bluuebunny/crossref_metadata_2025 huggingface dataset:
A turnpike theorem for continuous‐time control systems when the optimal stationary point is not unique
Authors: Mamedov Musa A.
Published: June 2003

We study the turnpike property for the nonconvex optimal control
problems described by the differential inclusion . We study the infinite horizon problem of maximizing the functional as T grows to infinity. The turnpike theorem is proved for the case when a turnpike set consists of several optimal stationary points.
Asymptotic formulas and critical exponents for two‐parameter nonlinear eigenvalue problems
Authors: Shibata Tetsutaro
Published: June 2003

We study the nonlinear two‐parameter problem −u″(x) + λu(x) q = μu(x) p, u(x) > 0, x ∈ (0, 1), u(0) = u(1) = 0. Here, 1 < q < p are constants and λ, μ > 0 are parameters. We establish precise asymptotic formulas with exact second term for variational eigencurve μ(λ) as λ → ∞. We emphasize that the critical case concerning the decaying rate of the second term is p = (3q − 1)/2 and this kind of criticality is new for two‐parameter problems.
Angiotensinogen Gene Polymorphism, Plasma Angiotensinogen, and Risk of Hypertension and Ischemic Heart Disease
Authors: Sethi Amar Akhtar , Nordestgaard Børge Grønne , Tybjærg-Hansen Anne
Published: June 2003

Objective—

The aim of this study was to investigate whether the M235T polymorphism in the angiotensinogen gene was associated with angiotensinogen levels, systolic and diastolic blood pressure, hypertension, and risk of ischemic cardiovascular disease in different ethnic populations.

Methods and Results—

One hundred twenty-seven studies published between January 1992 and March 2002 examining the association of angiotensinogen gene polymorphisms with the above-mentioned end points were selected. Pooled effect sizes and Mantel-Haenszel odds ratios were calculated using Review Manager. In white subjects, genotype was associated with a stepwise increase in plasma angiotensinogen levels of 5% (95% CI, 2% to 8%;
P
=0.0004) in MT heterozygotes and 11% (7% to 15%;
P
<0.00001) in TT homozygotes compared with MM individuals. Correspondingly, genotype was associated with a stepwise increase in aggregated odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) in MT individuals and 1.19 (1.10 to 1.30) in TT individuals in white subjects and of 1.29 (95% CI, 0.96 to 1.74) and 1.60 (1.19 to 2.15) in Asian subjects. M235T genotype did not predict systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group.

Conclusions—

Angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects.
Intravascular Modalities for Detection of Vulnerable Plaque
Authors: MacNeill Briain D. , Lowe Harry C. , Takano Masamichi , Fuster Valentin , Jang Ik-Kyung
Published: June 2003

Progress in the diagnosis, treatment, and prevention of atherosclerotic coronary artery disease is dependent on a greater understanding of the mechanisms of coronary plaque progression. Autopsy studies have characterized a subgroup of high-risk, or vulnerable, plaques that result in acute coronary syndromes or sudden cardiac death. These angiographically modest plaques share certain pathologic characteristics: a thin, fibrous cap, lipid-rich core, and macrophage activity. Diagnostic techniques for vulnerable-plaque detection, including serologic markers and noninvasive and invasive techniques, are needed. Recent advances in intravascular imaging have significantly improved the ability to detect high-risk, or vulnerable, plaque in vivo by using various features of plaque vulnerability as methods of identification. The characteristic anatomy of a thin, fibrous cap overlying a lipid pool has promoted high-resolution imaging, such as intravascular ultrasound, optical coherence tomography, and intracoronary magnetic resonance. The lipid-rich core is identifiable by angioscopically detected color changes on the plaque surface or by its unique absorption of energy, or “Raman shift,” of its cholesterol core, driving coronary spectroscopy. Finally, temperature heterogeneity arising at foci of plaque inflammation has prompted the development of intracoronary thermography. In this review, we will discuss these techniques, their relative advantages and limitations, and their potential clinical application.
Oxidized Phospholipid-Induced Endothelial Cell/Monocyte Interaction Is Mediated by a cAMP-Dependent R-Ras/PI3-Kinase Pathway
Authors: Cole Amy L. , Subbanagounder Ganesamoorthy , Mukhopadhyay Srirupa , Berliner Judith A. , Vora Devendra K.
Published: June 2003

Objective—Previous studies have demonstrated the importance of endothelial apical expression of connecting segment-1 (CS-1) fibronectin in mediating the entry of monocytes into atherosclerotic lesions and other sites of chronic inflammation. We previously demonstrated that oxidized PAPC (OxPAPC) increases monocyte-specific binding to arterial endothelium by causing deposition of CS-1 fibronectin on apical α5β1integrin. The present studies identify important signal transduction components regulating this pathway.

Methods and Results—Using endothelial cells in culture, we demonstrate that activation of R-Ras is responsible for CS-1–mediated monocyte binding. Although few natural activators of R-Ras have been demonstrated, OxPAPC activated endothelial R-Ras by 2.5-fold but decreased levels of activated H-Ras. The importance of R-Ras/H-Ras balance in regulating monocyte binding was shown by overexpression studies. Constitutively active R-Ras enhanced monocyte adhesion, whereas coexpression with constitutively active H-Ras was inhibitory. Elevated cAMP, mediated by OxPAPC and specific components POVPC and PEIPC, was responsible for R-Ras activation, and dibutyryl cAMP and pertussis toxin were also effective activators of R-Ras. Using inhibitor and dominant-negative constructs, we demonstrated that phosphatidylinositol 3-kinase (PI3K) was a key downstream effector of R-Ras in this pathway.

