bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients With Glanzmann Thrombasthenia Lacking Platelet Glycoprotein α
IIb
β
3
(GPIIb/IIIa) and α
v
β
3
Receptors Are Not Protected From Atherosclerosis
Authors: Shpilberg O. , Rabi I. , Schiller K. , Walden R. , Harats D. , Tyrrell K.S. , Coller B. , Seligsohn U.
Published: July 2002

Background
—

Platelets have been suggested to play a role in the early development of atherosclerosis. As one test of this hypothesis, we assessed whether patients with Glanzmann thrombasthenia who lack platelet glycoprotein α
IIb
β
3
(GPIIb/IIIa) complexes or both α
IIb
β
3
and the more ubiquitous α
v
β
3
cell membrane complexes are protected from development of atherosclerosis.

Methods and Results
—

Seven patients with Glanzmann thrombasthenia, 45 to 66 years of age, underwent bilateral carotid artery ultrasonography and screening for risk factors of atherosclerosis. Findings consistent with early atherosclerosis evaluated by measurement of intima-media thickness and presence of atherosclerotic plaques were observed in 6 of the 7 patients. Intima-media thickness values higher than the 75th and 90th percentiles of age- and sex-matched white control subjects of the Atherosclerosis Risk in Communities (ARIC) study were observed in 30 and 8 of 56 carotid artery measurements, respectively. Five of the 6 patients with signs consistent with early atherosclerosis lacked both α
IIb
β
3
and α
v
β
3
complexes and 1 only lacked α
IIb
β
3
.

Conclusions
—

Glanzmann thrombasthenia does not protect affected individuals from development of atherosclerosis.
Increased Prevalence of Carotid Atherosclerosis in Hepatitis B Virus Carriers
Authors: Ishizaka Nobukazu , Ishizaka Yuko , Takahashi Eiko , Toda Ei-ichi , Hashimoto Hideki , Ohno Minoru , Nagai Ryozo , Yamakado Minoru
Published: July 2002

Background
—

Recent experimental and epidemiological findings suggest that some infectious agents play a role in the development and promotion of atherosclerosis. We have investigated the possible association between hepatitis B virus surface antigen (HBsAg) positivity and carotid arteriosclerosis.

Methods and Results
—

In this cross-sectional cohort study, we analyzed data from subjects undergoing general health-screening tests, including both high-resolution B-mode carotid ultrasound and assessment of HBsAg status, between 1994 and 2001 at our institute. Of the 4686 study subjects (3137 men and 1549 women; age 22 to 88 years), 1294 (28%) had carotid artery plaque and 40 (0.9%) were positive for HBsAg, indicating they were hepatitis B virus carriers. No HBsAg-positive subjects were positive either for antibodies against the hepatitis C virus (HCV) or for HCV core proteins. Univariate analysis revealed HBsAg positivity was associated with carotid plaque with an odds ratio of 1.58 (95% CI, 1.14 to 2.19,
P
<0.05). When other confounding risk factors for atherosclerosis were included as covariates in the statistical analysis, HBsAg positivity was still positively associated with carotid plaque with an odds ratio of 1.57 (95% CI, 1.10 to 2.24,
P
<0.05).

Conclusions
—

These findings suggest a possible role of chronic hepatitis B infection in the pathogenesis of carotid arteriosclerosis.
Administration of a Decoy Against the Activator Protein-1 Binding Site Suppresses Neointimal Thickening in Rabbit Balloon-Injured Arteries
Authors: Kume Masazumi , Komori Kimihiro , Matsumoto Takuya , Onohara Toshihiro , Takeuchi Kensuke , Yonemitsu Yoshikazu , Sugimachi Keizo
Published: July 2002

Background

—

Transcription factor activator protein-1 (AP-1) is activated and upregulated in injured arterial smooth muscle cells in vivo, yet the exact role of the AP-1–related pathway in vascular disease in vivo has remained unclear. We examined the role of the transfer of synthetic double-stranded
cis
-element decoy oligodeoxynucleotides (ODNs) in balloon-injured rabbit carotid arteries and the effects of these ODNs on neointimal thickening.

Methods and Results

—

Transfection of fluorescein isothiocyanate–labeled ODNs using the hemagglutinating virus of Japan liposome method resulted in widespread distribution of fluorescent nuclear signals over the entire medial layer in injured arteries. Gel mobility shift assay revealed that AP-1 DNA binding was activated and that the AP-1 decoy reduced AP-1 DNA binding activity as a result of specific binding affinity to AP-1 in vivo. In morphometric analyses, AP-1 decoy led to a significant reduction in the neointimal area and a significant reduction in cell number and transforming growth factor-β
1
production of human aortic smooth muscle cells under conditions of platelet-derived growth factor stimulation.

Conclusions

—

Because AP-1 decoy transfection in vivo dramatically prevented neointimal thickening in balloon-injured arteries, AP-1 may be a useful molecular target for gene therapy to reduce restenosis.
Tumor Necrosis Factor-α Regulates Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 Expression in Vascular Smooth Muscle
Authors: Anwar A. , Zahid A.A. , Scheidegger K.J. , Brink M. , Delafontaine P.
Published: July 2002

Background

—

Inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, and interferon γ (IFN-γ) may change coronary plaque integrity by altering vascular smooth muscle cell (VSMC) survival and modifying the extracellular matrix. Insulin-like growth factor-1 (IGF-1) prevents apoptosis, promotes matrix formation, and can decrease TNF-α or IL-1β–induced proteoglycan degradation.

