r-TPA) protocol. We found that 93.2% of residents in Illinois lived in a county with at least 1 acute care facility with an r-TPA treatment protocol. However, many of the non-GCMA receiving hospitals did not have a neurologist or a neurosurgeon available. Furthermore, specialized stroke diagnostic technology (eg, transcranial Doppler, diffusion-weighted MRI, MR angiography) was generally lacking in both the GCMA and non-GCMA, as were stroke community awareness programs and acute care stroke teams.

Conclusions

—

Stroke is a preventable and treatable disease. However, there are barriers to stroke care that are based on the availability of personnel, diagnostic technology, and programs. A systematic approach to the organization, implementation, and maintenance of services could improve outcome for stroke patients and reduce the public health burden of this deadly disease.
Efficacy and Safety of Memantine in Patients With Mild to Moderate Vascular Dementia
Authors: Orgogozo Jean-Marc , Rigaud Anne-Sophie , Stöffler Albrecht , Möbius Hans-Jorgen , Forette Françoise
Published: July 2002

Background and Purpose

—

Based on the hypothesis of glutamate-induced neurotoxicity (excitotoxicity) in cerebral ischemia, this study examined the efficacy and tolerability of memantine, an uncompetitive
N
-methyl-
d
-aspartate antagonist, in the treatment of mild to moderate vascular dementia.

Methods

—

In this multicenter, 28-week trial carried out in France, 321 patients received 10 mg/d memantine or placebo twice a day; 288 patients were valid for intent-to-treat analysis. Patients had to meet the criteria for probable vascular dementia and have a Mini-Mental State (MMSE) score between 12 and 20 at inclusion. The 2 primary end points were the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and the global Clinician’s Interview Based Impression of Change (CIBIC-plus).

Results

—

After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo. In the intention-to-treat population, the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score had declined by 1.6 points, ie, a difference of 2.0 points (95% confidence interval, 0.49 to 3.60). The response rate for CIBIC-plus, defined as improved or stable, was 60% with memantine compared with 52% with placebo (
P
=0.227, intention to treat). Among the secondary efficacy parameters, which were analyzed in the per-protocol subset, MMSE was significantly improved with memantine compared with deterioration with placebo (
P
=0.003). The Gottfries-Brane-Steen Scale intellectual function subscore and the Nurses’ Observation Scale for Geriatric Patients disturbing behavior dimension also showed differences in favor of memantine (
P
=0.04 and
P
=0.07, respectively). Memantine was well tolerated with a frequency of adverse events comparable to placebo.

Conclusions

—

In patients with mild to moderate vascular dementia, memantine 20 mg/d improved cognition consistently across different cognitive scales, with at least no deterioration in global functioning and behavior. It was devoid of concerning side effects.
Effect of Intravenous Gadolinium-DTPA on Diffusion-Weighted Images
Authors: Yamada Kei , Kubota Hiroshi , Kizu Osamu , Nakamura Hisao , Ito Hirotoshi , Yuen Sachiko , Tanaka Osamu , Kubota Takao , Makino Masahiro , Van Cauteren Marc , Nishimura Tsunehiko
Published: July 2002

Background and Purpose

—

Diffusion-weighted imaging (DWI) is usually done before administration of intravenous contrast agents. Repetition of DWI is occasionally necessary after administration, but the effects of contrast material on DWI and apparent diffusion coefficient (ADC) values have not yet been fully examined. The present study assesses whether administration of gadolinium-based contrast material significantly affects DWI and ADC values.

Methods

—

We examined DWI data from 39 patients (mean age, 67.9 years; range, 34 to 87 years) who were evaluated with a stroke protocol at our institute. All patients were scanned at the acute or subacute stages of infarct from 3 hours to 5 days after symptom onset. We obtained DWI images using single-shot echo-planar imaging with a
b
value of 1000 s/mm
2
. Patients were injected with 0.1 mmol gadopentetate dimeglumine per 1 kg body weight. We examined the signal-to-noise ratio of the normal brain and the infarct and evaluated the contrast-to-noise ratio of each lesion. In addition, we compared the ADC values calculated from the DWI images before and after administration of contrast. The statistical significance of differences between precontrast and postcontrast administration was determined by use of a paired
t
test.