Conclusions—OxPAPC, POVPC, and PEIPC induce a cAMP/R-Ras/PI3K signaling pathway that contributes to monocyte/endothelial cell adhesion and potentially atherosclerosis.
Constitutively Active Glycogen Synthase Kinase-3β Gene Transfer Sustains Apoptosis, Inhibits Proliferation of Vascular Smooth Muscle Cells, and Reduces Neointima Formation After Balloon Injury in Rats
Authors: Park Kyung-Woo , Yang Han-Mo , Youn Seock-Won , Yang Hyun-Ju , Chae In-Ho , Oh Byung-Hee , Lee Myoung-Mook , Park Young-Bae , Choi Yun-Shik , Kim Hyo-Soo , Walsh Kenneth
Published: June 2003

Objective—Glycogen synthase kinase (GSK)-3β is a crucial factor in many cellular signaling pathways and may play an important role in smooth muscle proliferation and apoptosis after angioplasty.

Methods and Results—To investigate the effect of GSK-3β modulation on neointima formation, smooth muscle proliferation, and apoptosis after balloon injury in vivo, we delivered adenoviral vectors expressing the constitutively active form of GSK-3β (GSK-S9A: 9th serine switched to alanine) or a control gene into rat carotid arterial segments after balloon injury with a 2F Fogarty catheter. Viral infusion mixtures (5×108pfu) were incubated in the arterial lumen for 20 minutes, and the effects of gene delivery were evaluated 3 days and 2 weeks after gene delivery with morphometry and immunohistochemical staining for proliferating and apoptotic cells. There were no significant differences in intimal, medial, and lumen areas at 3 days after the procedure. However, 2 weeks after gene delivery, the active GSK-3β gene transfer resulted in a significantly lower intima to media ratio (0.29±0.06 versus 0.86±0.09,P<0.01) and a greater lumen area (0.41±0.02 versus 0.31±0.01 mm2,P<0.01) compared with the control gene transfected group. This was attributable to a significant reduction in intimal area (0.05±0.01 versus 0.15±0.02 mm2,P<0.01), whereas the medial area was similar (0.17±0.01 versus 0.18±0.01 mm2,P=0.21). Proliferation index was significantly reduced both at 3 days and 2 weeks in the active GSK-3β gene transferred group (2.97±0.29% versus 5.71±0.50%,P<0.01). In addition, apoptotic index, which was not significantly different between the 2 groups at 3 days, was significantly higher in the active GSK-3β gene transferred group at 2 weeks (3.14±0.68% versus 22.7±1.63%, n=10,P<0.01, for control versus active GSK-3β gene transfer).

Conclusions—In vivo delivery of the active GSK-3β gene inhibits smooth muscle proliferation, sustains apoptosis, and reduces neointima formation after balloon injury in rats and may be a future therapeutic target to limit neointima hyperplasia after angioplasty.
Paraoxonase Activity, But Not Haplotype Utilizing the Linkage Disequilibrium Structure, Predicts Vascular Disease
Authors: Jarvik Gail P. , Hatsukami Thomas S. , Carlson Chris , Richter Rebecca J. , Jampsa Rachel , Brophy Victoria H. , Margolin Sadie , Rieder Mark , Nickerson Deborah , Schellenberg Gerard D. , Heagerty Patrick J. , Furlong Clement E.
Published: June 2003

Objective—

The effects of paraoxonase (PON1) activity and of genetic variation in the PON1 promoter and coding region on carotid artery disease (CAAD) were investigated.

Methods and Results—

We identified functional promoter polymorphisms and examined their effects in a cohort with and without CAAD. We used the full sequences in 23 white subjects to determine the linkage disequilibrium (LD) structure of the
PON1
region and to direct the grouping of haplotypes for disease association testing. There are several discrete regions of the
PON1
gene with strong local LD, but the useful levels of LD do not extend across the entire gene. Indeed,
PON1

−
162/
−
108/55/192

haplotype did not predict additional variation in PON1 activities compared with the 4 genotypes separately. PON1 hydrolysis activity predicted CAAD status, but this was not attributable to the promoter or coding region polymorphisms or haplotype or to the effects of smoking or statin use on PON1 activity.

Conclusions—

PON1 does not have LD across the gene, and use of haplotypes in association studies should consider the LD structure. PON1 activity predicts CAAD, yet 4 functional polymorphisms do not. Additional investigations of genetic and environmental factors that influence PON1 activity as a risk factor for vascular disease are warranted.
Novel Proangiogenic Effect of Factor XIII Associated With Suppression of Thrombospondin 1 Expression
Authors: Dardik Rima , Solomon Arieh , Loscalzo Joseph , Eskaraev Regina , Bialik Ann , Goldberg Iris , Schiby Ginette , Inbal Aida
Published: June 2003

Objective—Factor XIII (FXIII), a plasma transglutaminase that stabilizes fibrin clots at the final stages of blood coagulation by crosslinking fibrin monomers, is essential for embryo implantation and participates in tissue remodeling and wound healing, processes that involve angiogenesis. The aim of our study was to analyze the effect of FXIII on angiogenesis using in vitro and in vivo models and to examine the role of FXIII in the basic steps of angiogenesis, ie, migration, proliferation, and apoptosis/cell survival.