Methods and Results

—

To determine the effects of cytokines on the IGF-1 system, rat aortic VSMCs were exposed to TNF-α (10 to 500 ng/mL), IL-1β (20 pg to 10 ng/mL), IL-6 (100 pg to 15 ng/mL), or IFN-γ (10 to 600 U/mL). IL-1β, IL-6, and IFN-γ did not regulate IGF-1, IGF-1 receptor (R), or IGF binding proteins (IGFBPs). However, TNF-α markedly decreased IGF-1 mRNA (85% reduction at 24 hours) and increased IGFBP-3 mRNA and protein (300% increase at 24 hours). These changes were blocked by actinomycin D, consistent with a transcriptional mechanism. Experiments using TNF binding protein-1 indicated that these effects were not attributable to secretion of an autocrine factor. Anti–IGFBP-3 antibodies increased VSMC DNA synthesis 3-fold. In addition, apoptosis induced by TNF-α, IFN-γ, and Fas ligand was markedly reduced by desamino-(1-3)-IGF-1.

Conclusions

—

TNF-α, a cytokine that is upregulated in atherosclerotic plaques, reduces IGF-1 and increases IGFBP-3 in VSMCs, likely leading to a reduction in bioactive IGF-1. Because IGF-1 is important for growth and survival of VSMCs, its downregulation by TNF-α possibly plays a crucial role in acute and chronic coronary syndromes by decreasing VSMC viability and promoting plaque instability.
Plasma Norepinephrine Predicts Survival and Incident Cardiovascular Events in Patients With End-Stage Renal Disease
Authors: Zoccali Carmine , Mallamaci Francesca , Parlongo Saverio , Cutrupi Sebastiano , Benedetto Francesco Antonio , Tripepi Giovanni , Bonanno Graziella , Rapisarda Francesco , Fatuzzo Pasquale , Seminara Giuseppe , Cataliotti Alessandro , Stancanelli Benedetta , Malatino Lorenzo Salvatore
Published: July 2002

Background

—

Sympathetic tone is consistently raised in patients with end-stage renal disease (ESRD). We therefore tested the hypothesis that sympathetic activation is associated with mortality and cardiovascular events in a cohort of 228 patients undergoing chronic hemodialysis who did not have congestive heart failure at baseline and who had left ventricular ejection fraction >35%.

Methods and Results

—

The plasma concentration of norepinephrine (NE) was used as a measure of sympathetic activity. Plasma NE exceeded the upper limit of the normal range (cutoff 3.54 nmol/L) in 102 dialysis patients (45%). In a multivariate Cox regression model that included all univariate predictors of death as well as the use of sympathicoplegic agents and β-blockers, plasma NE proved to be an independent predictor of this outcome (hazard ratio [1-nmol/L increase in plasma NE]: 1.07, 95% CI 1.01 to 1.14,
P
=0.03). Similarly, plasma NE emerged as an independent predictor of fatal and nonfatal cardiovascular events (hazard ratio [1-nmol/L increase in plasma NE] 1.08, 95% CI 1.02 to 1.15,
P
=0.01) in a model that included previous cardiovascular events, pulse pressure, age, diabetes, smoking, and use of sympathicoplegic agents and β-blockers. The adjusted relative risk for cardiovascular complications in patients with plasma NE >75th percentile was 1.92 (95% CI 1.20 to 3.07) times higher than in those below this threshold (
P
=0.006).

Conclusions

—

Sympathetic nerve overactivity is associated with mortality and cardiovascular outcomes in ESRD. Controlled trials with antiadrenergic drugs are needed to determine whether interference with the sympathetic system could reduce the high cardiovascular morbidity and mortality in dialysis patients.
BG9719 (CVT-124), an A
1
Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function Observed With Diuretic Therapy
Authors: Gottlieb Stephen S. , Brater D. Craig , Thomas Ignatius , Havranek Edward , Bourge Robert , Goldman Steven , Dyer Farere , Gomez Miguel , Bennett Donald , Ticho Barry , Beckman Evan , Abraham William T.
Published: July 2002

Background

—

Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerular feedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown.

Methods and Results

—

This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses of BG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day and the same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion were assessed. BG9719 alone caused an increase in urine output and sodium excretion (
P
<0.05). Although administration of furosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significant at the 0.75-μg/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses. Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearance remained at baseline at the 2 lower doses.

Conclusions

—

In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increased both urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR. When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deterioration in GFR. A
1
adenosine antagonism might preserve renal function while simultaneously promoting natriuresis during treatment for heart failure.
The Brain Renin-Angiotensin System in Transgenic Mice Carrying a Highly Regulated Human Renin Transgene
Authors: Morimoto Satoshi , Cassell Martin D. , Sigmund Curt D.
Published: July 2002