Results

—

The signal-to-noise and contrast-to-noise ratios of the DW images were not significantly different before and after administration of contrast agent. The ADC values were slightly lower after administration of contrast agent for both normal brain (
P
=0.0011) and infarcts (
P
=0.038). The estimated differences in the ADC values were ≈1.3% and 3.5% for normal brain and infarcts, respectively.

Conclusions

—

The lack of a significant difference between the signal-to-noise and contrast-to-noise ratios of DW images before and after administration of contrast agent indicates the feasibility of postcontrast DWI.
Weather, Chinook, and Stroke Occurrence
Authors: Field Thalia S. , Hill Michael D.
Published: July 2002

Background

—

Changes in weather and season have been linked to stroke occurrence. However, the association has been inconsistent across stroke types. Calgary is a city in the Chinook belt and is subject to high variability in weather conditions.

Methods

—

We obtained hourly weather data over a 5-year period from 1996 to 2000; Chinook events were identified according to the accepted definition. We reviewed administrative data to determine stroke occurrence and defined stroke types to maximize specificity of diagnosis. To examine the hypothesis that weather affected the number of strokes occurring in a given day, we compared average daily stroke occurrence on Chinook days and non-Chinook days; we compared mean daily temperature, relative humidity, barometric pressure, and wind speed by the number of strokes occurring on any given day.

Results

—

Annual variation in stroke frequency was observed. No seasonal, monthly, or weekly variation in overall stroke occurrence or occurrence by type was evident. No relationship with changes in weather parameters was observed.

Conclusions

—

We found no association between weather changes and stroke occurrence. A cause-and-effect relationship between weather and stroke occurrence is dubious because of a lack of consistency across studies.
Long-Term Follow-Up of Individuals With the Electrocardiographic Pattern of Right Bundle-Branch Block and ST-Segment Elevation in Precordial Leads V
1
to V
3
Authors: Brugada Josep , Brugada Ramon , Antzelevitch Charles , Towbin Jeffrey , Nademanee Koonlawee , Brugada Pedro
Published: July 2002

Background
—

The electrocardiographic pattern of right bundle-branch block with ST-segment elevation in leads V
1
to V
3
is increasingly recognized among patients who have aborted sudden cardiac death, but also in asymptomatic individuals, raising questions about its prognostic significance.

Methods and Results
—

The clinical, electrophysiological, and follow-up data of 334 patients with the Brugada phenotype were analyzed. A total of 79 women and 255 men with a mean age at diagnosis of 42±16 years were studied. The abnormal ECG was recognized after a resuscitated cardiac arrest in 71 patients (group A), after a syncopal episode in 73 patients (group B), and in 190 asymptomatic individuals (group C). Sustained ventricular arrhythmias were inducible in 83%, 63%, and 33% of patients in group A, group B, and group C, respectively. During 54±54 and 26±36 months of follow-up, respectively, 62% of patients in group A and 19% of group B patients had a new arrhythmic event. Inducibility of ventricular arrhythmias was the only predictor of arrhythmia occurrence in both groups. During a mean follow-up of 27±29 months, 8% of group C individuals had a first arrhythmic event. In these individuals, inducibility of ventricular arrhythmias and a basal abnormal ECG were predictors of arrhythmia occurrence.

Conclusions
—

An ECG showing right bundle-branch block and ST-segment elevation in the right precordial leads is a marker of malignant ventricular arrhythmias and sudden death. Recurrence of malignant arrhythmias is high after the occurrence of symptoms. Among asymptomatic individuals, those with a spontaneously abnormal ECG and inducible to ventricular arrhythmias have the poorer prognosis.
Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress
Authors: Esposito Giovanni , Rapacciuolo Antonio , Naga Prasad Sathyamangla V. , Takaoka Hideyuki , Thomas Steven A. , Koch Walter J. , Rockman Howard A.
Published: July 2002

Background
—

A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortality, thus casting doubt on the validity of this hypothesis.