Methods and Results—In the Matrigel tube formation model, only FXIIIa caused a dose-dependent enhancement of array formation. This proangiogenic effect was not associated with alterations in vascular endothelial growth factor (VEGF) protein levels nor VEGF or VEGFR2 mRNA levels. FXIIIa, but not nonactivated or transglutaminase-inactivated FXIII, significantly enhanced endothelial cell migration and proliferation and inhibited apoptosis. After treatment of HUVECs with FXIIIa, almost complete disappearance of mRNA of thrombospondin 1 (TSP-1) and a marked reduction in the secretion of TSP-1 protein were observed. A reduction in TSP-1 protein synthesis, although to a lesser extent, was observed on treatment of microvascular endothelial cells with FXIIIa. In a rabbit cornea model, injection of FXIIIa caused neovascularization associated with almost complete disappearance of TSP-1 in the cornea.

Conclusions—These results show that FXIIIa exhibits a novel proangiogenic activity that is associated with downregulation of TSP-1 and also involves stimulation of endothelial cell proliferation and migration and inhibition of apoptosis. These findings might shed light on the mechanism by which FXIII mediates tissue repair and remodeling.
Interaction of Oxidative Stress and Inflammatory Response in Coronary Plaque Instability
Authors: Kobayashi Seiichi , Inoue Nobutaka , Ohashi Yoshitaka , Terashima Mitsuyoshi , Matsui Kiyoko , Mori Takao , Fujita Hideki , Awano Kojiro , Kobayashi Katsuya , Azumi Hiroshi , Ejiri Junya , Hirata Ken-ichi , Kawashima Seinosuke , Hayashi Yoshitake , Yokozaki Hiroshi , Itoh Hiroshi , Yokoyama Mitsuhiro
Published: June 2003

Objective—C-reactive protein (CRP), a predictor of cardiovascular events, localizes in atherosclerotic arteries and exerts proinflammatory effects on vascular cells. Reactive oxygen species (ROS) have been implicated in atherogenesis and plaque instability.

Methods and Results—Expressional pattern of CRP in directional coronary atherectomy specimens from 39 patients was examined. Characteristics of histological plaque instability and higher levels of serum CRP and fibrinogen were associated with the CRP immunoreactivity. In situ hybridization revealed the presence of CRP mRNA in coronary vasculature. Furthermore, the expression of CRP mRNA and protein was detected in cultured human coronary artery smooth muscle cells (CASMCs) by reverse transcriptase–polymerase chain reaction and Western blotting. In addition, CRP was frequently colocalized with p22phox, an essential component of NADH/NADPH oxidase, which is an important source of ROS in vasculature. Moreover, the incubation of cultured CASMCs with CRP resulted in the enhanced p22phoxprotein expression and in the generation of intracellular ROS.

Conclusions—The expression of CRP in coronary arteries was associated with histological and clinical features of vulnerable plaque, and it had a prooxidative effect on cultured CASMCs, suggesting that it might play a crucial role in plaque instability and in the pathogenesis of acute coronary syndrome via its prooxidative effect.
A
cis
-Acting Region Regulates Oxidized Lipid-Mediated Induction of the Human Heme Oxygenase-1 Gene in Endothelial Cells
Authors: Hill-Kapturczak Nathalie , Voakes Christy , Garcia Jairo , Visner Gary , Nick Harry S. , Agarwal Anupam
Published: June 2003

Objective—

Several proatherogenic agents including oxidized LDL and its major component, 13-hydroperoxyoctadecadienoic acid (13-HPODE), upregulate heme oxygenase-1 (HO-1). Our previous studies have demonstrated that 13-HPODE-mediated HO-1 induction occurs via transcriptional mechanisms. The purpose of this study was to evaluate the molecular regulation and identify the signaling pathways involved in 13-HPODE-mediated HO-1 induction in human aortic endothelial cells.

Methods and Results—

The half-life of HO-1 mRNA after stimulation with 13-HPODE was ≈1.8 hours. Antioxidants such as
N
-acetylcysteine, iron chelation with deferoxamine mesylate, and protein kinase C inhibition with Gö6976 blocked HO-1 induction. Using promoter constructs up to 9.1 kb, no significant reporter activity was observed in response to 13-HPODE. A 13-HPODE-inducible DNase I hypersensitive site was identified that maps to a region ≈10 to 11 kb from the transcription start site of the human HO-1 gene. Based on the DNase I analysis, a −11.6-kb human HO-1 promoter construct was generated and elicited a 2.5-fold increase in reporter activity, indicating that 13-HPODE-mediated human HO-1 induction requires, at least in part, sequences that reside between 9.1 and 11.6 kb of the human HO-1 promoter.

Conclusions—

Elucidation of the molecular mechanisms which control HO-1 gene expression will allow us to develop therapeutic strategies to enhance the cytoprotective potential of HO-1 in atherosclerosis.
Adrenomedullin Reduces VEGF-Induced Endothelial Adhesion Molecules and Adhesiveness Through a Phosphatidylinositol 3′-Kinase Pathway
Authors: Kim Won , Moon Sang-Ok , Lee Sik , Sung Mi Jeong , Kim Sung Hoon , Park Sung Kwang
Published: June 2003

Objective—

In the initial phase of inflammation, vascular endothelial growth factor (VEGF) can act as a proinflammatory cytokine by inducing adhesion molecules that bind leukocytes to endothelial cells. Adrenomedullin (AM) is known to act as either a proinflammatory or an anti-inflammatory agent. In this study, we examined the effects of AM on adhesion molecule expression and leukocyte adhesiveness in VEGF-stimulated human umbilical vein endothelial cells.

