bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of Functional Bradykinin B
1
-Receptors in Normotensive Rats and Mice Under Chronic Angiotensin-Converting Enzyme Inhibitor Treatment
Authors: Marin-Castaño Maria E. , Schanstra Joost P. , Neau Eric , Praddaude Françoise , Pecher Christiane , Ader Jean-Louis , Girolami Jean-Pierre , Bascands Jean-Loup
Published: July 2002

Background

—

The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B
1
- and B
2
-receptor expression, which are the molecular entities responsible for the biological effects of kinins.

Methods and Results

—

Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT
1
-receptor antagonist, and B
1
- and B
2
-receptor antagonists. Chronic ACE inhibition induced both renal and vascular B
1
-receptor expression, whereas B
2
-receptor expression was not modified. Furthermore, with B
1
-receptor antagonists, it was shown that B
1
-receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor–induced expression of functional B
1
-receptors in all segments. ACE-inhibitor–induced B
1
-receptor induction involved homologous upregulation, because it was prevented by B
1
-receptor antagonist treatment. Finally, using B
2
-receptor knockout mice, we showed that ACE-inhibitor–induced B
1
-receptor expression was B
2
-receptor independent.

Conclusions

—

This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B
1
-receptor induction, which is involved in ACE-inhibitor–induced hypotension. The observed B
1
-receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.
Cost-Effectiveness of a Conservative, Ischemia-Guided Management Strategy After Non–Q-Wave Myocardial Infarction
Authors: Barnett Paul G. , Chen Shuo , Boden William E. , Chow Bruce , Every Nathan R. , Lavori Philip W. , Hlatky Mark A.
Published: July 2002

Background

—

Use of coronary angiography after myocardial infarction has been controversial, with some physicians advocating routine use and others advocating selective use only after documentation of residual myocardial ischemia. The effects of these strategies on economic outcomes have not been established.

Methods and Results

—

We analyzed data from a randomized, controlled clinical trial conducted in 17 Department of Veterans Affairs hospitals that enrolled 876 clinically uncomplicated patients 24 to 72 hours after an acute non–Q-wave myocardial infarction. The routine invasive strategy included early coronary angiography with revascularization based on established guidelines. The conservative, ischemia-guided strategy included noninvasive testing with radionuclide ventriculography and exercise thallium scintigraphy, followed by coronary angiography in patients with objective evidence of myocardial ischemia. We measured the cost of hospitalization and outpatient visits and tests during follow-up and calculated the incremental cost-effectiveness ratio. The conservative, ischemia-guided strategy had lower costs than the routine invasive strategy, both during the initial hospitalization ($14 733 versus $19 256,
P
<0.001) and after a mean follow-up of 1.9 years ($39 707 versus $41 893,
P
=0.04). The hazard ratio for death was 0.72 (confidence limits, 0.51 to 1.01) in the conservative strategy. The conservative strategy had lower costs and better outcomes in 76% of 1000 bootstrap replications, and a cost-effectiveness ratio below $50 000 per year of life added in 96% of replications.

Conclusions

—

A conservative, ischemia-guided strategy of selective coronary angiography and revascularization for patients who develop objective evidence of recurrent ischemia is more cost-effective than a strategy of routine coronary angiography after uncomplicated non–Q-wave myocardial infarction.
Calmodulin Inhibitor W-7 Unmasks a Novel Electrocardiographic Parameter That Predicts Initiation of Torsade de Pointes
Authors: Gbadebo T. David , Trimble Robert W. , Khoo Michelle S.C. , Temple Joel , Roden Dan M. , Anderson Mark E.
Published: July 2002

Background

—

We have shown that the calmodulin inhibitor W-7 suppresses torsade de pointes (TdP) without shortening the QT interval, which is consistent with other findings that QT prolongation, per se, is insufficient to generate TdP. ECGs were analyzed from a well-characterized animal model of TdP to identify more reliable predictors of this life-threatening ventricular arrhythmia.

Methods and Results

—

TdP was induced using methoxamine and clofilium in 12 of 14 rabbits pretreated with vehicle control, whereas pretreatment with W-7 (50 μmol/kg), an inhibitor of the intracellular Ca
2+
-binding protein calmodulin, significantly suppressed TdP induction (1 of 11 rabbits with TdP,
P
<0.001). W-7 did not affect heart rate, increases in QT intervals, or dispersion compared with measurements in vehicle-treated control animals. However, a progressive and significant increase in the ratio of U-wave to T-wave amplitude (UTA) occurred before TdP onset in control animals, and this was prevented by W-7.