We previously reported the generation of 2 novel transgenic mouse models containing the human renin (hREN) gene encoded on P1 artificial chromosomes (PAC) containing large amounts of 5′-flanking DNA. These mice exhibit a very narrow tissue-specific expression profile and exhibit tightly regulated expression in kidney in response to physiological cues. In brain, transcription of hREN occurs from an alternative upstream promoter, causing translation to initiate within exon-II and potentially generating an intracellular form of active renin. Double transgenic mice containing a PAC transgene and the human angiotensinogen (hAGT) gene (P+/A+) are moderately hypertensive. We tested whether increased RAS activity in the brain contributes to the mechanism of hypertension in P+/A+ double transgenic mice. Expression of hREN mRNA in brain was confirmed in 4 independent PAC transgenic lines and utilization of the alternative transcription start site in brain was confirmed in each line. Human REN immunostaining was observed in the dorsal cochlear nucleus, hypothalamus, and cortex. P+/A+ mice exhibited a greater fall in mean arterial pressure after intracerebroventricular injection of losartan than controls. P+/A+ mice exhibited a greater drop in arterial pressure after intravenous injection of a vasopressin V
1
receptor antagonist, and an equivalent drop in arterial pressure after intravenous injection of a ganglion blocker compared with controls. These results support the hypothesis that renin is endogenously expressed in the brain and suggest that increased brain RAS activity may contribute to the maintenance of moderate hypertension in P+/A+ transgenic mice at least in part by a vasopressin-dependent mechanism.
Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide
Authors: Ignarro Louis J. , Napoli Claudio , Loscalzo Joseph
Published: July 2002

Nitric oxide (NO) mediates multiple physiological and pathophysiological processes in the cardiovascular system. Pharmacological compounds that release NO have been useful tools for evaluating the pivotal role of NO in cardiovascular physiology and therapeutics. These agents constitute two broad classes of compounds, those that release NO or one of its redox congeners spontaneously and those that require enzymatic metabolism to generate NO. In addition, several commonly used cardiovascular drugs exert their beneficial action, in part, by modulating the NO pathway. Here, we review these classes of agents, summarizing their fundamental chemistry and pharmacology, and provide an overview of their cardiovascular mechanisms of action.
Modulation of Ca
2+
Release in Cardiac Myocytes by Changes in Repolarization Rate
Authors: Sah Rajan , Ramirez Rafael J. , Backx Peter H.
Published: July 2002

The early rate of action potential (AP) repolarization varies in the mammalian heart regionally, during development, and in disease. We used confocal microscopy to assess the effects of changes in repolarization rate on spatially resolved sarcoplasmic reticulum (SR) Ca
2+
release. The kinetics and peak amplitude of Ca
2+
transients were reduced, and the amplitude, frequency, and temporal synchronization of Ca
2+
spikes decreased as the rate of repolarization was slowed. The first latencies and temporal dispersion of Ca
2+
spikes tracked closely with the time to peak and the width of the L-type Ca
2+
current (
I
Ca,L
), suggesting that the effects of repolarization on excitation-contraction coupling occur primarily via changes in
I
Ca,L
. Next, we examined the effect of changes in the rapid early repolarization rate (phase 1) of a model human AP on SR Ca
2+
release by varying the amount of transient outward K
+
current. Slowing of phase-1 repolarization also caused a loss of temporal synchrony and recruitment of Ca
2+
-release events, associated with a reduced amplitude and lengthened time to peak of
I
Ca,L
. Isoproterenol application enhanced and largely resynchronized SR Ca
2+
release, while it increased the magnitude and shortened the time to peak of
I
Ca,L
. Our data demonstrate that membrane repolarization modulates the recruitment and synchronization of SR Ca
2+
release via
I
Ca,L
and illustrate a physiological role for the phase-1 notch of the AP in optimizing temporal summation and recruitment of Ca
2+
-release events. The effects of slowing phase-1 repolarization can be overcome by β-adrenergic stimulation.
Localization of Cardiac Sodium Channels in Caveolin-Rich Membrane Domains
Authors: Yarbrough Tracy L. , Lu Tong , Lee Hon-Chi , Shibata Erwin F.
Published: July 2002

This study demonstrates that caveolae, omega-shaped membrane invaginations, are involved in cardiac sodium channel regulation by a mechanism involving the α subunit of the stimulatory heterotrimeric G-protein, Gα
s
, via stimulation of the cell surface β-adrenergic receptor. Stimulation of β-adrenergic receptors with 10 μmol/L isoproterenol in the presence of a protein kinase A inhibitor increased the whole-cell sodium current by a “direct” cAMP-independent G-protein mechanism. The addition of antibodies against caveolin-3 to the cell’s cytoplasm via the pipette solution abrogated this direct G protein-induced increase in sodium current, whereas antibodies to caveolin-1 or caveolin-2 did not. Voltage-gated sodium channel proteins were found to associate with caveolin-rich membranes obtained by detergent-free buoyant density separation. The purity of the caveolar membrane fraction was verified by Western blot analyses, which indicated that endoplasmic/sarcoplasmic reticulum, endosomal compartments, Golgi apparatus, clathrin-coated vesicles, and sarcolemmal membranes were excluded from the caveolin-rich membrane fraction. Additionally, the sodium channel was found to colocalize with caveolar membranes by immunoprecipitation, indirect immunofluorescence, and immunogold transmission electron microscopy. These results suggest that stimulation of β-adrenergic receptors, and thereby Gα
s
, promotes the presentation of cardiac sodium channels associated with caveolar membranes to the sarcolemma.
Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53
Authors: Scott Stephen , O’Sullivan Michael , Hafizi Sassan , Shapiro Leonard M. , Bennett Martin R.
Published: July 2002

