bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of Intact and Ruptured Atherosclerotic Plaques in Brachiocephalic Arteries of Apolipoprotein E Knockout Mice
Authors: Williams Helen , Johnson Jason Lee , Carson Kevin George Stephen , Jackson Christopher Langdale
Published: July 2002

The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. Ruptured and intact plaques differed in terms of plaque cross-sectional area (intact, 0.109±0.016 mm
2
; ruptured, 0.192±0.009 mm
2
;
P
=0.0005), luminal occlusion (intact, 35.3±3.3%; ruptured, 57.7±1.9%;
P
<0.0001), the number of buried caps within the lesion (intact, 1.06±0.12; ruptured, 2.66±0.16;
P
<0.0001), fibrous cap thickness (intact, 4.7±0.6 μm; ruptured, 2.0±0.3 μm;
P
=0.0004), and lipid fractional volume (intact, 35.9±3.0%; ruptured, 50.7±2.2%;
P
=0.0019). This study confirms that plaque rupture is a frequent occurrence in the brachiocephalic arteries of apolipoprotein E knockout mice on a high-fat diet. The data also show that ruptured plaques in these mice show many of the characteristics of vulnerable plaques in humans. This supports the use of this model in studies of the mechanisms and therapy of plaque rupture.
Hyperhomocysteinemia Evoked by Folate Depletion
Authors: Symons J. David , Mullick Adam E. , Ensunsa Jodi L. , Ma Amy A. , Rutledge John C.
Published: July 2002

High circulating concentrations of homocysteine (ie, hyperhomocysteinemia [Hhcy]) impair the vascular function of peripheral conduit arteries and arterioles perfusing splanchnic and skeletal muscle regions. The effects of HHcy on coronary resistance vessel function and other indexes of vascular function, ie, arterial permeability and stiffening, are unclear. We tested the hypotheses that HHcy impairs coronary resistance vessel reactivity; increases carotid arterial permeability; and initiates arterial stiffening. Male rats that consumed folate-replete (CON, n=44) or folate-deplete (HHcy, n=48) chow for 4 to 5 weeks had total plasma homocysteine concentrations of 7±2 or 58±4 μmol/L, respectively. Maximal acetylcholine-evoked relaxation (≈40% vs ≈60%) and tension development from baseline in response to nitric oxide synthase inhibition (≈20% vs ≈40%) were lower (both
P
<0.05) in coronary resistance vessels (≈120 μm, internal diameter) isolated from HHcy versus CON animals, respectively, whereas sodium nitroprusside-evoked relaxation and contractile responses to serotonin and potassium chloride were similar between groups. Permeability to 4400 MW and 65 000 MW fluorescently labeled (TRITC) dextran reference macromolecules (quantitative fluorescence microscopy) was ≈44% and ≈24% greater (
P
<0.05), respectively, in carotid arteries from HHcy versus CON rats. Maximal strain, evaluated by using a vessel elastigraph, was less (≈32% vs 42%,
P
<0.05) in carotid arterial segments from HHcy versus CON animals, respectively. Finally, estimates of oxidative (copper-zinc+manganese superoxide dismutase activity) and glycoxidative (pentosidine) stress were elevated (
P
<0.05) in arterial tissue from HHcy versus CON rats. These findings suggest that moderately severe HHcy evoked by folate-depletion impairs endothelium-dependent relaxation of coronary resistance vessels, increases carotid arterial permeability, and initiates arterial stiffening. HHcy may produce these effects by a mechanism associated with increased oxidative and glycoxidative stress.
Increased Atherosclerosis in Hyperlipidemic Mice With Inactivation of ABCA1 in Macrophages
Authors: Aiello Robert J. , Brees Dominique , Bourassa Patricia-Ann , Royer Lori , Lindsey Saralyn , Coskran Timothy , Haghpassand Mehrdad , Francone Omar L.
Published: July 2002

The ATP-binding cassette transporter A1 (ABCA1) encodes a membrane protein that promotes cholesterol and phospholipid efflux from cells. Mutations in ABCA1 lead to HDL deficiency and tissue accumulation of macrophages in patients with homozygous Tangier disease. In this study, we examined whether the complete absence of ABCA1 or selected inactivation in macrophages is accompanied by an increase in atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E–deficient (apoE
−/−
) mice and LDLR receptor–deficient (LDLr
−/−
) mice. The absence of ABCA1 led to reduced plasma cholesterol levels in both the apoE
−/−
and LDLr
−/−
mice, along with severe skin xanthomatosis characterized by marked foamy macrophages and cholesterol ester accumulation. However, the complete absence of ABCA1 did not affect the development, progression, or composition of atherosclerotic lesions in either the LDLr
−/−
or the apoE
−/−
mice fed a chow or atherogenic diet. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE
−/−
. Taken together, these findings demonstrate that the complete absence of ABCA1 has a major impact on plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is compensated by a less atherogenic profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels.
Production of the Long Pentraxin PTX3 in Advanced Atherosclerotic Plaques
Authors: Rolph Michael S. , Zimmer Sabine , Bottazzi Barbara , Garlanda Cecilia , Mantovani Alberto , Hansson Göran K.
Published: July 2002