Conclusions

—

Selective suppression of TdP inducibility by W-7, without shortening the duration of cardiac repolarization, allowed identification of the UTA ratio as a new electrocardiographic index for predicting TdP onset. These findings are consistent with the idea that prolonged repolarization is not the proximate cause of arrhythmia initiation, and they suggest that an increased UTA ratio reflects activation of intracellular Ca
2+
/calmodulin–dependent processes that are required for triggering TdP in this model.
Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2
Authors: Simons Michael , Annex Brian H. , Laham Roger J. , Kleiman Neal , Henry Timothy , Dauerman Harold , Udelson James E. , Gervino Ernesto V. , Pike Marilyn , Whitehouse M.J. , Moon Thomas , Chronos Nicolas A.
Published: July 2002

Background—

Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2).

Methods and Results—

FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 μg/kg (n=337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall
P
=0.035) and the physical component summary scale of the Short-Form 36 (pairwise
P
=0.033, all FGF groups versus placebo). These differences were more pronounced in highly symptomatic patients (baseline angina frequency score ≤40 or Canadian Cardiovascular Society score of III or IV). None of the differences were significant at 180 days because of continued improvement in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the 30-μg/kg rFGF2 group.

Conclusions—

A single intracoronary infusion of rFGF2 does not improve exercise tolerance or myocardial perfusion but does show trends toward symptomatic improvement at 90 (but not 180) days.
Analysis of T-Wave Morphology From the 12-Lead Electrocardiogram for Prediction of Long-Term Prognosis in Male US Veterans
Authors: Zabel Markus , Malik Marek , Hnatkova Katerina , Papademetriou Vasilios , Pittaras Andreas , Fletcher Ross D. , Franz Michael R.
Published: July 2002

Background
—

The aim of the present study was to assess the prognostic value of novel repolarization descriptors from the 12-lead ECG in a large cohort of US veterans.

Methods and Results
—

Male US veterans (n=813) with cardiovascular disease had digital 12-lead ECGs recorded at the VA Medical Center, Washington, DC, between 1984 and 1991. The patient series was retrospectively compiled in 1991; follow-up was prospectively assessed until 2000. Novel ECG variables characterizing repolarization and the T-wave loop were automatically analyzed. Of 772 patients with technically analyzable data, 252 patients (32.6%) died after a mean follow-up of 10.4±3.8 years. Direct comparison between dead and alive patients showed that the so-called T-wave residua (the absolute and relative amount of nondipolar contents within the T wave) predicted mortality (111 900±164 700 versus 85 600±144 800 between dead and alive patients,
P
<0.0002; and 0.43±0.62% versus 0.33±0.56%,
P
<0.0005 for the absolute and relative T-wave residuum, respectively). On Cox regression analysis entering age, left ventricular ejection fraction, echocardiographic left ventricular hypertrophy, and either of the T-wave residua, risk prediction was independent for the absolute (
P
=0.022) and for the relative (
P
=0.006) T-wave residuum, respectively, with age (
P
<0.0001), presence of left ventricular hypertrophy (
P
=0.002), and left ventricular ejection fraction (
P
=0.004) also being predictors of survival.

Conclusions
—

The heterogeneity of myocardial repolarization, measured by the so-called T-wave residuum in the ECG, confers long-term independent prognostic information in US veterans with cardiovascular disease.
Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Inhibition of Cardiac Hypertrophy In Vitro and In Vivo
Authors: Asakawa Masayuki , Takano Hiroyuki , Nagai Toshio , Uozumi Hiroki , Hasegawa Hiroshi , Kubota Naoto , Saito Toshihiro , Masuda Yoshiaki , Kadowaki Takashi , Komuro Issei
Published: July 2002

Background

—

Peroxisome proliferator-activated receptors (PPARs) are transcription factors of the nuclear receptor superfamily. It has been reported that the thiazolidinediones, which are antidiabetic agents and high-affinity ligands for PPARγ, regulate growth of vascular cells. In the present study, we examined the role of PPARγ in angiotensin II (Ang II)-induced hypertrophy of neonatal rat cardiac myocytes and in pressure overload-induced cardiac hypertrophy of mice.