Methods and Results—

When stimulated with VEGF, the mRNAs of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin were dose-dependently upregulated. AM inhibited the VEGF-induced protein and mRNA expression of ICAM-1, VCAM-1, and E-selectin. Phosphatidylinositol 3′-kinase inhibitor and a dominant-negative form of Akt significantly inhibited the suppressive effect of AM on VEGF-induced adhesion molecule expression. Thus, AM inhibits VEGF-stimulated ICAM-1 and VCAM-1 expression through a phosphatidylinositol 3′-kinase/Akt pathway. AM reduced VEGF-induced endothelial adhesiveness for leukocytes.

Conclusions—

These results suggest that AM might have an anti-inflammatory role in controlling VEGF-induced adhesion molecule gene expression and adhesiveness toward leukocytes in endothelial cells.
Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase
Authors: Achan Vinod , Broadhead Michael , Malaki Mohammed , Whitley Guy , Leiper James , MacAllister Raymond , Vallance Patrick
Published: June 2003

Objective—

Plasma levels of an endogenous nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA), are elevated in chronic renal failure, hypertension, and chronic heart failure. In patients with renal failure, plasma ADMA levels are an independent correlate of left ventricular ejection fraction. However, the cardiovascular effects of a systemic increase in ADMA in humans are not known.

Methods and Results—

In a randomized, double-blind, placebo-controlled study in 12 healthy male volunteers, we compared the effects of intravenous low-dose ADMA and placebo on heart rate, blood pressure, cardiac output, and systemic vascular resistance at rest and during exercise. We also tested the hypothesis that ADMA is metabolized in humans in vivo by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Low-dose ADMA reduced heart rate by 9.2±1.4% from 58.9±2.0 bpm (
P
<0.001) and cardiac output by 14.8±1.2% from 4.4±0.3 L/min (
P
<0.001). ADMA also increased mean blood pressure by 6.0±1.2% from 88.6±3.4 mm Hg (
P
<0.005) and SVR by 23.7±2.1% from 1639.0±91.6 dyne · s · cm
−5
(
P
<0.001). Handgrip exercise increased cardiac output in control subjects by 96.8±23.3%, but in subjects given ADMA, cardiac output increased by only 35.3±10.6% (
P
<0.05). DDAHs metabolize ADMA to citrulline and dimethylamine. Urinary dimethylamine to creatinine ratios significantly increased from 1.26±0.32 to 2.73±0.59 after ADMA injection (
P
<0.01). We estimate that humans generate approximately 300 μmol of ADMA per day, of which approximately 250 μmol is metabolized by DDAHs.

Conclusions—

This study defines the cardiovascular effects of a systemic increase in ADMA in humans. These are similar to changes seen in diseases associated with ADMA accumulation. Finally, our data also indicate that ADMA is metabolized by DDAHs extensively in humans in vivo.
Lack of Insulin Receptor Substrate-2 Causes Progressive Neointima Formation in Response to Vessel Injury
Authors: Kubota Tetsuya , Kubota Naoto , Moroi Masao , Terauchi Yasuo , Kobayashi Tsuneo , Kamata Katsuo , Suzuki Ryo , Tobe Kazuyuki , Namiki Atsushi , Aizawa Shinichi , Nagai Ryozo , Kadowaki Takashi , Yamaguchi Tetsu
Published: June 2003

Background—

Insulin resistance is associated with atherosclerosis, but its mechanism is unknown. It has been reported that insulin receptor substrate (IRS)-1 deficient (
IRS-1
−/−
) mice showed insulin resistance without type 2 diabetes, whereas the IRS-2 deficient (
IRS-2
−/−
) mice showed insulin resistance with type 2 diabetes.

Methods and Results—

We investigated neointima formation in the
IRS-1
−/−
and
IRS-2
−/−
mice at 8 and 20 weeks. The
IRS-2
−/−
mice showed much greater neointima formation than the
IRS-1
−/−
and wild-type mice at 8 weeks. At 20 weeks, the
IRS-2
−/−
mice had greater neointima formation than the
IRS-1
−/−
mice, which showed more enhanced neointima formation than the wild-type mice. The
IRS-1
−/−
and
IRS-2
−/−
mice had dyslipidemia, hypertension, and insulin resistance. The
IRS-2
−/−
mice had more metabolic abnormalities than the
IRS-1
−/−
mice at 8 and 20 weeks. IRS-2 expression was detected, but IRS-1 expression was not detected in the vessels.

Conclusions—

The neointima formation in the
IRS-1
−/−
and
IRS-2
−/−
mice appears to be related to abnormalities induced by the altered metabolic milieu in insulin-resistant states. Moreover, because neointima formation was much greater in the
IRS-2
−/−
mice than in the
IRS-1
−/−
mice at 8 and 20 weeks, it is suggested that a lack of IRS-2 renders the vasculature more susceptible to injury in the abnormal metabolic milieu, and IRS-2 may have a protective effect on neointima formation. We conclude that IRS-2 is protective and retards the development of neointima formation in insulin-resistant states.
Noncultured, Autologous, Skeletal Muscle Cells Can Successfully Engraft Into Ovine Myocardium
Authors: Borenstein Nicolas , Bruneval Patrick , Hekmati Mehrak , Bovin Christophe , Behr Luc , Pinset Christian , Laborde François , Montarras Didier
Published: June 2003

Background—

There is compelling evidence showing that cellular cardiomyoplasty can improve cardiac function. Considering the potential benefit of using noncultured muscle cells (little time, lower cost, reduced risk of contamination), we investigated the feasibility of grafting cells obtained directly after enzymatic dissociation of skeletal muscle biopsies into ovine myocardium. We hypothesized that those noncultured muscle cells would engraft massively.