The p53 tumor suppressor gene regulates growth arrest and apoptosis after DNA damage. Recent studies suggest that p53 is inactive in vascular smooth muscle cells (VSMCs) in human angioplasty restenosis, promoting VSMC accumulation and vessel stenosis. In contrast, the success of irradiation (brachytherapy) for in-stent restenosis argues that DNA-damage p53 responses are intact. We examined p53 expression and function in human VSMCs from normal vessels (n-VSMCs) and angioplasty/in-stent restenosis sites (r-VSMCs). p53 expression was uniformly low in all VSMCs and was induced by DNA damage. However, p53 induced profoundly different biological effects in r-VSMCs versus n-VSMCs, causing growth arrest and apoptosis in r-VSMCs only. In addition, dominant-negative p53 promoted cell proliferation and apoptosis in r-VSMCs but not n-VSMCs. Cytotoxic drug– or irradiation-induced growth arrest and apoptosis in both cell types was mediated only partly by p53. In contrast, cyclin D degradation in response to DNA damage, a critical early mediator of growth arrest, was impaired in r-VSMCs, an effect that required p53. We conclude that p53 expression and function are normal or increased in r-VSMCs and may underlie the success of brachytherapy. We also identify a restenosis VSMC-specific defect in cyclin D degradation induced by DNA damage.
Proteoglycans Synthesized by Arterial Smooth Muscle Cells in the Presence of Transforming Growth Factor-β1 Exhibit Increased Binding to LDLs
Authors: Little Peter J. , Tannock Lisa , Olin Katherine L. , Chait Alan , Wight Thomas N.
Published: July 2002

The “response-to-retention” hypothesis of atherogenesis states that atherogenic lipoproteins, such as low density lipoprotein (LDL), are retained in vessels by proteoglycans and undergo proatherosclerotic modifications. Transforming growth factor (TGF)-β1 has been identified in atherosclerotic vessels and has been shown to stimulate the synthesis of chondroitin sulfate– and dermatan sulfate–containing proteoglycans by arterial smooth muscle cells (ASMCs), but whether it promotes lipid retention has not been addressed. We investigated whether TGF-β1 modulates the biosynthesis of proteoglycans by ASMCs in a manner that promotes binding to LDL. Proteoglycans isolated from TGF-β1–treated ASMCs exhibited enhanced binding to native LDL compared with the binding of proteoglycans isolated from control cultures (
K
d
18 μg/mL LDL versus 81 μg/mL LDL, respectively). The increase in proteoglycan-LDL binding caused by TGF-β1 could be attributed primarily to the glycosaminoglycan portion of the proteoglycans, since the glycosaminoglycan chains liberated from the core proteins of these proteoglycans synthesized in the presence of TGF-β1 exhibited increased LDL binding as well. Furthermore, glycosaminoglycan chains initiated on xyloside (an initiator of glycosaminoglycan synthesis) in the presence of TGF-β1 were longer and displayed enhanced binding to LDL compared with the LDL binding of xyloside-initiated glycosaminoglycan chains from control cultures. These results indicate that TGF-β1 promotes LDL-proteoglycan interaction primarily by its effects on the glycosaminoglycan synthetic machinery of the ASMCs. Therefore, this study supports a proatherogenic role for TGF-β1.
Shear Stress Activation of SREBP1 in Endothelial Cells Is Mediated by Integrins
Authors: Liu Yi , Chen Benjamin P.-C. , Lu Min , Zhu Yi , Stemerman Michael B. , Chien Shu , Shyy John Y.-J.
Published: July 2002

We investigated the effect of shear stress on the sterol regulatory element–binding protein 1 (SREBP1) in vascular endothelial cells (ECs) and the mechanotransduction mechanism involved. Application of a shear stress (12 dyn/cm
2
) caused the proteolytic cleavage of SREBP1 and the ensuing translocation of its transcription factor domain into the nucleus. As a result, shear stress increased the mRNAs encoding the low density lipoprotein receptor (LDLR), as well as the binding of
125
I-LDL. Using a step flow channel, we showed that SREBP1 activation in ECs under laminar flow is transient, but disturbed flow causes sustained activation. In studying the shear stress–elicited molecular signaling that activates SREBP1, we found that blocking the β
1
-integrin with the AIIB2 blocking-type monoclonal antibody inhibited SREBP1 activation induced by shear stress. EC attachment to fibronectin or the activation of β
1
-integrin in the suspended ECs by the TS2/16 monoclonal antibody was sufficient for SREBP1 activation. Furthermore, transient transfection assays showed that dominant-negative mutants of focal adhesion kinase and c-Src attenuated the shear stress–increased LDLR promoter activity. These results demonstrate that integrin signaling plays a critical role in the modulation of SREBP in ECs in response to shear stress.
Inhibition of Platelet Glycoprotein Ib, Glycoprotein IIb/IIIa, or Both by Monoclonal Antibodies Prevents Arterial Thrombosis in Baboons
Authors: Wu Dongmei , Meiring Muriel , Kotze Harry F. , Deckmyn Hans , Cauwenberghs Nancy
Published: July 2002

The antithrombotic efficacy of the monoclonal antibodies 6B4-Fab and MA-16N7C2 against platelet glycoprotein (GP) Ib and GP IIb/IIIa, respectively, on acute platelet-mediated thrombosis was evaluated in a baboon model of femoral artery stenosis, which is a modification of the original Folts model: platelet thrombi form on the injured stenosed artery, producing cyclic flow reductions (CFRs). A dose of 0.6 mg/kg 6B4-Fab significantly reduced the CFRs by 59±15%, whereas 2 mg/kg 6B4-Fab completely abolished the CFRs without prolongation of the bleeding time. MA-16N7C2 inhibited CFRs by 43±8% at a dose of 0.1 mg/kg and abolished the CFRs at a dose of 0.3 mg/kg but with a significant prolongation of the bleeding time. Finally, the combination of 0.6 mg/kg 6B4-Fab and 0.1 mg/kg MA-16N7C2 fully prevented the CFRs without prolongation of the bleeding time. The present study demonstrates that the inhibition of platelet GP Ib function by 6B4-Fab is a powerful intervention to prevent platelet thrombus formation in injured arteries without prolongation of the bleeding time; the latter is in contrast to the result after the inhibition of GP IIb/IIIa. Moreover, we demonstrate that combining a GP Ib blocker with a GP IIb/IIIa blocker can achieve a strong antithrombotic effect without increasing the bleeding time. This provides new information that will be beneficial in designing clinical therapeutic approaches.
Tumor Necrosis Factor-α Inhibits Growth Factor–Mediated Cell Proliferation Through SHP-1 Activation in Endothelial Cells
Authors: Nakagami Hironori , Cui Tai-Xing , Iwai Masaru , Shiuchi Tetsuya , Takeda-Matsubara Yuko , Wu Lan , Horiuchi Masatsugu
Published: July 2002