Methods and Results

—

Treatment of cultured cardiac myocytes with PPARγ ligands such as troglitazone, pioglitazone, and rosiglitazone inhibited Ang II-induced upregulation of skeletal α-actin and atrial natriuretic peptide genes and an increase in cell surface area. Treatment of mice with a PPARγ ligand, pioglitazone, inhibited pressure overload-induced increases in the heart weight-to-body weight ratio, wall thickness, and myocyte diameter in wild-type mice and an increase in the heart weight-to-body weight ratio in heterozygous PPARγ-deficient mice. In contrast, pressure overload-induced increases in the heart weight-to-body weight ratio and wall thickness were more prominent in heterozygous PPARγ-deficient mice than in wild-type mice.

Conclusions

—

These results suggest that the PPARγ-dependent pathway is critically involved in the inhibition of cardiac hypertrophy.
Effect of Azithromycin Treatment on Endothelial Function in Patients With Coronary Artery Disease and Evidence of

Chlamydia pneumoniae

Infection
Authors: Parchure Nikhil , Zouridakis Emmanouil G. , Kaski Juan Carlos
Published: July 2002

Background

—

It has been suggested that infection with
Chlamydia pneumoniae
(
CPn
) can trigger inflammatory mechanisms that may in turn impair vascular endothelial function. The aim of the present study was to assess whether treatment with the macrolide antibiotic azithromycin improves endothelial function in patients with coronary artery disease and antibodies positive to
CPn.

Methods and Results

—

We carried out a randomized, prospective, double-blind, placebo-controlled trial in 40 male patients (mean age, 55±9 years) with documented coronary artery disease and positive
CPn
-IgG antibody titers. After baseline evaluation, patients were randomized to receive either azithromycin or placebo for 5 weeks. Flow-mediated dilation (FMD) of the brachial artery and E-selectin, von Willebrand factor, and C-reactive protein (CRP) levels were assessed at study entry and at the end of the treatment period. Our results showed that patients who received azithromycin had a significant improvement in FMD (mean change, 2.1±1.1%;
P
<0.005). In contrast, FMD was not significantly changed in the placebo group (mean change, −0.02±0.2%,
P
=0.64). Azithromycin therapy also resulted in a significant decrease of E-selectin and von Willebrand factor levels. CRP levels were not significantly altered by treatment with either azithromycin or placebo. Beneficial effects of azithromycin treatment were independent from the presence of low (<1:32) or high (≥1:32)
CPn
antibody titers.

Conclusions

—

Our findings indicate that treatment with azithromycin has a favorable effect on endothelial function in patients with documented coronary artery disease and evidence of
CPn
infection irrespective of antibody titer levels. Whether these favorable actions of antibiotic treatment will translate into a beneficial effect on atherogenesis and cardiac events needs further investigation.
Mice Lacking Endothelial Angiotensin-Converting Enzyme Have a Normal Blood Pressure
Authors: Cole Justin , Quach Du Le , Sundaram Karthik , Corvol Pierre , Capecchi Mario R. , Bernstein Kenneth E.
Published: July 2002

To test the hypothesis that local vascular production of angiotensin II is necessary for the normal regulation of blood pressure, we engineered a new line of genetically altered mice that lack endothelial angiotensin-converting enzyme (ACE). This was accomplished using a novel strategy of targeted homologous recombination to separate the transcriptional control of somatic ACE from its endogenous promoter and to substitute control to the albumin promoter. These new mice, termed ACE.3, do not produce ACE within the lung, the aorta, or any vascular structure. ACE activity within the kidney is only about 14% that of wild-type mice and is limited to tubular epithelium. In contrast, hepatic ACE expression in ACE.3 mice is about 87-fold that of wild-type. The blood pressure, plasma angiotensin II levels, response to ACE inhibitors, and renal function of ACE.3
−/−
mice are indistinguishable from littermate wild-type mice. These data show that, under basal conditions, the normal regulation of blood pressure and renal function is possible in a mouse devoid of endothelial ACE.
Bone Marrow-Derived Endothelial Progenitor Cells Participate in Cerebral Neovascularization After Focal Cerebral Ischemia in the Adult Mouse
Authors: Zhang Zheng Gang , Zhang Li , Jiang Quan , Chopp Michael
Published: July 2002