Elevated plasma levels of the pentraxin protein family member C-reactive protein (CRP) are associated with increased risk of cardiovascular disease in both healthy and high-risk subjects. The long pentraxin family member, pentraxin 3 (PTX3), was recently described. Like CRP, PTX3 is induced by acute inflammatory stimuli and is increased in the blood of patients with acute myocardial infarction. Unlike CRP, it is expressed in a wide range of cell types, but not in hepatocytes. In this study, we have investigated the expression of PTX3 in atherosclerosis. Immunohistochemical staining of advanced atherosclerotic lesions revealed strong expression of PTX3. In contrast, no PTX3 expression was observed in nonatherosclerotic internal mammary arteries. By staining serial sections with cell type– and PTX3-specific antibodies, we observed that PTX3 was produced principally by macrophages and endothelial cells. Infrequent expression by smooth muscle cells was also observed. Our results suggest that PTX3 may contribute to the pathogenesis of atherosclerosis.
Role of Isoprenylcysteine Carboxyl Methyltransferase in Tumor Necrosis Factor-α Stimulation of Expression of Vascular Cell Adhesion Molecule-1 in Endothelial Cells
Authors: Ahmad Mushtaq , Zhang Yan , Zhang Yong , Papharalambus Christopher , Alexander R. Wayne
Published: July 2002

We have previously shown that cytokine stimulation of the expression of vascular cell adhesion molecule-1 (VCAM-1), but not that of intercellular adhesion molecule-1 (ICAM-1), is redox sensitive in endothelial cells. Here, we investigated the role of isoprenylcysteine carboxyl methyltransferase (ICMTase), which methylates isoprenylated CAAX (where C indicates cysteine; A, aliphatic amino acids; and X, almost any other amino acid) proteins, including Rac1, a component of superoxide-generating NAD(P)H oxidase, in the expression of VCAM-1. Pretreatment of endothelial cells withN-acetyl-S-farnesyl-l-cysteine (AFC) orN-acetyl-S-geranylgeranyl-l-cysteine (AGGC), specific inhibitors of ICMTase, inhibited the tumor necrosis factor-α (TNF-α) stimulation of mRNA expression of VCAM-1 but not that of ICAM-1. Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells. TNF-α stimulation of the cells significantly increased the methylation of AFC and Rac1 in endothelial cells. That ICMTase was a component of the redox-sensitive signaling pathway was also suggested by the AFC inhibition of the generation of reactive oxygen species by TNF-α. Interestingly, the dominant-negative isoform of Rac1 was not selective but inhibited the TNF-α stimulation of the mRNA expression of VCAM-1 and ICAM-1. Thus, ICMTase is a critical component of the redox-sensitive VCAM-1-selective signaling pathway, and it appears to activate a discrete inflammatory signaling pathway, at least in part, through the methylation of Rac1.
Central Roles of α
5
β
1
Integrin and Fibronectin in Vascular Development in Mouse Embryos and Embryoid Bodies
Authors: Francis Sheila E. , Goh Keow Lin , Hodivala-Dilke Kairbaan , Bader Bernhard L. , Stark Margaret , Davidson Duncan , Hynes Richard O.
Published: July 2002

Vascular development and maturation are dependent on the interactions of endothelial cell integrins with surrounding extracellular matrix. Previous investigations of the primacy of certain integrins in vascular development have not addressed whether this could also be a secondary effect due to poor embryonic nutrition. Here, we show that the α
5
integrin subunit and fibronectin have critical roles in blood vessel development in mouse embryos and in embryoid bodies (EBs) differentiated from embryonic stem cells (a situation in which there is no nutritional deficit caused by the mutations). In contrast, vascular development in vivo and in vitro is not strongly dependent on α
v
or β
3
integrin subunits. In mouse embryos lacking α
5
integrin, greatly distended blood vessels are seen in the vitelline yolk sac and in the embryo itself. Additionally, overall blood vessel pattern complexity is reduced in α
5
-null tissues. This defective vascular phenotype is correlated with a decrease in the ligand for α
5
integrin, fibronectin (FN), in the endothelial basement membranes. A striking and significant reduction in early capillary plexus formation and maturation was apparent in EBs formed from embryonic stem cells lacking α
5
integrin or FN compared with wild-type EBs or EBs lacking α
v
or β
3
integrin subunits. Vessel phenotype could be partially restored to FN-null EBs by the addition of whole FN to the culture system. These findings confirm a clear role for α
5
and FN in early blood vessel development not dependent on embryo nutrition or α
v
or β
3
integrin subunits. Thus, successful early vasculogenesis and angiogenesis require α
5
-FN interactions.
Genome-Wide Linkage Analysis of the Acute Coronary Syndrome Suggests a Locus on Chromosome 2
Authors: Harrap Stephen B. , Zammit Kim S. , Wong Zilla Y.H. , Williams Fiona M. , Bahlo Melanie , Tonkin Andrew M. , Anderson Stanley T.
Published: July 2002

A positive family history is a recognized cardiovascular risk factor, and genome-wide scans may reveal susceptibility loci for coronary artery disease. The acute coronary syndrome, consisting of myocardial infarction and unstable angina, is the most important manifestation of coronary disease and is characterized by atherosclerotic plaque disruption and coronary thrombosis. From ≈6000 hospital admissions to cardiology units, we identified affected sibling pairs (n=61) who had documented acute coronary syndrome before the age of 70 years. A 10-cM resolution genetic map and MAPMAKER/SIBS were used for genome-wide linkage analysis. One locus on chromosome 2q36-q37.3 showed linkage with a lod score of 2.63 (
P
<0.0001). Separate multipoint fine-mapping of this locus with independent markers replicated the linkage results (lod 2.64). Two other regions on chromosomes 3q26-q27 and 20q11-q13 showed lod scores in excess of 1.5 (
P
<0.005). This genome scan in acute coronary syndrome suggests 1 locus that encompasses the gene encoding the insulin receptor substrate-1 gene. Two other potential loci were identified. These data imply that a limited number of potent susceptibility genes exist for the acute coronary syndrome. Such genes are likely to be relevant to the combined processes of atherosclerosis, plaque instability, and coronary thrombosis.
Protein C, Antithrombin, and Venous Thromboembolism Incidence
Authors: Folsom Aaron R. , Aleksic Nena , Wang Lu , Cushman Mary , Wu Kenneth K. , White Richard H.
Published: July 2002

Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for ≈2.5% of venous thromboembolic events in the ARIC population.
Reversal of Thrombin-Induced Deactivation of CD39/ATPDase in Endothelial Cells by HMG-CoA Reductase Inhibition
Authors: Kaneider Nicole C. , Egger Petra , Dunzendorfer Stefan , Noris Patrizia , Balduini Carlo L. , Gritti Donatella , Ricevuti Giovanni , Wiedermann Christian J.
Published: July 2002

Adenosine triphosphate and diphosphate that activate platelet, leukocyte, and endothelium functions are hydrolyzed by endothelial CD39/ATPDase. Because CD39/ATPDase is downregulated in endothelial cells by inflammation and this may be affected by HMG-CoA reductase inhibitors, we examined the role of cerivastatin and simvastatin in regulation of endothelial CD39/ATPDase expression, metabolism of ATP/ADP, and function in platelets. Thrombin-stimulated endothelial cells in vitro were treated with the statins, and hydrolysis of exogenous ADP and ATP was assessed by high-performance liquid chromatography and malachite green assay. Platelet aggregation studies were performed with endothelial cell supernatants as triggers. CD39/ATPDase surface expression by endothelial cells was determined immunologically by fluorescence-activated cell sorter, mRNA expression by RT-PCR, and thrombin-induced dissociation of Rho-GTPases by Western blotting. Treatment by simvastatin or cerivastatin restored impaired metabolism of exogenous ATP and ADP in thrombin-activated endothelial cells by preventing thrombin-induced downregulation of CD39/ATPDase. In platelet aggregation studies, ATP and ADP supernatants of thrombin-activated endothelial cells were less stimulatory in the presence of statins than in their absence. Data show that statins preserve CD39/ATPDase activity in thrombin-treated endothelial cells involving alterations by statins of Rho-GTPase function and CD39/ATPDase expression. Preservation of adenine nucleotide metabolism may directly contribute to the observed anti-thrombotic and anti-inflammatory actions of statins.
Monocyte Chemoattractant Protein-1 Induces Proliferation and Interleukin-6 Production in Human Smooth Muscle Cells by Differential Activation of Nuclear Factor-κB and Activator Protein-1
Authors: Viedt Christiane , Vogel Judith , Athanasiou Thomas , Shen Weili , Orth Stephan R. , Kübler Wolfgang , Kreuzer Jörg
Published: July 2002

Inflammatory response and chemotaxis of vascular wall cells play an important pathogenic role in the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for monocytes. Besides the induction of monocyte recruitment, it has been suggested that MCP-1 may directly activate smooth muscle cells. We investigated whether MCP-1 affects the proliferation and cytokine production of human vascular smooth muscle cells (VSMCs) and determined the underlying signal transduction pathways. Stimulation of VSMCs with MCP-1 induced proliferation and resulted in a concentration- and time-dependent release of the proinflammatory cytokine interleukin-6 (IL-6). Pretreatment with pertussis toxin, GF109203X, and pyrrolidine dithiocarbamate inhibited MCP-1–dependent IL-6 release, suggesting the involvement of Giproteins, protein kinase C, and nuclear factor-κB (NF-κB). MCP-1 also induced extracellular signal–regulated kinase, which, along with IL-6 release, was inhibited by pertussis toxin. PD98059 prevented MCP-1–induced extracellular signal–regulated kinase activation and cell proliferation. MCP-1 stimulated the binding activity of NF-κB and of activator protein-1 (AP-1). As demonstrated byciselement double-stranded (decoy) oligodeoxynucleotides, NF-κB was involved in IL-6 release by MCP-1, whereas proliferation was dependent on AP-1. The results clearly demonstrate that MCP-1 induces differential activation of NF-κB and AP-1 in VSMCs. Thus, our data propose a new mechanism for the proatherogenic effect of MCP-1.
Tranilast Prevents Activation of Transforming Growth Factor-β System, Leukocyte Accumulation, and Neointimal Growth in Porcine Coronary Arteries After Stenting
Authors: Ward Michael R. , Agrotis Alex , Kanellakis Peter , Hall John , Jennings Garry , Bobik Alex
Published: July 2002

N
(3,4-Dimethoxycinnamoyl) anthranilic acid (tranilast) prevents the synchronous upregulation of isoforms and receptors of the transforming growth factor (TGF)-β system after arterial injury and reduces restenosis after human coronary angioplasty. However, the effects of tranilast and the importance of the TGF-β system in stent restenosis, in which inward remodeling is unimportant but inflammatory cell stimulation of neointima formation is exaggerated, are uncertain. Boston minipigs, treated with tranilast or vehicle, were subjected to endoluminal stenting, and the expression of TGF-β
1
and TGF-β
3
, the expression of their signaling receptors ALK-5 and TβR-II, leukocyte numbers around the stent struts, and neointima development were assessed over 28 days. Stenting greatly increased early (5-day) mRNA expression of the 2 TGF-β isoforms and their receptors. Immunohistochemical localization later showed that their concentrations were greatest in regions adjacent to stent struts, where leukocytes and collagen deposition were prevalent. Tranilast suppressed these elevations in TGF-β mRNAs and reduced their immunoreactive peptides detectable around stent struts. The accumulation of leukocytes and deposition of collagen in these regions was also greatly inhibited by tranilast. These effects were associated with a 48% reduction in maximal neointimal cross-sectional area and 43% reduction in mean neointimal cross-sectional area at 28 days (
P
<0.05). We conclude that tranilast suppresses neointima development after stenting, effects that can be at least partly attributed to its ability to attenuate the induction of the TGF-β system and leukocyte accumulation around stent struts.
Antithrombotic Effect of Tissue Factor Inhibition by Inactivated Factor VIIa
Authors: Lev Eli I. , Marmur Jonathan D. , Zdravkovic Milan , Osende Julio I. , Robbins Jonathan , Delfin Jenny A. , Richard Merwin , Erhardtsen Elisabeth , Thomsen Mikael S. , Lincoff A. Michael , Badimon Juan J.
Published: July 2002