Methods and Results—

Autologous, intramyocardial skeletal muscle cell implantation was performed in 8 sheep. A skeletal muscle biopsy sample (≈10 g) was explanted from each animal. The sheep were left to recover for ≈3 hours and reanesthetized when the cells were ready for implantation. A left fifth intercostal thoracotomy was performed, and 10 epicardial injections of the muscle preparation (between 10 and 20 million cells) were carried out. All sheep were euthanized 3 weeks after myocardial implantation. Immunohistochemistry was performed with monoclonal antibodies to a fast skeletal isoform of myosin heavy chain. Skeletal myosin heavy-chain expression was detected in all slides at 3 weeks after implantation in 8 of 8 animals, confirming engraftment of skeletal muscle cells. Massive areas of engraftment (from 2 to 9 mm in diameter) or discrete loci were noted within the myocardial wall.

Conclusions—

Our results indicate that noncultured skeletal muscle cells can successfully and massively engraft in ovine myocardium. Thus, avoiding the cell culture expansion phase is feasible and could become a promising option for cellular cardiomyoplasty.
Abnormal Cardiac and Skeletal Muscle Energy Metabolism in Patients With Type 2 Diabetes
Authors: Scheuermann-Freestone Michaela , Madsen Per L. , Manners David , Blamire Andrew M. , Buckingham Robin E. , Styles Peter , Radda George K. , Neubauer Stefan , Clarke Kieran
Published: June 2003

Background—

It is well known that patients with type 2 diabetes have increased risk of cardiovascular disease, but it is not known whether they have underlying abnormalities in cardiac or skeletal muscle high-energy phosphate metabolism.

Methods and Results—

We studied 21 patients with type 2 diabetes with no evidence of coronary artery disease or impaired cardiac function, as determined by echocardiography, and 15 age-, sex-, and body mass index-matched control subjects. Cardiac high-energy phosphate metabolites were measured at rest using
31
P nuclear magnetic resonance spectroscopy (MRS). Skeletal muscle high-energy phosphate metabolites, intracellular pH, and oxygenation were measured using
31
P MRS and near infrared spectrophotometry, respectively, before, during, and after exercise. Although their cardiac morphology, mass, and function appeared to be normal, the patients with diabetes had significantly lower phosphocreatine (PCr)/ATP ratios, at 1.50±0.11, than the healthy volunteers, at 2.30±0.12. The cardiac PCr/ATP ratios correlated negatively with the fasting plasma free fatty acid concentrations. Although skeletal muscle energetics and pH were normal at rest, PCr loss and pH decrease were significantly faster during exercise in the patients with diabetes, who had lower exercise tolerance. After exercise, PCr recovery was slower in the patients with diabetes and correlated with tissue reoxygenation times. The exercise times correlated negatively with the deoxygenation rates and the hemoglobin (Hb)A
1c
levels and the reoxygenation times correlated positively with the HbA
1c
levels.

Conclusions—

Type 2 diabetic patients with apparently normal cardiac function have impaired myocardial and skeletal muscle energy metabolism related to changes in circulating metabolic substrates.
Enhanced Lipid Peroxidation and Platelet Activation in the Early Phase of Type 1 Diabetes Mellitus
Authors: Davì Giovanni , Chiarelli Francesco , Santilli Francesca , Pomilio Mariapina , Vigneri Sergio , Falco Angela , Basili Stefania , Ciabattoni Giovanni , Patrono Carlo
Published: June 2003

Background—

To investigate early events possibly related to the development of diabetic angiopathy, we examined whether 8-iso-prostaglandin F
2α
(8-iso-PGF
2α
) formation, a marker of in vivo oxidant stress, is altered in different stages of type 1 diabetes (T1DM) and whether it correlates with the rate of thromboxane (TX) A
2
biosynthesis, a marker of in vivo platelet activation. We also investigated the relationship between inflammatory markers and F
2
-isoprostane formation in this setting.

Methods and Results—

A cross-sectional study was performed in 23 insulin-treated patients aged <18 years with new-onset T1DM (≤6 weeks, group A), matched for age and gender with 23 patients with stable disease (>1 year, group B). Urinary 8-iso-PGF
2α
and 11-dehydro-TXB
2
were measured in all patients and in age- and gender-matched controls. Circulating interleukin-6 (IL-6), tumor necrosis factor-α, and C-reactive protein were also determined as markers of the inflammatory response. Fifteen of the 23 children in group A were reexamined after 12 months. Compared with either controls or group B, diabetic children in group A showed significantly higher levels of 8-iso-PGF
2α
, 11-dehydro-TXB
2
, IL-6, tumor necrosis factor-α, and C-reactive protein. Statistically significant correlations between IL-6 and both 8-iso-PGF
2α
(
r
=0.63,
P
<0.001) and 11-dehydro-TXB
2
(
r
=0.51,
P
<0.01) were observed. The 15 patients reexamined after 1 year showed a significant reduction in lipid peroxidation and platelet activation (
P
<0.02 and
P
<0.001, respectively), consistent with reduced levels of IL-6 and tumor necrosis factor-α.

Conclusions—

These results demonstrate that enhanced lipid peroxidation and platelet activation represent early events in T1DM that are possibly related to an acute inflammatory response. These noninvasive indexes may help in further examining T1DM pathophysiology and monitoring pharmacological interventions to interfere with disease development and progression.
Genetic Variation in Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 (LOX1) Gene and the Risk of Coronary Artery Disease
Authors: Chen Qi , Reis Steven E. , Kammerer Candace , Craig Wendy Y. , LaPierre Sue E. , Zimmer Erin Luedecking , McNamara Dennis M. , Pauly Daniel F. , Sharaf Barry , Holubkov Richard , Bairey Merz C. Noel , Sopko George , Bontempo Franklin , Kamboh M. Ilyas
Published: June 2003

Background—

We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women’s Ischemia Syndrome Evaluation (WISE) study population.