Methods and Results
—

To determine whether cardiac hypertrophy is necessary to preserve cardiac function, we used 2 genetically altered mouse models that have an attenuated hypertrophic response to 8 weeks of pressure overload. End-systolic wall stress (ς
es
) obtained by sonomicrometry after 1 week of pressure overload showed complete normalization of ς
es
in pressure-overloaded wild-type mice (287±39 versus sham, 254±34 g/cm
2
), whereas the blunted hypertrophic response in the transgenic mice was inadequate to normalize ς
es
(415±81 g/cm
2
,
P
<0.05). Remarkably, despite inadequate normalization of ς
es
, cardiac function as measured by serial echocardiography showed little deterioration in either of the pressure-overloaded genetic models with blunted hypertrophy. In contrast, wild-type mice with similar pressure overload showed a significant increase in chamber dimensions and progressive deterioration in cardiac function. Analysis of downstream signaling pathways in the late stages of pressure overload suggests that phosphoinositide 3-kinase may play a pivotal role in the transition from hypertrophy to heart failure.

Conclusions
—

These data suggest that under conditions of pressure overload, the development of cardiac hypertrophy and normalization of wall stress may not be necessary to preserve cardiac function, as previously hypothesized.
Antecedent Blood Pressure and Risk of Cardiovascular Disease
Authors: Vasan Ramachandran S. , Massaro Joseph M. , Wilson Peter W.F. , Seshadri Sudha , Wolf Philip A. , Levy Daniel , D’Agostino Ralph B.
Published: July 2002

Background
—

Casual blood pressure (BP) is a powerful predictor of risk of cardiovascular disease (CVD), but a single BP determination may not accurately reflect the residual impact of antecedent BP levels on vascular risk. It is unclear whether time-averaged past BP measures incrementally improve CVD risk assessment.

Methods and Results
—

We used sex- and age-specific multivariable Cox regression to evaluate the association of current BP (at baseline), recent antecedent BP (average of readings for all available examinations 1 to 10 years before baseline), and remote antecedent BP (average for all available examinations 11 to 20 years before baseline) with the 10-year risk of CVD in 2313 Framingham Study subjects (910 men, 1403 women) free of CVD at baseline. During follow-up, 899 incident initial CVD events were observed (479 in women). In multivariable models incorporating established CVD risk factors, recent and remote antecedent BP predicted CVD risk incrementally over current BP. This effect was consistent in multiple subgroups: men and women, older and younger age groups, and lower and higher BP groups. The relations of antecedent BP to CVD risk were consistent for systolic BP, diastolic BP, and pulse pressure.

Conclusions
—

Antecedent BP is an important determinant of future risk of CVD events above and beyond current BP. When available, use of long-term average BP may improve the prognostic utility of conventional CVD risk prediction that is based on current BP. Our findings suggest that effective prevention of CVD requires adequate control of BP throughout life.
Clinical and Echocardiographic Characteristics of Patients With Left Atrial Thrombus and Sinus Rhythm
Authors: Agmon Yoram , Khandheria Bijoy K. , Gentile Federico , Seward James B.
Published: July 2002

Background
—

Left atrial (LA) thrombus is infrequently detected in the presence of sinus rhythm (SR) and, in these cases, is usually associated with additional cardiac pathologies. We sought to determine the clinical and echocardiographic characteristics of patients with LA thrombus and SR to define a high-risk group of patients prone to this uncommon clinical presentation.

Methods and Results
—

The institution’s echocardiographic laboratory database was searched to identify patients with LA thrombus, diagnosed by transesophageal echocardiography (TEE), who were in SR during the TEE examination. Of 20 643 consecutive TEE examinations performed during an 11-year period, LA thrombus was detected in 314 patients in 380 TEE examinations. Of these, SR was present in 20 patients (age 69±13 years; 40% men) in 23 examinations (0.1% of all TEE examinations; 6.1% of TEE examinations with LA thrombus). High-risk structural heart disease (severe left ventricular dysfunction or significant left-sided valve disease [predominantly mitral valve disease]), previous documented episodes of atrial fibrillation, or both (structural heart disease and previous atrial fibrillation) were present in 10, 4, and 5 of the 20 patients, respectively. Only 1 patient with LA thrombus and SR did not have high-risk features.