FFR-rFVIIa is an inactivated recombinant factor VIIa (rFVIIa) that inhibits the binding of factor VIIa to tissue factor (TF). It has been shown to prevent TF-induced thrombosis in animals. The present study is a substudy of the Active Site Inhibited Seven (ASIS) trial and examines the antithrombotic effect of 3 doses of FFR-rFVIIa in 24 patients undergoing percutaneous coronary intervention (PCI). Group 1 (n=9) received 400 μg/kg FFR-rFVIIa and 40 to 50 U/kg heparin, group 2 (n=7) received 200 μg/kg FFR-rFVIIa and 100 U/kg heparin, and group 3 (n=8) received 50 μg/kg FFR-rFVIIa and 100 U/kg heparin. Blood thrombogenicity was assessed as total thrombus area and fibrin deposition on the perfusion chamber at shear rate conditions typical of mild-moderate coronary stenosis. Baseline blood thrombogenicity was evaluated a day before PCI, after heparin administration. A second perfusion chamber study was performed just before PCI, 15 minutes after the administration of heparin and FFR-rFVIIa. Thrombus formation at a high shear rate was markedly reduced in groups 1 and 2 after drug administration, by 79% to 84% and 76% to 87%, respectively (
P
<0.004 [group 1],
P
<0.04 [group 2]). In group 3, moderate thrombus reduction of 46% to 48% was achieved (
P
<0.04). Fibrin deposition in all 3 groups was nearly eliminated after drug administration. Our data demonstrate that FFR-rFVIIa has a potent antithrombotic effect at different shear rates and severe arterial injury conditions.
Elevated Fibrinogen and Homocysteine Levels Enhance the Risk of Mortality in Patients From a High-Risk Preventive Cardiology Clinic
Authors: Acevedo Monica , Pearce Gregory L. , Kottke-Marchant Kandice , Sprecher Dennis L.
Published: July 2002

Fibrinogen (Fib) plays an important role in platelet aggregation and thrombus formation, and homocysteine (tHcy) causes endothelial dysfunction and injury. Therefore, an interaction toward an enhanced risk of thrombotic events and consequent mortality might be expected in patients with both factors elevated. To determine whether patients exposed jointly to high Fib and high tHcy were at increased risk of mortality, we compared them with those with only one or neither risk factors elevated. Prevalence of coronary artery disease (cross-section) and short-term mortality (30±14 months) were assessed in 2084 patients with available baseline tHcy and Fib. Upper quartiles were used to define high tHcy (>14.2 μmol/L) and high Fib (>382 mg/dL). Cox models adjusting for Framingham risk score, creatinine, and coronary artery disease status were used to estimate the risk of high tHcy and high Fib and their combinations. Mean age of the patients was 56±12 years (35% women) with 71 (3.4%) recorded deaths. Risk-adjusted longitudinal models showed a hazard ratio of 2.14 (
P
=0.03) for isolated high tHcy, 2.28 (
P
=0.02) for isolated high Fib, and 3.29 (
P
<0.001) for both high tHcy and high Fib in comparison with neither risk factor high. Independence of each parameter and lack of synergism was found on longitudinal as well as cross-sectional analyses. Conjoint elevation of Fib and tHcy increased the risk of death by approximately 3-fold in three years. Although no significant interaction between Fib and tHcy was demonstrated, both provided independent information after adjustment for traditional risk factors.
Chronic Exercise Improves Endothelial Calcium Signaling and Vasodilatation in Hypercholesterolemic Rabbit Femoral Artery
Authors: Jen Chauying J. , Chan Hung-Pin , Chen Hsiun-ing
Published: July 2002

Objective

—

This study was to investigate the effects of chronic exercise on vasodilatation and endothelial intracellular calcium (EC [Ca
2+
]
i
) signaling in atherosclerotic animals.

Methods and Results

—

For 8 weeks, male New Zealand White rabbits were fed rabbit chow with or without the addition of 2% cholesterol. They were further divided into control and exercise groups. Animals in the exercise groups ran on a leveled treadmill at 0.88 km/h for 10 to 60 minutes gradually for 5 days per week for a total of 8 weeks. At the end of experiments, femoral arteries were dissected, loaded with fura 2-AM, and mounted in a tissue flow chamber. PE-precontracted vessel specimens were exposed to acetylcholine (ACh). The EC [Ca
2+
]
i
elevation and vasorelaxation were determined simultaneously under an epifluorescence microscope equipped with a ratio-imaging capability. Our results showed the following: (1) high cholesterol diet feeding caused lipid deposition on vascular surface, reduced the ACh-evoked EC [Ca
2+
]
i
elevation, and impaired endothelium-dependent and endothelium-independent vascular responses, but chronic exercise had the opposite effects; (2) ACh-induced vasorelaxation was associated with EC [Ca
2+
]
i
elevation in all groups; and (3) vasorelaxation at high levels of EC [Ca
2+
]
i
elevation decreased in hypercholesterolemia.