Src homology 2–containing protein-tyrosine phosphatase 1 (SHP-1) is known to regulate signal transduction through the dephosphorylation of tyrosine kinases. In this study, we addressed the role of SHP-1 under tumor necrosis factor-α (TNF-α) stimulation in endothelial cells. The addition of recombinant vascular endothelial growth factor (50 ng/mL) or epidermal growth factor (50 ng/mL) significantly increased thymidine incorporation and c-
fos
promoter activity, whereas TNF-α (5 ng/mL) attenuated these effects in human or bovine aortic endothelial cells. In bovine aortic endothelial cells, we confirmed endogenous SHP-1 expression and that TNF-α activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF-α on thymidine incorporation and c-
fos
promoter activity. In addition, TNF-α attenuated vascular endothelial growth factor– and epidermal growth factor–induced extracellular signal–regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prevented this inhibitory effect of TNF-α. Taken together, our results suggested that TNF-α inhibited growth factor–mediated cell proliferation through SHP-1 activation.
Increased Intima-Media Thickness in Familial Combined Hyperlipidemia Associated With Apolipoprotein B
Authors: Keulen Eric T.P. , Kruijshoop Margriet , Schaper Nicolaas C. , Hoeks Arnold P.G. , de Bruin Tjerk W.A.
Published: July 2002

The aim of the present study was to quantify intima-media thickness (IMT) in familial combined hyperlipidemia (FCHL) and to evaluate the relationship of IMT in FCHL-affected subjects with lipids and apolipoproteins, blood pressure values, and surrogate markers of insulin resistance. IMT was measured by ultrasound at the left and right common carotid arteries in 46 FCHL-affected subjects who were free of clinical manifestations of atherosclerosis and in 55 age- and sex-matched healthy control subjects. FCHL-affected subjects had significantly increased IMT compared with healthy control subjects, with a difference of 57 μm (age- and sex-corrected P<0.01). In the FCHL group, significantly positive age- and sex-corrected univariate correlations were observed between IMT and total cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B. Multivariate regression analyses revealed that age, sex, and apolipoprotein B were significant and independent predictors of IMT, whereas body mass index was of borderline significance. Combined, these factors explained almost 50% of the observed IMT variation (
P
<0.001). The increased IMT observed in FCHL corresponds with ≈7 years of physiological IMT increase in excess of the average IMT in age- and sex-matched control subjects. These novel findings show the important relationship between lipoprotein particles, marked by increased apolipoprotein B concentrations, and an increased IMT in FCHL. The increased IMT in FCHL-affected subjects is in agreement with the known high risk of cardiovascular disease in FCHL.
Greater Oxidative Stress in Healthy Young Men Compared With Premenopausal Women
Authors: Ide Tomomi , Tsutsui Hiroyuki , Ohashi Noriko , Hayashidani Shunji , Suematsu Nobuhiro , Tsuchihashi Miyuki , Tamai Hiroshi , Takeshita Akira
Published: July 2002

Abstract—

Coronary risk factors, including age, hypertension, diabetes mellitus, hyperlipidemia, and smoking, are associated with enhanced oxidative stress, which is implicated as a potential mechanism for atherogenesis and atherosclerotic cardiovascular diseases. Male sex is one of the well-known cardiovascular risk factors. We tested the hypothesis that oxidative stress is greater in men than in women. Plasma thiobarbituric acid-reactive substances (TBARS) and urinary 8-isoprostaglandin F
2α
(8-iso-PGF2α) were measured in 52 young men and 51 age-matched women. The subjects were healthy, were not smokers, and were not taking any medications or vitamins. Age, blood pressure, plasma cholesterol, and glucose did not differ between the groups. Baseline TBARS (2.32±0.11 [men] versus 1.87±0.09 [women] nmol/mL,
P
<0.01) and 8-iso-PGF2α (292±56 [men] versus 164±25 [women] pg/mg creatinine,
P
<0.05) were higher in men than in women. Supplementation of antioxidant vitamins for 4 weeks in men produced a significant reduction in TBARS and 8-iso-PGF2α by 34% (
P
<0.01) and 48% (
P
<0.05), respectively. Plasma superoxide dismutase, catalase, and vitamin E levels were comparable between the groups. Enhanced oxidative stress in men may provide a biochemical link between male sex and atherosclerotic diseases related to oxidative stress.
Novel 5′ Exon of Scavenger Receptor CD36 Is Expressed in Cultured Human Vascular Smooth Muscle Cells and Atherosclerotic Plaques
Authors: Zingg Jean-Marc , Ricciarelli Roberta , Andorno Enzo , Azzi Angelo
Published: July 2002