Conclusions
—

LA thrombus is very infrequently detected in the presence of SR. Patients with LA thrombus and SR constitute a high-risk group characterized by specific structural cardiac abnormalities or previous atrial fibrillation, abnormalities that are potentially detectable before TEE.
Activated Monocytes Induce Smooth Muscle Cell Death
Authors: Seshiah Puvi N. , Kereiakes Dean J. , Vasudevan Sanjay S. , Lopes Neuza , Su Baogen Y. , Flavahan Nicholas A. , Goldschmidt-Clermont Pascal J.
Published: July 2002

Background
—

Plaque disruption is the inciting event for coronary thrombosis and acute coronary syndromes. Multiple factors influence plaque rupture, including the loss of vascular smooth muscle cells (VSMCs). We hypothesized that monocytes/macrophages (MMs) activated by macrophage colony-stimulating factor (M-CSF) are responsible for VSMC death.

Methods and Results
—

VSMC apoptosis was markedly increased in the presence of both M-CSF and MMs (58.8±3.3%) compared with VSMCs plus M-CSF without MMs (15.7±1.5%,
P
≤0.00005), VSMCs plus MMs without M-CSF (22.7±3.7%,
P
≤0.0001), or control VSMCs alone (13.2±2.1%,
P
≤0.0001). MM cell contact was required for M-CSF–stimulated killing of VSMCs, and MMs displayed an M-CSF concentration-dependent killing effect. Abciximab binds Mac-1 (CD11b/CD18) on MMs. When added to VSMCs exposed to MMs and M-CSF, abciximab (7 μg/mL) significantly reduced VSMC apoptosis (19.1±2.2%,
P
≤0.0003). Therapeutic doses of tirofiban (0.35 μg/mL) and eptifibatide (5 μg/mL), which inhibit platelet glycoprotein (GP) IIb/IIIa but not Mac-1, did not block activated MM-induced VSMC apoptosis (65.0±3.4% and 51.3±2.5%, respectively). A recombinant anti–CD-18 antibody had an effect similar to that of abciximab (16.5±0.4%).

Conclusions
—

These data suggest that monocytes and physiological concentrations of M-CSF trigger VSMC apoptosis. Abciximab and specific inhibitors of the Mac-1 receptor can antagonize this process.
Slow Breathing Increases Arterial Baroreflex Sensitivity in Patients With Chronic Heart Failure
Authors: Bernardi Luciano , Porta Cesare , Spicuzza Lucia , Bellwon Jerzy , Spadacini Giammario , Frey Axel W. , Yeung Leata Y.C. , Sanderson John E. , Pedretti Roberto , Tramarin Roberto
Published: July 2002

Background
—

It is well established that a depressed baroreflex sensitivity may adversely influence the prognosis in patients with chronic heart failure (CHF) and in those with previous myocardial infarction.

Methods and Results
—

We tested whether a slow breathing rate (6 breaths/min) could modify the baroreflex sensitivity in 81 patients with stable (2 weeks) CHF (age, 58±1 years; NYHA classes I [6 patients], II [33], III [27], and IV [15]) and in 21 controls. Slow breathing induced highly significant increases in baroreflex sensitivity, both in controls (from 9.4±0.7 to 13.8±1.0 ms/mm Hg,
P
<0.0025) and in CHF patients (from 5.0±0.3 to 6.1±0.5 ms/mm Hg,
P
<0.0025), which correlated with the value obtained during spontaneous breathing (
r
=+0.202,
P
=0.047). In addition, systolic and diastolic blood pressure decreased in CHF patients (systolic, from 117±3 to 110±4 mm Hg,
P
=0.009; diastolic, from 62±1 to 59±1 mm Hg,
P
=0.02).