Conclusions

—

Our data suggest that hypercholesterolemia induces vascular structural changes and impairs EC [Ca
2+
]
i
signaling and vasodilatation, whereas chronic exercise partially reverses these adverse effects.
Value of HDL Cholesterol, Apolipoprotein A-I, Lipoprotein A-I, and Lipoprotein A-I/A-II in Prediction of Coronary Heart Disease
Authors: Luc Gérald , Bard Jean-Marie , Ferrières Jean , Evans Alun , Amouyel Philippe , Arveiler Dominique , Fruchart Jean-Charles , Ducimetière Pierre
Published: July 2002

Objective

—

We have examined the association between the incidence of coronary heart disease (CHD) and plasma high density lipoprotein (HDL) cholesterol, apolipoprotein A-I (apoA-I), and 2 HDL fractions, lipoprotein A-I and lipoprotein A-I:A-II.

Methods and Results

—

These parameters were measured in subjects recruited in France and in Northern Ireland in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a prospective cohort study. Among the subjects free of CHD on entry, 176 in France and 113 in Northern Ireland suffered an ischemic attack (CHD patients) during the 5-year follow-up, whereas 6612 French and 2172 Northern Irish men showed no CHD symptoms (CHD-free subjects). All 4 HDL parameter levels were lower in CHD patients than in CHD-free subjects. After the cohort was divided into quintiles based on the distribution of HDL parameter levels, a significant (
P
<0.0001) linear increase in relative risk was observed for each HDL parameter level. However, regression logistic analyses showed that apoA-I was the strongest predictor (more powerful than HDL cholesterol) and that lipoprotein A-I and lipoprotein A-I:A-II did not supplement apoA-I in predicting CHD.

Conclusions

—

Among the parameters related to HDL, apoA-I appears to be the strongest independent risk factor.
Switching off Embolization From Symptomatic Carotid Plaque Using
S
-Nitrosoglutathione
Authors: Kaposzta Zoltan , Martin John F. , Markus Hugh S.
Published: July 2002

Background

—

Current antiplatelet regimens fail to prevent the majority of recurrent strokes. Asymptomatic circulating emboli can be detected by transcranial Doppler ultrasound, are frequent in patients with symptomatic carotid stenosis, and predict recurrent stroke risk.
S
-Nitrosoglutathione (GSNO) is a nitric oxide donor that appears to have relative platelet specificity. We evaluated its effectiveness in reducing embolization in patients with symptomatic carotid stenosis who already were taking aspirin.

Methods and Results

—

Twenty patients with ≥50% internal carotid artery stenosis and with ≥3 embolic signals detected during a half-hour screening recording were recruited. All had taken aspirin for at least 7 days. They were randomly assigned in a double-blind fashion to either GSNO (4.4 mmol/kg per minute) or saline placebo for 90 minutes. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after treatment. Before treatment, the mean (range) of embolic signals per hour was 6.9 (3 to 13) in the GSNO group and 7.3 (4 to 12) in the placebo group (
P
=0.68). GSNO resulted in a rapid reduction in the frequency of embolic signals of 84% at 0 to 3 hours, 95% at 6 hours, and 100% at 24 hours (
P
<0.0001,
P
=0.003, and
P
<0.0001 versus placebo, respectively).

Conclusions

—

Continued embolization is common in patients with carotid stenosis despite aspirin therapy. GSNO was highly effective in rapidly reducing the frequency of embolic signals in this patient group. Despite its short administration time and its short half-life, it resulted in therapeutic effects lasting 24 hours.
New Bayesian Discriminator for Detection of Atrial Tachyarrhythmias
Authors: Xu Weichao , Tse Hung-Fat , Chan Francis H.Y. , Fung Peter Chin Wan , Lee Kathy Lai-Fun , Lau Chu-Pak
Published: July 2002

Background—

Accurate, rapid detection of atrial tachyarrhythmias has important implications in the use of implantable devices for treatment of cardiac arrhythmia. Currently available detection algorithms for atrial tachyarrhythmias, which use the single-index method, have limited sensitivity and specificity.

Methods and Results—

In this study, we evaluated the performance of a new Bayesian discriminator algorithm in the detection of atrial fibrillation (AF), atrial flutter (AFL), and sinus rhythm (SR). Bipolar recording of 364 rhythms (AF=156, AFL=88, SR=120) at the high right atrium were collected from 20 patients who underwent electrophysiological procedures. After initial signal processing, a column vector of 5 features for each rhythm were established, based on the regularity, rate, energy distribution, percent time of quiet interval, and baseline reaching of the rectified autocorrelation coefficient functions. Rhythm identification was obtained by use of Bayes decision rule and assumption of Gaussian distribution. For the new Bayesian discriminator, the overall sensitivity for detection of SR, AF, and AFL was 97%, 97%, and 94%, respectively; and the overall specificity for detection of SR, AF, and AFL was 98%, 98%, and 99%, respectively. The overall accuracy of detection of SR, AF, and AFL was 98%, 97% and 98%, respectively. Furthermore, sensitivity, specificity, and accuracy of this algorithm were not affected by a range of white Gaussian noises with different intensities.