CD36, a member of the scavenger receptor family, is centrally involved in the uptake of oxidized low density lipoproteins (oxLDLs) from the bloodstream. During the atherosclerotic process, the lipid cargo of oxLDL accumulates in macrophages and smooth muscle cells (SMCs), inducing their pathological conversion to foam cells. Increased expression of CD36 occurs in human atherosclerotic lesions, and CD36 knockout mice show reduced uptake of modified LDLs and reduced atherosclerosis. Here, we describe a novel exon 1b and extended CD36 promoter in human SMCs. Exon 1b is specifically transcribed in activated aortic SMCs and mainly expressed in atherosclerotic plaques. Thus, switching to exon 1b transcription may be an important step for the activation of SMCs and their conversion to foam cells. Using an antisense oligonucleotide to exon 1b, we inhibit CD36 translation and highly reduce oxLDL uptake. The antisense to exon 1b does not affect CD36 in cell lines not expressing the new exon. The possibility of a novel antiatherosclerotic therapy and the use of exon 1b as a marker of atherosclerosis are discussed.
Different Effects of High and Low Shear Stress on Platelet-Derived Growth Factor Isoform Release by Endothelial Cells
Authors: Palumbo Roberta , Gaetano Carlo , Antonini Annalisa , Pompilio Giulio , Bracco Enrico , Rönnstrand Lars , Heldin Carl-Henrik , Capogrossi Maurizio C.
Published: July 2002

In the present study, we analyzed the effect of conditioned media (CM) from bovine aortic endothelial cells exposed to laminar shear stress (SS) of 5 dyne/cm
2
(SS5) or 15 dyne/cm
2
(SS15) for 16 hours on smooth muscle cell (SMC) migration. In response to CM from bovine aortic endothelial cells exposed to SS5 (CMSS5) and SS15 (CMSS15), migration was 45±5.5 and 30±1.5 cells per field, respectively (
P
<0.05). Similar results were obtained with SS of 2 versus 20 dyne/cm
2
and also when SS of 5 and 15 dyne/cm
2
lasted 24 hours. Platelet-derived growth factor (PDGF)-AA levels in CMSS5 and CMSS15 were 9±7 and 18±5 ng/10
6
cells for 16 hours, respectively (
P
<0.05); PDGF-BB levels in CMSS5 and CMSS15 were 38±10 and 53±10 ng/10
6
cells for 16 hours, respectively (
P
<0.05). PDGF receptor α (PDGFRα) and PDGF receptor β (PDGFRβ) in SMCs were phosphorylated by CMSS15>CMSS5. In response to CMSS15, a neutralizing antibody against PDGF-AA enhanced SMC migration to a level comparable to that of CMSS5; in contrast, antibodies against PDGF-BB abolished SMC migration. Transfection of SMCs with a dominant-negative PDGFRα or PDGFRβ increased or inhibited, respectively, SMC migration in response to CMSS15. Overexpression of wild-type PDGFRα inhibited SMC migration in response to CMSS5, CMSS15, or recombinant PDGF-BB (
P
<0.001). These results suggest that the ability of high SS to inhibit arterial wall thickening in vivo may be related to enhanced activation of PDGFRα in SMCs by PDGF isoforms secreted by the endothelium.
Purinergic Signaling and Vascular Cell Proliferation and Death
Authors: Burnstock Geoffrey
Published: July 2002

Abstract—

Evidence for the role of purinergic signaling (via P1 and P2Y receptors) in the proliferation of vascular smooth muscle and endothelial cells is reviewed. The involvement of the mitogen-activated protein kinase second-messenger cascade in this action is clearly implicated, although details of the precise intracellular pathways involved still remain to be determined. Synergistic actions of purines and pyrimidines with growth factors occur in promoting cell proliferation. Interaction between purinergic signaling for vascular cell proliferation and cell death mediated by P2X
7
receptors is discussed. There is evidence of the release of ATP from endothelial cells, platelets, and sympathetic nerves as well as from damaged cells in atherosclerosis, hypertension, restenosis, and ischemia; furthermore, there is evidence that vascular smooth muscle and endothelial cells proliferate in these pathological conditions. Thus, the involvement of ATP and its breakdown product, adenosine, is implicated; it is hoped that with the development of selective P1 (A
2
) and P2Y receptor agonists and antagonists, new therapeutic strategies will be explored.
CCR2 Deficiency Decreases Intimal Hyperplasia After Arterial Injury
Authors: Roque Merce , Kim William J.H. , Gazdoin Michaela , Malik Alia , Reis Ernane D. , Fallon John T. , Badimon Juan J. , Charo Israel F. , Taubman Mark B.
Published: July 2002

Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks after injury, arteries from CCR2
−/−
mice showed a 61.4% reduction (
P
<0.01) in intimal area and a 62% reduction (
P
<0.05) in intima/media ratio when compared with CCR2
+/+
littermates. The response of CCR2
+/−
mice was not significantly different from that of CCR2
+/+
mice. Five days after injury, the medial proliferation index, determined by bromodeoxyuridine incorporation, was decreased by 59.8% in CCR2
−/−
mice when compared with CCR2
+/+
littermates (
P
<0.05). Although leukocytes rapidly adhered to the injured arterial surface, there was no significant macrophage infiltration in the arterial wall of either CCR2
−/−
or CCR2
+/+
mice 5 and 28 days after injury. These results demonstrate that CCR2 plays an important role in mediating smooth muscle cell proliferation and intimal hyperplasia in a non-hyperlipidemic model of acute arterial injury. CCR2 may thus be an important target for inhibiting the response to acute arterial injury.
Adherence to Postacute Rehabilitation Guidelines Is Associated With Functional Recovery in Stroke
Authors: Duncan Pamela W. , Horner Ronnie D. , Reker Dean M. , Samsa Gregory P. , Hoenig Helen , Hamilton Byron , LaClair Barbara J. , Dudley Tara K.
Published: July 2002

Background and Purpose

—

The purpose of this study was to determine if compliance with poststroke rehabilitation guidelines was associated with better functional outcomes.