Conclusions
—

These data suggest that in patients with CHF, slow breathing, in addition to improving oxygen saturation and exercise tolerance as has been previously shown, may be beneficial by increasing baroreflex sensitivity.
Detection of Vein Graft Disease Using High-Resolution Magnetic Resonance Angiography
Authors: Langerak Susan E. , Vliegen Hubert W. , de Roos Albert , Zwinderman Aeilko H. , Jukema J. Wouter , Kunz Patrik , Lamb Hildo J. , van der Wall Ernst E.
Published: July 2002

Background

—

The application of previous magnetic resonance (MR) angiography techniques has enabled noninvasive differentiation between patent and occluded coronary artery bypass grafts. However, the detection of graft stenosis remains difficult. The purpose of our study was to determine the accuracy of high-resolution navigator-gated 3-dimensional (3-D) MR angiography in detecting vein graft disease.

Methods and Results

—

MR angiography was performed in addition to coronary angiography with quantitative coronary analysis in 56 vein grafts from 38 patients (mean age 66.6±9.3 years), who presented with recurrent chest pain after bypass surgery. Eighteen grafts showed a luminal stenosis ≥50%, 11 grafts a stenosis ≥70%, and 6 grafts were occluded. All MR angiograms were evaluated independently by 2 blinded observers, who scored the presence of graft occlusion and graft stenosis ≥50% and ≥70% with a confidence level of 1 to 10. MR image quality was judged as insufficient in 6 grafts and these were excluded. Receiver-operator characteristic analysis revealed an area under the curve of 0.89 and 0.89 for identifying graft occlusion, 0.81 and 0.87 for stenosis ≥50%, and 0.82 and 0.79 for stenosis ≥70% for the 2 observers, respectively. Interobserver agreement in assessing graft occlusion and stenosis ≥50% and ≥70% was 94% (κ=0.74,
r
=0.81), 72% (κ=0.40,
r
=0.66), and 82% (κ=0.53,
r
=0.72), respectively.

Conclusions

—

High-resolution navigator-gated 3-D MR angiography allows not only good differentiation between patent and occluded vein grafts but also the assessment of vein graft disease with a fair diagnostic accuracy. This approach offers perspective as a noninvasive diagnostic tool for patients who present with recurrent chest pain after vein graft surgery.
Neutral Endopeptidase Is Activated in Cardiomyocytes in Human Aortic Valve Stenosis and Heart Failure
Authors: Fielitz Jens , Dendorfer Andreas , Pregla Reinhard , Ehler Elisabeth , Zurbrügg Heinz R. , Bartunek Jozef , Hetzer Roland , Regitz-Zagrosek Vera
Published: July 2002

Background

—

The regulation of the cardiac neutral endopeptidase (EC 24.10, NEP) that degrades bradykinin and natriuretic peptides has been investigated in human cardiac hypertrophy and heart failure.

Methods and Results

—

NEP mRNA was quantitated by real-time polymerase chain reaction (PCR) in left ventricular biopsies from patients with aortic valve stenosis (AS, n=19) and heart failure due to dilated cardiomyopathy (DCM, n=14), and control subjects with normal systolic function (CON, n=14). Left ventricular NEP mRNA content was increased 3-fold in AS (
P
<0.005) and 4.1-fold in DCM (
P
<0.002). The increase in NEP mRNA was related to the increase in end diastolic pressure in AS and DCM. In a second series, myocardial NEP enzymatic activity was determined. It increased 3.6-fold in AS (
P
<0.02) and 4-fold in DCM (
P
<0.002). NEP was localized in the myocardium by immunofluorescence microscopy and in situ PCR to myocytes and nonmyocyte areas and cells.