Conclusions—

This new Bayesian discriminator algorithm, based on Bayes decision of multiple features of atrial electrograms, allows rapid on-line and accurate (98%) detection of AF with robust anti-noise performance.
Withdrawal of Statins Increases Event Rates in Patients With Acute Coronary Syndromes
Authors: Heeschen Christopher , Hamm Christian W. , Laufs Ulrich , Snapinn Steven , Böhm Michael , White Harvey D.
Published: July 2002

Background

—

HMG-CoA Reductase Inhibitors (statins) reduce cardiac event rates in patients with stable coronary heart disease. Withdrawal of chronic statin treatment during acute coronary syndromes may impair vascular function independent of lipid-lowering effects and thus increase cardiac event rate.

Methods and Results

—

We investigated the effects of statins on the cardiac event rate in 1616 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study who had coronary artery disease and chest pain in the previous 24 hours. We recorded death and nonfatal myocardial infarction during the 30-day follow-up. Baseline clinical characteristics did not differ among 1249 patients without statin therapy, 379 patients with continued statin therapy, and 86 patients with discontinued statin therapy after hospitalization. Statin therapy was associated with a reduced event rate at 30-day follow-up compared with patients without statins (adjusted hazard ratio, 0.49 [95% CI, 0.21 to 0.86];
P
=0.004). If the statin therapy was withdrawn after admission, cardiac risk increased compared with patients who continued to receive statins (2.93 [95% CI, 1.64 to 6.27];
P
=0.005) and tended to be higher compared with patients who never received statins (1.69 [95% CI, 0.92 to 3.56];
P
=0.15). This was related to an increased event rate during the first week after onset of symptoms and was independent of cholesterol levels. In a multivariate model, troponin T elevation (
P
=0.005), ST changes (
P
=0.02), and continuation of statin therapy (
P
=0.008) were the only independent predictors of patient outcome.

Conclusions

—

Statin pretreatment in patients with acute coronary syndromes is associated with improved clinical outcome. However, discontinuation of statins after onset of symptoms completely abrogates this beneficial effect.
Fragment Reconstruction of Coronary Arteries by Transesophageal Echocardiography
Authors: Wild Philipp S. , Zotz Rainer J.
Published: July 2002

Background—

If transesophageal echocardiography (TEE) is to play a role in coronary diagnostics, satisfactory image documentation of the coronary status is indispensable so that the requirements for validity and quality assurance of a medical examination can be met. Our goal was to develop a suitable and valid procedure for imaging coronary arteries with 2D TEE.

Methods and Results

mdash;

After pilot trials and formulation of requirements, a new method of imaging coronary arteries was designed, supported by theoretical and mathematical principles: FRC-TEE, or fragment reconstruction of coronary arteries by means of 2D TEE. The method generates images of successive vessel fragments so that reconstruction in a summation picture is possible. The procedure orients itself to the vessel and ensures proof of identity by permanently following it on the screen. FRC-TEE was evaluated in 12 consecutive patients with an indication for TEE. One hundred percent visualization in proximal, middle, and distal segments was achieved. The total lengths visualized were 10.74±2.56 cm for the right and 8.67±1.12 cm for the left coronary artery. Stents and stenoses within the vessels were identified convincingly. Because of a technical problem, investigation of the left anterior descending artery was initially avoided. In a pilot trial series (n=12), 6.65±0.92 cm of this vessel was imaged.

Conclusions

—

FRC-TEE is a newly developed method of visualizing coronary arteries by means of ultrasound, which permits good pictorial documentation. Initial studies have achieved promising results. Representation of the length of coronary arteries with ultrasound was considerably improved with this technique.
Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus
Authors: Guzik Tomasz J. , Mussa Shafi , Gastaldi Daniela , Sadowski Jerzy , Ratnatunga Chandi , Pillai Ravi , Channon Keith M.
Published: July 2002

Background

—

Increased superoxide production contributes to reduced vascular nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of diabetes. We characterized the sources and mechanisms underlying vascular superoxide production in human blood vessels from diabetic patients with coronary artery disease compared with nondiabetic patients.

Methods and Results

—

Vascular superoxide production was quantified in both saphenous veins and internal mammary arteries from 45 diabetic and 45 matched nondiabetic patients undergoing coronary artery bypass surgery. NAD(P)H-dependent oxidases were important sources of vascular superoxide in both diabetic and nondiabetic patients, but both the activity of this enzyme system and the levels of NAD(P)H oxidase protein subunits (p22phox, p67phox, and p47phox) were significantly increased in diabetic veins and arteries. In nondiabetic vessels, endothelial NO synthase produced NO that scavenged superoxide. However, in diabetic vessels, the endothelium was an additional net source of superoxide production because of dysfunctional endothelial NO synthase that was corrected by intracellular tetrahydrobiopterin supplementation. Furthermore, increased superoxide production in diabetes was abrogated by the protein kinase C inhibitor chelerythrine.

Conclusions

—

These observations suggest important roles for NAD(P)H oxidases, endothelial NO synthase uncoupling, and protein kinase C signaling in mediating increased vascular superoxide production and endothelial dysfunction in human diabetes mellitus.
Cardiovascular Influences of α
1b
-Adrenergic Receptor Defect in Mice
Authors: Vecchione Carmine , Fratta Luigi , Rizzoni Damiano , Notte Antonella , Poulet Roberta , Porteri Enzo , Frati Giacomo , Guelfi Daniele , Trimarco Valentina , Mulvany Michael J. , Agabiti-Rosei Enrico , Trimarco Bruno , Cotecchia Susanna , Lembo Giuseppe
Published: July 2002

Background—

The α
1
-adrenergic receptors (α
1
-ARs) play a key role in cardiovascular homeostasis. However, the functional role of α
1
-AR subtypes in vivo is still unclear. The aim of this study was to evaluate the cardiovascular influences of α
1b
-AR.