We investigated whether circulating endothelial progenitor cells contribute to neovascularization after stroke. Donor bone marrow cells obtained from transgenic mice constitutively expressing β-galactosidase transcriptionally regulated by an endothelial-specific promoter, Tie2, were injected into adult mice. Focal cerebral ischemia was induced by embolic middle cerebral artery (MCA) occlusion and changes of cerebral blood flow (CBF) were measured by perfusion-weighted magnetic resonance imaging (MRI). Laser scanning confocal microscopy (LSCM), immunohistochemistry and X-gal staining were performed. Perfusion-weighted MRI demonstrated increases in CBF around the boundary of an infarct area 1 month after ischemia. Morphological and 3-dimensional image analyses revealed enlarged and thin-walled blood vessels with sprouting or intussusception at the boundary of the ischemic lesion, which closely corresponded to elevated CBF areas detected on perfusion-weighted MRI, indicating the presence of neovascularization. X-gal and double immunostaining demonstrated that Tie2-lacZ-positive cells incorporated into sites of neovascularization at the border of the infarct, and these cells exhibited an endothelial antigenic marker (von Willebrand factor). In addition, bone marrow recipient mice without ischemia showed incorporation of Tie2-lacZ-expressing cells into vessels of the choroid plexus. These data suggest that formation of new blood vessels in the adult brain after stroke is not restricted to angiogenesis but also involves vasculogenesis and that circulating endothelial progenitor cells from bone marrow contribute to the vascular substructure of the choroid plexus.
Increased Association of ZO-1 With Connexin43 During Remodeling of Cardiac Gap Junctions
Authors: Barker Ralph J. , Price Robert L. , Gourdie Robert G.
Published: July 2002

The intercellular geometry of connexin43 (Cx43) gap junctional coupling is key to coordinated spread of electrical activation through the ventricle of the mammalian heart. A progressive redistribution of electrical and mechanical junctions into intercalated discs occurs during postnatal development. Breakdown of disc-localized pattern in the adult heart, to recapitulate immature distributions, is thought to be key to the genesis of conduction disturbance and arrhythmia. Recently, ZO-1 (a PDZ-MAGUK protein), has been suggested to have a role in generating coupling geometries between myocytes. We therefore investigated the codistribution of ZO-1 with Cx43 and N-cadherin in the adult rat ventricle using quantitative immunoconfocal and immunoelectron microscopy. These analyses indicated that, whereas ZO-1 and Cx43 codistribute within discs, only low to moderate point-by-point colocalization of Cx43 and ZO-1 is found within these domains compared with the relatively high level of colocalization between N-cadherin and ZO-1. By contrast, levels of association between Cx43 and ZO-1 increased rapidly and significantly (
P
<0.001) after partial or complete enzymatic dissociation of myocytes from intact ventricle—a treatment known to induce gap junction endocytosis. Coimmunoprecipitation using Cx43- and ZO-1-specific antibodies confirmed that significantly (
P
<0.03) increased ZO-1 is precipitated relative to Cx43 in freshly dissociated myocytes as compared with intact ventricle. On immunoblots, decreases in Cx43 relative mobility, consistent with increased phosphorylation, were observed following myocyte dissociation. The increased ZO-1-Cx43 association that occurs after remodeling of myocyte intercellular contacts indicates the possibility of unanticipated roles for ZO-1 in gap junction turnover during cardiac development and disease processes.
Lovastatin Enhances Ecto-5′-Nucleotidase Activity and Cell Surface Expression in Endothelial Cells
Authors: Ledoux S. , Laouari D. , Essig M. , Runembert I. , Trugnan G. , Michel J.B. , Friedlander G.
Published: July 2002