Conclusions

—

Elevated cardiac NEP activity in pressure loaded and failing human hearts may increase the local degradation of bradykinin and natriuretic peptides.
Na,K-ATPase Overexpression Improves Alveolar Fluid Clearance in a Rat Model of Elevated Left Atrial Pressure
Authors: Azzam Zaher S. , Dumasius Vidas , Saldias Fernando J. , Adir Yochai , Sznajder Jacob I. , Factor Phillip
Published: July 2002

Background
—

Acute elevation of left atrial pressure (LAP) increases extravascular water and impairs active Na
+
transport in rat lungs. We have reported that overexpression of Na,K-ATPase subunit genes in the alveolar epithelium increases alveolar fluid clearance (AFC) in normal and injured rat lungs with normal LAP. We reasoned that adenovirus-mediated transfer of an Na,K-ATPase β-subunit gene to the alveolar epithelium could improve AFC in rat lungs in the presence of acutely elevated LAP.

Methods and Results
—

Normal rats were infected with 4×10
9
plaque-forming units of E1a
−
/E3
−
recombinant adenoviruses that contained a cytomegalovirus promoter coupled to a rat Na,K-ATPase β
1
-subunit cDNA (adβ
1
) or no cDNA (adNull) 7 days before study. Na,K-ATPase α
1
- and β
1
-subunit abundance in basolateral cell membranes isolated from the peripheral lung was significantly increased in adβ
1
-infected lungs compared with sham and adNull-infected controls. In all groups, elevation of LAP reduced membrane-bound Na,K-ATPase abundance; however, abundance in adβ
1
-infected lungs remained greater than in controls. AFC, measured with a fluid-filled isolated lung preparation in the presence of elevated LAP (15 cmH
2
O), in Na,K-ATPase β
1
-subunit-overexpressing lungs was up to 100% greater than in controls and was not different from rats studied at normal LAP (0 cmH
2
O).

Conclusions
—

These data suggest that alveolar overexpression of an Na,K-ATPase β
1
-subunit can counteract downregulation of membrane-bound solute transporters owing to elevated pulmonary vascular pressures and can restore active Na
+
transport and AFC in this rat model of acute hydrostatic pulmonary edema.
Mechanisms of Coronary Microcirculatory Dysfunction in Patients With Aortic Stenosis and Angiographically Normal Coronary Arteries
Authors: Rajappan Kim , Rimoldi Ornella E. , Dutka David P. , Ariff Ben , Pennell Dudley J. , Sheridan Desmond J. , Camici Paolo G.
Published: July 2002

Background
—

Development of left ventricular hypertrophy in aortic stenosis (AS) is accompanied by coronary microcirculatory dysfunction, demonstrated by an impaired coronary vasodilator reserve (CVR). However, evidence for regional abnormalities in myocardial blood flow (MBF) and the potential mechanisms is limited. The aims of this study were to quantitatively demonstrate differences in subendocardial and subepicardial microcirculation and to investigate the relative contribution of myocyte hypertrophy, hemodynamic load, severity of AS, and coronary perfusion to impairment in microcirculatory function.

Methods and Results
—

Twenty patients with isolated moderate to severe AS were studied using echocardiography to assess severity of AS, cardiovascular magnetic resonance to measure left ventricular mass (LVM), and PET to quantify resting and hyperemic (dipyridamole 0.56 mg/kg) MBF and CVR in both the subendocardium and subepicardium. In the patients with most severe AS (n=15), the subendocardial to subepicardial MBF ratio decreased from 1.14±0.17 at rest to 0.92±0.17 during hyperemia (
P
<0.005), and subendocardial CVR (1.43±0.33) was lower than subepicardial CVR (1.78±0.35;
P
=0.01). Resting total LV blood flow was linearly related to LVM, whereas CVR was not. Increase of total LV blood flow during hyperemia (mean value, 89.6±59.6%; range, 17% to 233%) was linearly related to aortic valve area. The decrease in CVR was related to severity of AS, increase in hemodynamic load, and reduction in diastolic perfusion time, particularly in the subendocardium.

Conclusions
—

CVR was more severely impaired in the subendocardium in patients with LVH attributable to severe AS. Severity of impairment was related to aortic valve area, hemodynamic load imposed, and diastolic perfusion rather than to LVM.