Methods and Results—

In transgenic mice lacking α
1
-AR (KO) and their wild-type controls (WT), we evaluated blood pressure profile and cardiovascular remodeling induced by the chronic administration (18 days via osmotic pumps) of norepinephrine, angiotensin II, and subpressor doses of phenylephrine. Our results indicate that norepinephrine induced an increase in blood pressure levels only in WT mice. In contrast, the hypertensive state induced by angiotensin II was comparable between WT and KO mice. Phenylephrine did not modify blood pressure levels in either WT or KO mice. The cardiac hypertrophy and eutrophic vascular remodeling evoked by norepinephrine was observed only in WT mice, and this effect was independent of the hypertensive state because it was similar to that observed during subpressor phenylephrine infusion. Finally, the cardiac hypertrophy induced by thoracic aortic constriction was comparable between WT and KO mice.

Conclusions—

Our data demonstrate that the lack of α
1b
-AR protects from the chronic increase of arterial blood pressure induced by norepinephrine and concomitantly prevents cardiovascular remodeling evoked by adrenergic activation independently of blood pressure levels.
Vessel Imaging by Interferometric Phase-Contrast X-Ray Technique
Authors: Takeda Tohoru , Momose Atsushi , Wu Jin , Yu Quanwen , Zeniya Tsutomu , Lwin Thet-Thet- , Yoneyama Akio , Itai Yuji
Published: July 2002

Background—

Phase-contrast x-ray imaging using an x-ray interferometer has great potential to reveal the structures inside soft tissues, because the sensitivity of this method to hydrogen, carbon, nitrogen, and oxygen is ≈1000 times higher than that of the absorption-contrast x-ray method. Imaging of vessels is very important to understand the vascular distribution of organs and tumors, so the possibility of selective angiography based on phase contrast is examined with a physiological material composed of low-atomic-number elements.

Methods and Results—

Phase-contrast x-ray imaging was performed with a synchrotron x-ray source. Differences in refractive index, dδ, of physiological saline, lactated Ringer’s solution, 5% glucose, artificial blood such as pyridoxylated hemoglobin–polyoxyethylene conjugate, and perfluorotributylamine were measured. Because the dδ of physiological saline has highest contrast, it was used for the phase-contrast x-ray imaging of vessel, and this was compared with absorption-contrast x-ray images. Vessels >0.03 mm in diameter of excised liver from rats and a rabbit were revealed clearly in phase-contrast x-ray imaging, whereas the vessel could not be revealed at all by the absorption-contrast x-ray image. Absorption-contrast x-ray images with iodine microspheres depicted only portal veins >0.1 mm in diameter with nearly the same x-ray dose as the present phase-contrast x-ray imaging.

Conclusions—

Phase-contrast x-ray imaging explored clear depiction of the vessels using physiological saline with small doses of x-rays.
Strain Rate Imaging for Assessment of Regional Myocardial Function
Authors: Abraham Theodore P. , Nishimura Rick A. , Holmes David R. , Belohlavek Marek , Seward James B.
Published: July 2002

Background

—

Regional myocardial function assessment is essential in the management of coronary artery disease (CAD). Tissue Doppler imaging (TDI) by depicting local myocardial motion can potentially quantify regional myocardial function. Strain rate imaging (SRI) that depicts regional deformation is less susceptible to cardiac translation and tethering and may be superior to TDI for regional function analysis. We examined regional myocardial function using TDI and SRI in a unique clinical model of a small, discrete myocardial infarction.

Method and Results

—

Ten patients with severely symptomatic septal hypertrophy underwent basal septal ablation via intracoronary alcohol injection and had TDI and SRI pre- and postablation. Invasive hemodynamics showed no appreciable change in global function. Peak systolic strain rate was significantly lower postablation versus preablation (−0.5 versus −1.2 s
−1
,
P
<0.001) and when comparing infarct and noninfarct areas (−0.5 versus −1.5 s
−1
,
P
<0.001). In contrast, peak systolic tissue velocities were similar pre- and postablation (3.9 versus 2.9 cm/s,
P
=0.16) and between infarct and noninfarct areas (2.9 versus 2.2 cm/s,
P
=0.13). SRI analysis demonstrated reduced systolic function in the peri-infarct zone and preserved systolic function in the remote nonischemic zone.

Conclusion

—

In the clinical setting of a small, discrete infarct unaccompanied by changes in global function, SRI accurately depicted changes in regional function. These data suggest that SRI may be the optimal method for objective, quantitative assessment of regional myocardial dysfunction.
Endothelial Healing in Vein Grafts
Authors: Ehsan Afshin , Mann Michael J. , Dell’Acqua Giorgio , Tamura Koichi , Braun-Dullaeus Ruediger , Dzau Victor J.
Published: July 2002

Background—

Although inhibition of neointimal hyperplasia by cell cycle gene blockade therapy results in improved endothelial cell function in experimental vein grafts, little is known either about endothelial healing immediately after vein grafting or about the effect of this therapy on the healing process.

Methods and Results—

Scanning electron microscopy demonstrated an immediate decrease in vein graft endothelial cell density associated with vein graft wall stretch, followed by a return to baseline by postoperative day 3. En face detection of bromodeoxyuridine incorporation confirmed a rapid endothelial proliferation by 48 hours. Despite inhibition of underlying vascular smooth muscle cell proliferation, E2F decoy oligonucleotide did not inhibit either endothelial bromodeoxyuridine incorporation or the return to baseline cell density. This differential response to E2F decoy was also observed in human umbilical vein endothelial cell culture, which resisted the E2F decoy inhibition of cell growth that was observed in human umbilical artery smooth muscle cells, despite evidence for nuclear localized delivery of the oligonucleotide into both cell types. Furthermore, the reduction of E2F binding activity seen in a nuclear gel shift assay of cultured smooth muscle cells was not observed in endothelial cells.