Methods and Results—

The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: <20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and ≥50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G→A, intron 5/T→G, and 3′ UTR/T→C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3′UTR/T allele was significantly higher in whites than blacks (49% versus 19%;
P
<0.0001). Among white women, the frequency of the 3′UTR/T allele carriers (TC+TT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the <20%, 20% to 49%, and ≥50% stenosis groups, respectively (χ
2
trend=6.23;
P
=0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90;
P
=0.007) and LOX1 (odds ratio, 1.67;
P
=0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3′UTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94±0.20 versus 0.86±0.16;
P
=0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3′UTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner.

Conclusions—

Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women.
Determination of the Upper Limit of Vulnerability Using Implantable Cardioverter-Defibrillator Electrograms
Authors: Swerdlow Charles , Shivkumar Kalyanam , Zhang Jianxin
Published: June 2003

Background—

The upper limit of vulnerability (ULV) correlates with the defibrillation threshold and can be determined with 1 episode of ventricular fibrillation (VF). To automate the ULV in an implantable cardioverter-defibrillator (ICD), the most vulnerable intervals must be identified from an ICD electrogram rather than the latest-peaking surface T wave (T
peak
). We hypothesized that the recovery time (T
R
), defined as the maximum derivative (dV/dt) of the T wave of the shock electrogram, correlates with the most vulnerable intervals.

Methods and Results—

We determined ULV, defibrillation threshold, and the most vulnerable intervals in 25 patients at ICD implantation. The ULV was the weakest T-wave shock that did not induce VF. The most vulnerable intervals were the ones associated with the strongest shocks that induced VF. Telemetered shock electrograms were stored on digital tape and differentiated offline to measure T
R
. T
peak
and T
R
were highly correlated (T
peak
−T
R
=−2±11 ms; ρ=0.80,
P
<0.001). At least 1 most vulnerable interval timed between −20 ms and +20 ms relative to T
peak
in all patients and between −40 ms and +20 ms relative to T
R
in 96% of patients.

Conclusions—

The recovery time of shock electrograms provides accurate information about global repolarization. T
R
closely approximates T
peak
. The ULV method may be automated in an ICD by timing T-wave shocks relative to T
R
.
Increased Expression of Thrombospondin-1 in Vessel Wall of Diabetic Zucker Rat
Authors: Stenina Olga I. , Krukovets Irene , Wang Kai , Zhou Zhongmin , Forudi Farhad , Penn Marc S. , Topol Eric J. , Plow Edward F.
Published: June 2003

Background—

Thrombospondin-1 (TSP-1) expression in the vascular wall has been related to the development of atherosclerotic lesions and restenosis. TSP-1 promotes the development of neointima and has recently been associated with atherogenesis at a genetic level. Because TSP-1 expression is responsive to glucose stimulation in mesangial cells, we hypothesized that glucose may stimulate its production by vascular cells. Thus, TSP-1 expression in the blood vessel wall may increase, providing a molecular link between diabetes and accelerated vascular lesion development.

Methods and Results—

To determine whether the expression level of TSP-1 in vessel wall is increased in diabetes, aorta and carotid arteries of Zucker rats were used for immunostaining, Western blotting, and in situ RNA hybridization. A significant increase in TSP-1 expression was found in the adventitia of blood vessels from diabetic rats. Consistent with the well-known antiangiogenic effect of TSP-1, the number of vasa vasorum was reduced in aortas from diabetic rats. In cultured endothelial cells, vascular smooth muscle cells, and fibroblasts, TSP-1 expression increased in response to glucose stimulation (>30-fold). After balloon catheter injury to carotid arteries, expression of TSP-1 protein and mRNA was higher at all time points in the vessels of diabetic rats.

Conclusions—

Increased expression of TSP-1 in blood vessels in diabetes may represent a new link between diabetes, atherogenesis, and accelerated restenosis. This increase in TSP-1 production may be a direct response of vascular cells to glucose.
Overexpression of the Serotonin 5-HT
2B
Receptor in Heart Leads to Abnormal Mitochondrial Function and Cardiac Hypertrophy
Authors: Nebigil Canan G. , Jaffré Fabrice , Messaddeq Nadia , Hickel Pierre , Monassier Laurent , Launay Jean-Marie , Maroteaux Luc
Published: June 2003

Background—

Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. We previously reported that 5-HT
2B
receptor ablation in mice leads to dilated cardiomyopathy. In this study, we investigated the pathological consequence of overexpressing 5-HT
2B
receptors in heart in vivo.

Methods and Results—

We have generated transgenic mice overexpressing the Gq-coupled 5-HT
2B
receptor specifically in heart. We found that overexpression of 5-HT
2B
receptor in heart leads to ventricular hypertrophy as the result of increased cell number and size. Increased atrial natriuretic peptide and myosin heavy chain expression demonstrated activation of the molecular program for cardiac hypertrophy. Echocardiographic analysis indicated the presence of thickened ventricular free wall without alteration of the systolic function, showing that transgenic mice have compensated hypertrophy. Electron microscopic analysis revealed structural abnormalities including mitochondrial proliferation, as also manifested by histological staining. Transgenic mouse heart displayed a specific reduction in the expression levels of the adenine nucleotide translocator associated to increase in the succinate dehydrogenase and cytochrome C oxidase mitochondrial activities.