Methods

—

An inception cohort of 288 stroke patients in 11 Department of Veteran Affairs Medical Centers hospitalized between January 1998 and March 1999 were followed prospectively for 6 months. Data were abstracted from medical records and telephone interviews. The primary study outcome was the Functional Independence Motor Score (FIM). Secondary outcomes included Instrumental Activities of Daily Living (IADL), SF-36 physical functioning, and the Stroke Impact Scale (SIS). Acute and postacute rehabilitation guideline compliance scores (range 0 to 100) were derived from an algorithm. All outcomes were adjusted for case-mix.

Results

—

Average compliance scores in acute and postacute care settings were 68.2% (SD 14) and 69.5% (SD 14.4), respectively. After case-mix adjustment, level of compliance with postacute rehabilitation guidelines was significantly associated with FIM motor, IADL, and the SIS physical domain scores. SF-36 physical function was not associated with guideline compliance. Level of compliance with rehabilitation guidelines in acute settings was unrelated to any of the outcome measures.

Conclusion

—

Greater levels of adherence to postacute stroke rehabilitation guidelines were associated with improved patient outcomes. Compliance with guidelines may be viewed as a quality-of-care indicator with which to evaluate new organizational and funding changes involving postacute stroke rehabilitation.
Cerebral Protection During Carotid Artery Stenting
Authors: Angelini Annalisa , Reimers Bernhard , Barbera Mila Della , Saccà Salvatore , Pasquetto Giampaolo , Cernetti Carlo , Valente Marialuisa , Pascotto Pietro , Thiene Gaetano
Published: July 2002

Background and Purpose

—

Histopathologic analysis was performed to better understand quantity, particle size, and composition of embolized debris collected in protection filters during carotid artery stent implantation.

Methods

—

Elective carotid stent implantation with the use of a distal filter protection was attempted in 38 consecutive lesions (36 patients) of the internal carotid artery presenting >70% diameter stenosis (mean, 82.1±11.1%). Mean age of the patients was 70.7±7.7 years; 75% were men, and 50% of patients had previous neurological symptoms.

Results

—

In 37 lesions (97.4%) it was possible to position the filter device, and in all lesions a stent was successfully implanted. The only complication occurring in the hospital and during the 30-day follow-up was 1 death due to acute myocardial infarction. Neurological sequelae did not occur. Histomorphometric analysis was performed on the filters. Presence of debris was detected in 83.7% of filters. The mean surface area of the polyurethane membrane filter covered with material was 53.2±19.8%. Particle size ranged from 1.08 to 5043.5 μm (mean, 289.5±512 μm) in the major axis and 0.7 to 1175.3 μm (mean, 119.7±186.7 μm) in the minor axis. Collected debris consisted predominantly of thrombotic material, foam cells, and cholesterol clefts.

Conclusions

—

By the use of distal protection filters during carotid artery stenting, it was possible to collect particulate debris potentially leading to distal vessel occlusion in a high percentage of cases. Qualitative analysis of embolized material showed debris dislocated during the percutaneous intervention from atheromatous plaques.
Speed-Dependent Treadmill Training in Ambulatory Hemiparetic Stroke Patients
Authors: Pohl Marcus , Mehrholz Jan , Ritschel Claudia , Rückriem Stefan
Published: July 2002

Background and Purpose—A new gait training strategy for patients with stroke seeks to increase walking speed through treadmill training. This study compares the effects of structured speed-dependent treadmill training (STT) (with the use of an interval paradigm to increase the treadmill speed stepwise according to principles of sport physiology) with limited progressive treadmill training (LTT) and conventional gait training (CGT) on clinical outcome measures for patients with hemiparesis.

Methods—Sixty ambulatory poststroke patients were each randomly selected to receive 1 of the 3 different gait therapies: 20 subjects were treated with STT, 20 subjects were trained to walk on a treadmill with a 20% increase of belt speed over the treatment period (LTT), and 20 subjects were treated with CGT. Treatment outcomes were assessed on the basis of overground walking speed, cadence, stride length, and Functional Ambulation Category scores.

Results—After a 4-week training period, the STT group scored significantly higher than the LTT and CGT groups for overground walking speed (STT versus LTT,P<0.001; STT versus CGT,P<0.001), cadence (STT versus LTT,P=0.007; STT versus CGT,P<0.001), stride length (STT versus LTT,P<0.001; STT versus CGT,P<0.001), and Functional Ambulation Category scores (STT versus LTT,P=0.007; STT versus CGT,P<0.001).

Conclusions—Structured STT in poststroke patients resulted in better walking abilities than LTT or CGT. This gait training strategy provides a dynamic and integrative approach for the treatment of gait dysfunction after stroke.
Stroke Is Associated With Coronary Calcification as Detected by Electron-Beam CT
Authors: Vliegenthart Rozemarijn , Hollander Monika , Breteler Monique M.B. , van der Kuip Deirdre A.M. , Hofman Albert , Oudkerk Matthijs , Witteman Jacqueline C.M.
Published: July 2002

Background and Purpose

—

Coronary calcification as detected by electron-beam CT measures the atherosclerotic plaque burden and has been reported to predict coronary events. Because atherosclerosis is a generalized process, coronary calcification may also be associated with manifest atherosclerotic disease at other sites of the vascular tree. We examined whether coronary calcification as detected by electron-beam CT is related to the presence of stroke.