Conclusions—

These results suggest a burst of graft endothelial cell proliferation that allows a rapid restoration of cell density in the monolayer. Additionally, there is a selective effect of E2F decoy gene therapy on target smooth muscle cells with sparing of this endothelial healing.
Endothelial Cell Senescence in Human Atherosclerosis
Authors: Minamino Tohru , Miyauchi Hideaki , Yoshida Toshihiko , Ishida Yasuo , Yoshida Hideo , Komuro Issei
Published: July 2002

Background

—

The functional changes associated with cellular senescence may be involved in human aging and age-related vascular disorders. We have shown the important role of telomere and telomerase in vascular cell senescence in vitro. Progressive telomere shortening in vivo has been observed in the regions susceptible to atherosclerosis, implying contributions to atherogenesis. However, whether senescent vascular cells are present in the vasculature and contribute to the pathogenesis of atherosclerosis remains unclear.

Methods and Results

—

Senescence-associated β-galactosidase (β-gal) activity was examined in the coronary arteries and the internal mammary arteries retrieved from autopsied individuals who had had ischemic heart diseases. Strong β-gal stainings were observed in atherosclerotic lesions of the coronary arteries but not in the internal mammary arteries. An immunohistochemical analysis using anti-factor VIII antibody demonstrated that β-gal stained cells are vascular endothelial cells. To determine whether endothelial cell senescence causes endothelial dysfunction, we induced senescence in human aortic endothelial cells (HAECs) by inhibiting telomere function and examined the expression of intercellular adhesion molecule (ICAM)-1 and endothelial nitric oxide synthase (eNOS) activity. Senescent HAECs exhibited increased ICAM-1 expression and decreased eNOS activity, both of which are alterations implicated in atherogenesis. In contrast, introduction of telomerase catalytic component significantly extended the life span and inhibited the functional alterations associated with senescence in HAECs.

Conclusions

—

Vascular endothelial cells with senescence-associated phenotypes are present in human atherosclerotic lesions, and endothelial cell senescence induced by telomere shortening may contribute to atherogenesis.
Inhalation of Fine Particulate Air Pollution and Ozone Causes Acute Arterial Vasoconstriction in Healthy Adults
Authors: Brook Robert D. , Brook Jeffrey R. , Urch Bruce , Vincent Renaud , Rajagopalan Sanjay , Silverman Frances
Published: July 2002

Background

—

Fine particulate air pollution and ozone are associated with increased cardiovascular events. To help explain the mechanism behind these observations, we investigated the effect of air pollution exposure on vascular function.

Methods and Results

—

Twenty-five healthy adults underwent a randomized, double-blind, crossover study comparing the vascular response to the 2-hour inhalation of ≈150 μg/m
3
of concentrated ambient fine particles (CAP) plus ozone (120 ppb) versus the response to the inhalation of filtered air. High-resolution vascular ultrasonography was used to measure alterations in brachial artery diameter, endothelial-dependent flow-mediated dilatation (FMD) and endothelial-independent nitroglycerin-mediated dilatation (NMD). Exposure to CAP plus ozone caused a significant brachial artery vasoconstriction compared with filtered air inhalation (−0.09±0.15 mm versus +0.01±0.18 mm,
P
=0.03). There were no significant differences in FMD (+0.29±4.11% versus −0.03±6.63%,
P
=0.88), NMD (+3.87±5.43% versus +3.46±7.92%,
P
=0.83), or blood pressure responses between exposures.

Conclusions

—

Short-term inhalation of fine particulate air pollution and ozone at concentrations that occur in the urban environment causes acute conduit artery vasoconstriction.
Angiotensin-(1–7) Attenuates the Development of Heart Failure After Myocardial Infarction in Rats
Authors: Loot Annemarieke E. , Roks Anton J.M. , Henning Robert H. , Tio René A. , Suurmeijer Albert J.H. , Boomsma Frans , van Gilst Wiek H.
Published: July 2002

Background

—

The renin-angiotensin system (RAS) is a key player in the progression of heart failure. Angiotensin-(1–7) is thought to modulate the activity of the RAS. Furthermore, this peptide may play a part in the beneficial effects of angiotensin-converting enzyme inhibitors in cardiovascular disease. We assessed the effects of angiotensin-(1–7) on the progression of heart failure.

Methods and Results

—

Male Sprague-Dawley rats underwent either coronary ligation or sham surgery. Two weeks after induction of myocardial infarction, intravenous infusion of angiotensin-(1–7) (24 μg/kg per hour) or saline was started by minipump. After 8 weeks of treatment, hemodynamic parameters were measured, endothelial function was assessed in isolated aortic rings, and plasma angiotensin-(1–7) levels were determined. Myocardial infarction resulted in a significant deterioration of left ventricular systolic and diastolic pressure, dP/dt, and coronary flow. Raising plasma levels 40-fold, angiotensin-(1–7) infusion attenuated this impairment to a nonsignificant level, markedly illustrated by a 40% reduction in left ventricular end-diastolic pressure. Furthermore, angiotensin-(1–7) completely preserved aortic endothelial function, whereas endothelium-dependent relaxation in aortas of saline-treated infarcted rats was significantly decreased.

Conclusions

—

Angiotensin-(1–7) preserved cardiac function, coronary perfusion, and aortic endothelial function in a rat model for heart failure.