Conclusions—

Our results constitute the first genetic evidence that overexpression of the 5-HT
2B
receptor in the heart leads to compensated hypertrophic cardiomyopathy associated with proliferation of the mitochondria. This observation suggests a role for mitochondria in the hypertrophic signaling that is regulated by serotonin. These transgenic mice provide a new genetic model for hypertrophic heart disease.
D-Dimer, Inflammatory Markers, and Lower Extremity Functioning in Patients With and Without Peripheral Arterial Disease
Authors: McDermott Mary McGrae , Greenland Philip , Green David , Guralnik Jack M. , Criqui Michael H. , Liu Kiang , Chan Cheeling , Pearce William H. , Taylor Lloyd , Ridker Paul M , Schneider Joseph R. , Martin Gary , Rifai Nader , Quann Maureen , Fornage Myriam
Published: June 2003

Background—

We determined whether higher levels of D-dimer, C-reactive protein (CRP), fibrinogen, and serum amyloid A are associated independently with functional impairment in patients with and without peripheral arterial disease (PAD).

Methods and Results—

Participants were 370 men and women with PAD (ankle brachial index <0.90) and 231 without PAD. Functional outcomes were 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ankle brachial index, comorbidities, and other potential mediators and confounders, D-dimer levels were associated independently and inversely with performance on all 3 functional measures in the entire cohort and among patients with and without PAD, respectively. Adjusting for known and potential confounders, CRP levels were associated independently with 6-minute walk distance and the summary performance score among participants with PAD. No significant associations were observed between CRP and the functional measures among participants without PAD. Fibrinogen and SAA levels were not associated independently with the functional measures.

Conclusions—

Higher D-dimer levels are associated with poorer functioning among individuals with and without PAD. Higher CRP levels were associated with poorer 6-minute walk performance and a lower summary performance score among participants with PAD but not among those without PAD. Additional study is needed to determine whether D-dimer and CRP are involved in the pathophysiology of functional impairment or whether they are simply sensitive markers of the extent of systemic atherosclerosis.
Regular Physical Activity Improves Endothelial Function in Patients With Coronary Artery Disease by Increasing Phosphorylation of Endothelial Nitric Oxide Synthase
Authors: Hambrecht R. , Adams V. , Erbs S. , Linke A. , Kränkel N. , Shu Y. , Baither Y. , Gielen S. , Thiele H. , Gummert J.F. , Mohr F.W. , Schuler G.
Published: June 2003

Background—

In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD.

Methods and Results—

In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOS-Ser
1177
, Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase–polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56±8% (from +48±8% at beginning to +104±11% after 4 weeks,
P
<0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0±0.7 versus C 0.5±0.3 arbitrary units,
P
<0.05) and 4-fold higher eNOS Ser
1177
-phosphorylation levels in LIMA-endothelium (1.2±0.9 versus 0.3±0.2 arbitrary units,
P
<0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (
R
=0.80,
P
<0.05) and between phospho-eNOS and Δ APV (
R
=0.59,
P
<0.05).

Conclusions—

Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress–induced/Akt-dependent phosphorylation of eNOS on Ser
1177
.
Estrogen Increases Bone Marrow–Derived Endothelial Progenitor Cell Production and Diminishes Neointima Formation
Authors: Strehlow Kerstin , Werner Nikos , Berweiler Jan , Link Andreas , Dirnagl Ulrich , Priller Josef , Laufs Kerstin , Ghaeni Leyli , Milosevic Milan , Böhm Michael , Nickenig Georg
Published: June 2003

Background—

Estrogens improve endothelial function and accelerate reendothelialization after vascular injury via largely unknown mechanisms. Bone marrow–derived endothelial progenitor cells (EPCs) are thought to positively influence endothelialization, vascular repair, and angiogenesis.

Methods and Results—

In mice subjected to sham operation, ovariectomy, or ovariectomy and estrogen replacement treatment, estrogen deficiency significantly decreased EPCs circulating in the peripheral blood and residing in the bone marrow, as well as EPCs that were in vitro expanded from spleen-derived mononuclear cells. These effects were completely prevented by estrogen replacement. Human women with increased estrogen plasma concentrations also displayed profoundly increased levels of circulating EPCs. Estrogens increase EPC numbers through a decreased apoptosis rate, which is mediated via a caspase-8–dependent pathway. Estrogen deficiency increased neointima formation after carotid artery injury in mice, but this effect was diminished by estrogen replacement therapy. In mice transplanted with green fluorescent protein–positive bone marrow, reendothelialization of injured vessel segments by bone marrow–derived cells was decreased during estrogen deficiency and increased in response to estrogen treatment.

Conclusions—

Estrogens increase numbers of EPCs by antiapoptotic effects leading to accelerated vascular repair and decreased neointima formation.
Elasticity Imaging of Atheroma With Transcutaneous Ultrasound
Authors: Kanai Hiroshi , Hasegawa Hideyuki , Ichiki Masataka , Tezuka Fumiaki , Koiwa Yoshiro
Published: June 2003

Background—

Knowledge of the physical properties of atherosclerotic plaque is essential when evaluating its vulnerability in a clinical setting. Such knowledge, however, is still difficult to obtain with the various approaches developed to date.

Methods and Results—

This article describes a noninvasive method for evaluating the regional elasticity (the elastic modulus in the circumferential direction) of tissue surrounding atherosclerotic plaque in which a novel phased tracking method is applied to measure minute changes in thickness of each of the multiple layers of the arterial wall during one heartbeat. By comparing the pathological findings with the distribution of elasticity, average elasticity of lipid and that of a mixture of smooth muscle and collagen fiber can be determined. On the basis of these reference parameters, each point is statistically categorized as lipid, mixture, or other. Thus, the plaque is electronically stained using transcutaneous ultrasound. By applying the method to the common carotid arteries, the presence of thin collagen fiber was clarified along the arterial axis for normal subjects, whereas soft inclusion of lipid was found for every plaque in subjects with hyperlipidemia.