Extracellular adenosine production by the GPI-anchored Ecto-5′-Nucleotidase (Ecto-5′-Nu) plays an important role in the cardiovascular system, notably in defense against hypoxia. It has been previously suggested that HMG-CoA reductase inhibitors (HRIs) could potentiate the hypoxic stimulation of Ecto-5′Nu in myocardial ischemia. In order to elucidate the mechanism of Ecto-5′-Nu stimulation by HRIs, Ecto-5′-Nu activity and expression were determined in an aortic endothelial cell line (SVAREC) incubated with lovastatin. Lovastatin enhanced Ecto-5′-Nu activity in a dose-dependent manner. This increase was not supported by de novo synthesis of the enzyme because neither the mRNA content nor the total amount of the protein were modified by lovastatin. By contrast, lovastatin enhanced cell surface expression of Ecto-5′-Nu and decreased endocytosis of Ecto-5′-Nu, as evidenced by immunostaining. This effect appeared unrelated to modifications of cholesterol content or Ecto-5′-Nu association with detergent-resistant membranes. The effect of lovastatin was reversed by mevalonate, the substrate of HMG-CoA reductase, by its isoprenoid derivative, geranyl-geranyl pyrophosphate, and by cytotoxic necrotizing factor, an activator of Rho-GTPases. Stimulation of Ecto-5′-Nu by lovastatin enhanced the inhibition of platelet aggregation induced by endothelial cells. In conclusion, lovastatin enhances Ecto-5′-Nu activity and membrane expression in endothelial cells. This effect seems independent of lowering cholesterol content but could be supported by an inhibition of Ecto-5′-Nu endocytosis through a decrease of Rho-GTPases isoprenylation.
Xanthine Oxidase–Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia
Authors: Bagi Zsolt , Ungvari Zoltan , Koller Akos
Published: July 2002

We hypothesized that in hyperhomocysteinemia (HHcy), flow-induced arteriolar constriction is due to an enhanced generation of reactive oxygen and/or nitrogen species, causing an impairment of nitric oxide (NO) and prostaglandin mediation of the response. Changes in diameter of isolated, pressurized (at 80 mm Hg) gracilis muscle arterioles (diameter ≈170 μm) from control and methionine diet–induced HHcy rats were measured by videomicroscopy. Increases in intraluminal flow (from 0 to 25 μL/min) resulted in NO- and prostaglandin-mediated dilations of control arterioles (maximum, control, 30±4 μm) but elicited significant constrictions of HHcy arterioles (maximum, HHcy, −32±3 μm), which were abolished by the thromboxane A
2
receptor blocker SQ 29,548. Intraluminal administration of superoxide dismutase plus catalase did not affect flow-mediated dilations of control arterioles, but in HHcy arterioles, it reversed the flow-induced constrictions to dilations (maximum 18±4 μm), which were abolished by an NO synthase inhibitor. Flow-induced constrictions of HHcy arterioles were prevented by the presence of the xanthine oxidase inhibitor oxypurinol [but not by the NAD(P)H-oxidase inhibitor diphenyleneiodonium] and by urate, a known peroxynitrite scavenger. Also, authentic peroxynitrite elicited arteriolar constrictions (−31±8 μm) that were eliminated by urate and SQ 29,548. Thus, we suggest that in HHcy, xanthine oxidase–derived superoxide scavenges NO released to flow, forming peroxynitrite, which promotes release of thromboxane A
2
, resulting in arteriolar constriction.
Semicarbazide-Sensitive Amine Oxidase in Vascular Smooth Muscle Cells
Authors: El Hadri Khadija , Moldes Marthe , Mercier Nathalie , Andreani Marise , Pairault Jacques , Feve Bruno
Published: July 2002

Cultured vascular smooth muscle cells (VSMCs) derived from rat aortic media were used to examine semicarbazide-sensitive amine oxidase (SSAO) expression during their differentiation process. In a defined serum-free medium permissive for in vitro VSMC differentiation, there was a large increase in SSAO mRNA and protein levels and in the related enzyme activity during the course of cell culture. This pattern of expression was concomitant with that of some smooth muscle–specific mRNA markers of differentiation. mRNAs in differentiated cultured VSMCs were comparable to those detected in total aorta and media. Pharmacological properties of SSAO present in VSMCs were similar to enzyme activities previously described in the aortic wall. In this model, we also demonstrated that methylamine, a physiological substrate of SSAO, activated 2-deoxyglucose transport in a time- and dose-dependent manner. This methylamine effect was reproduced by other SSAO substrates and was prevented by the SSAO inhibitor semicarbazide. It was antagonized in the presence of catalase, suggesting that SSAO-activated glucose transport was mediated through H
2
O
2
production. In addition, methylamine promoted glucose transporter 1 accumulation at the cell surface. Thus, we demonstrate for the first time the differentiation-dependent expression of SSAO in VSMCs and its role in the regulation of VSMC glucose uptake.
Upregulation of Nox-Based NAD(P)H Oxidases in Restenosis After Carotid Injury
Authors: Szöcs Katalin , Lassègue Bernard , Sorescu Dan , Hilenski Lula L. , Valppu Liisa , Couse Tracey L. , Wilcox Josiah N. , Quinn Mark T. , Lambeth J.David , Griendling Kathy K.
Published: July 2002