Methods

—

From 1997 onward, subjects were invited to participate in the prospective Rotterdam Coronary Calcification Study and undergo electron-beam CT to detect coronary calcification. The study was embedded in the population-based Rotterdam Study. Calcifications were quantified in a calcium score according to Agatston’s method. Calcium scores were available for 2013 subjects (mean age [SD], 71 [5.7] years). Fifty subjects had experienced stroke before scanning.

Results

—

Subjects were 2 times more likely to have experienced stroke when their calcium score was between 101 and 500 (odds ratio [OR], 2.1; 95% CI, 0.9 to 4.7) and 3 times more likely when their calcium score was above 500 (OR, 3.3; 95% CI, 1.5 to 7.2), compared with subjects in the lowest calcium score category (0 to 100). Additional adjustment for cardiovascular risk factors did not materially alter the risk estimates.

Conclusions

—

In this population-based study, a markedly graded association was found between coronary calcification and stroke. The results suggest that coronary calcification as detected by electron-beam CT may be useful to identify subjects at high risk of stroke.
Abciximab Bolus Injection Does Not Reduce Cerebral Ischemic Complications of Elective Carotid Artery Stenting
Authors: Hofmann Robert , Kerschner Klaus , Steinwender Clemens , Kypta Alexander , Bibl Dietmar , Leisch Franz
Published: July 2002

Background and Purpose
—

Abciximab has been shown to significantly reduce thromboembolic complications of coronary artery stenting. A prospective, randomized study was performed to test whether abciximab has comparable beneficial effects in carotid artery stenting.

Methods
—

Seventy-four consecutive patients undergoing elective stenting of the carotid artery were included in the study. Standard antithrombotic medication consisted of aspirin, clopidogrel, and heparin. In addition, half of the patients received an abciximab bolus of 0.25 mg/kg body weight given prophylactically before the intervention.

Results
—

The procedure was successful in all but 1 patient. In patients receiving abciximab, ischemic complications consisted of 4 transient ischemic attacks, 1 minor stroke, 1 nonfatal major stroke, and 1 fatal stroke caused by cerebral hemorrhage. In the control group, 2 transient ischemic attacks and 1 major nonfatal stroke occurred. In summary, the total number of periprocedural ischemic events was 7 (19%) in the abciximab group and 3 (8%) in the control group. Nonischemic complications consisted of 1 inguinal hematoma requiring blood transfusions in each group.

Conclusions
—

Abciximab bolus given prophylactically before elective carotid artery stenting does not reduce ischemic complications.
N-Terminal Pro-Brain Natriuretic Peptide After Myocardial Infarction
Authors: Luchner Andreas , Hengstenberg Christian , Löwel Hannelore , Trawinski Jürgen , Baumann Matthias , Riegger Günter A.J. , Schunkert Heribert , Holmer Stephan
Published: July 2002

N-terminal pro-brain natriuretic peptide (NT-proBNP) is increased early after acute myocardial infarction. We assessed the relationship of NT-proBNP with left ventricular function and mass as well as with renal function, hemodynamic, and anthropometric variables in 625 outpatients in the chronic phase after myocardial infarction and 465 siblings without infarction (control). NT-proBNP was measured by nonextracted, enzyme-linked, sandwich immunoassay. NT-proBNP was correlated with left ventricular ejection fraction, mass index, and renal function, in addition to infarction history, gender, and age, in univariate and multivariate analysis (all
P
<0.01). Increases in NT-proBNP observed in subjects with infarction (96.6±13.7 versus 31.2±1.8 pmol/L in control subjects,
P
<0.001) were particularly pronounced in the presence of significant left ventricular dysfunction (182.8±41.9 pmol/L), left ventricular hypertrophy (214.5±61.7 pmol/L), and renal dysfunction (210.3±51.4 pmol/L, all
P
<0.01). Patients with an ejection fraction <35% were detected by NT-proBNP with a sensitivity, specificity, and negative predictive value of 75%, 62%, and 99%, respectively, at an optimal cutoff of 44 pmol/L. Patients with an ejection fraction <35% and concomitant left ventricular hypertrophy were detected with a sensitivity, specificity, and negative predictive value of 90%, 80%, and 99.9%, respectively, at a cutoff of 76 pmol/L. Similar results were obtained for patients with an ejection fraction <35% and concomitant renal dysfunction at a cutoff of 162 pmol/L. NT-proBNP is a biochemical marker of integrated cardio-renal function in the chronic phase after myocardial infarction and a potential diagnostic tool for the detection and exclusion of significant left ventricular dysfunction. Cutoff concentrations have to be chosen according to renal function to optimize the predictive value of NT-proBNP.
Integrins Play a Critical Role in Mechanical Stress–Induced p38 MAPK Activation
Authors: Aikawa Ryuichi , Nagai Toshio , Kudoh Sumiyo , Zou Yunzeng , Tanaka Mariko , Tamura Masahito , Akazawa Hiroshi , Takano Hiroyuki , Nagai Ryozo , Komuro Issei
Published: July 2002

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal–regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH
2
-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch–induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.