Conclusion—

This novel method offers potential as a diagnostic technique for detection of plaque vulnerability with high spatial resolution.
Is There a Side Predilection for Cerebrovascular Disease?
Authors: Hernández Sergio A. Rodríguez , Kroon Abraham A. , van Boxtel Martin P.J. , Mess Werner H. , Lodder Jan , Jolles Jelle , de Leeuw Peter W.
Published: June 2003

In studies on carotid artery intima-media thickness and stroke, researchers implicitly assume that cerebrovascular abnormalities show a symmetrical distribution. To evaluate whether there is a difference in intima-media thickness between the 2 carotids, we compared left and right common carotid artery intima-media thickness as measured by B-mode ultrasonography in a group of 102 untreated hypertensive patients. This yielded a significant difference between both sides (left, 0.75±0.11 mm; right, 0.71±0.11 mm;
P
<0.001). This was associated with a higher cross-sectional area of the intima-media complex and a higher flow velocity at the left side. Arterial diameters, however, were not different. We also assessed whether there is a side preference with respect to cerebrovascular accidents. To this end, we explored our population-based Stroke Registry of 1843 subjects and indeed found a significantly higher incidence of nonlacunar cerebrovascular stroke at the left side, whereas lacunar infarcts were symmetrically distributed. Our findings suggest a predilection for cerebrovascular disease at the left side, which may be related to greater hemodynamic stress and intimal damage in the left carotid artery.
Downregulation of Angiotensin Subtype 1 Receptor in Rostral Ventrolateral Medulla During Endotoxemia
Authors: Chan Julie Y.H. , Wang Ling-Lin , Ou Chen-Chun , Chan Samuel H.H.
Published: June 2003

We reported recently that an upregulation of the inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, is a crucial determinant for the elicitation of cardiovascular depression during experimental endotoxemia. The current study evaluated the hypothesis that a downregulation of the molecular synthesis and functional expression of angiotensin subtype 1 receptor (AT1R) in the RVLM is consequential to this upregulated iNOS. In adult Sprague-Dawley rats maintained under propofol anesthesia, intravenous administration of
Escherichia coli
lipopolysaccharide (15 mg/kg) elicited a reduction, followed by an augmentation and a secondary decrease in sympathetic vasomotor outflow, together with progressive hypotension and bradycardia. There was also a progressive increase in iNOS mRNA and protein level in the ventrolateral medulla. This was followed by a significant downregulation of both mRNA and protein levels of AT1R in the ventrolateral medulla, alongside reduced efficacy of angiotensin II (50 pmol) to induce an increase in systemic arterial pressure, heart rate, or sympathetic vasomotor outflow on unilateral microinjection into the RVLM. Pretreatment with microinjection of a selective iNOS inhibitor,
S
-methylisothiourea (250 pmol) bilaterally into the RVLM significantly reversed the reduction in both synthesis and activity of AT1R. We conclude that a downregulation of molecular synthesis and functional expression of AT1R in the ventrolateral medulla is consequential to the overproduction of NO through upregulation of iNOS in the RVLM and may underlie the cardiovascular depression that takes place during experimental endotoxemia.
Time Course of Vascular Structural Changes During and After Short-Term Antihypertensive Treatment
Authors: Hale Taben M. , Shoichet Martin J. , Bushfield Terri L. , Adams Michael A.
Published: June 2003

The present study characterized the persistent changes (ie, off-treatment) resulting from short-term antihypertensive treatments on mean arterial pressure (MAP) and structurally based vascular resistance. Rats were treated for 14 days with enalapril (30 mg · kg
−1
· d
−1
) with regular (ENAL, 0.4%) or low salt (ELS, 0.04%) diets, or a triple therapy (Triple: hydralazine 45 mg · kg
−1
· d
−1
, hydrochlorothiazide 100 mg/L, and nifedipine 200 mg/d). MAP was continuously recorded via radiotelemetry. Structurally based hindlimb vascular resistance properties (resistance at maximum dilation [Max Dil]; resistance at maximum constriction [Max Con]) were assessed after 14-day enalapril treatment and 2 to 3 weeks after all drugs were withdrawn. Aortic urokinase plasminogen activator (uPA) activity was measured by zymography after 14 days of ELS. All treatments induced a significant, persistent decrease in the off-treatment MAP (ENAL ↓12±4.6%, ELS ↓16±2.6%, Triple ↓5±4.17%). During treatment (14 days) the enalapril group had significant changes in the index of medial bulk (Max Con ↓15±2.6%), but only minimal changes in lumen properties (Max Dil ↓3±6.5%, NS). After stopping therapy, vascular properties at Max Dil were significantly decreased only in the 2 enalapril groups (ENAL ↓15±7.9%,
P
<0.05; ELS ↓9±6.0%,
P
<0.05; Triple ↓2±9.8%, NS), whereas Max Con was significantly decreased in all groups (ENAL ↓12±8.0%, ELS ↓16±6.1%, Triple ↓7±5.4%). At 14 days of ELS treatment, there was increased aortic uPA activity (1.6-fold). The findings reveal that various short-term antihypertensive treatments can produce persistent long-term changes in MAP and vascular structure. Further, the magnitude of the depressor response may be as important in inducing persistent changes as is the removal of angiotensin II.