Restenosis, a frequent complication of coronary angioplasty, is associated with increased superoxide (O
2
·
−
) production. Although the molecular identity of the responsible oxidase is unclear, an NAD(P)H oxidase appears to be involved. In smooth muscle, p22phox and 2 homologues of gp91phox, nox1 and nox4, are expressed, whereas fibroblasts contain gp91phox. To begin investigating the possibility that these oxidase components might contribute to the increased O
2
·
−
that accompanies neointimal formation, we measured their expression after balloon injury of the rat carotid artery. The increase in O
2
·
−
production 3 to 15 days after surgery was not due to inflammatory cell infiltration but appeared to be derived from medial and neointimal smooth muscle cells and adventitial fibroblasts. Nox1 and p22phox mRNAs were increased 2.7- and 3.6-fold, respectively, at day 3 after injury and remained elevated for 15 days. gp91Phox was increased 7 to 15 days after injury, and nox4 expression was increased 2-fold, but only at day 15 after surgery. These results confirm and extend our previous in vitro data and suggest that in the vasculature, the nox-based NAD(P)H oxidases serve different functions. This dynamic regulation of oxidase components may be critical to smooth muscle phenotypic modulation in restenosis and atherosclerosis.
Transgenic Expression of Cholesterol-7-α-Hydroxylase Prevents Atherosclerosis in C57BL/6J Mice
Authors: Miyake Jon H. , Duong-Polk Xuandao T. , Taylor John M. , Du Emma Z. , Castellani Lawrence W. , Lusis Aldons J. , Davis Roger A.
Published: July 2002

C57BL/6J mice are susceptible to atherosclerosis when fed a diet consisting of fat, cholesterol, and taurocholate. The susceptibility to diet-induced atherosclerosis is linked to a reduction in plasma high density lipoprotein (HDL). Diet-induced reduction of plasma HDL shows a physiological and a genetic correlation with repression of cholesterol-7-α-hydroxylase, the liver-specific enzyme that regulates the conversion of cholesterol into bile acids. To examine the hypothesis that the repression of cholesterol-7-α-hydroxylase is responsible for initiating the metabolic alterations leading to the formation of atherosclerosis and gallstones, we determined whether constitutive transgenic expression of cholesterol-7-α-hydroxylase in C57BL/6J mice would confer resistance to these 2 common human diseases. When fed the atherogenic diet, nontransgenic littermates, but not cholesterol-7-α-hydroxylase transgenic mice, accumulated cholesterol and cholesterol esters in their livers and plasma. Although the atherogenic diet caused a marked decrease in plasma HDL cholesterol in nontransgenic mice, HDL levels in transgenic mice remained relatively unchanged. Moreover, the ability of cholesterol-7-α-hydroxylase transgenic mice to maintain cholesterol and lipoprotein homeostasis completely prevented the formation of atherosclerosis and gallstones. These data establish the integral role that cholesterol-7-α-hydroxylase has in maintaining hepatic cholesterol homeostasis and, thus, in the susceptibility to the formation of gallstones and atherosclerosis.
Postprandial Plasma ApoB-48 Levels Are Influenced by a Polymorphism in the Promoter of the Microsomal Triglyceride Transfer Protein Gene
Authors: Lundahl Björn , Hamsten Anders , Karpe Fredrik
Published: July 2002

The microsomal triglyceride transfer protein (MTP) plays a key role in the secretion of apolipoprotein B (apoB)-containing lipoproteins. The rare variant of a functional polymorphism in the promoter region of the MTP gene has been associated with elevated transcriptional activity of the gene in vitro (MTP−493G/T). With use of a “recruit-by-genotype” approach, we investigated one of the potentially complex phenotypes of this polymorphism, the appearance in plasma of apoB-48 after a meal intake. A total of 12 homozygous carriers of the rare MTP−493T variant were identified from a population-based screening of 50-year-old healthy white men. All subjects were of the apoE3/3 genotype. Along with 48 baseline well-matched heterozygotes (n=24) plus homozygotes (n=24) for the common variant, they were given a standardized oral fat meal. Postprandial plasma concentrations of apoB-48 were determined by the combination of density gradient ultracentrifugation and analytical SDS-PAGE. The postprandial plasma concentrations of triglycerides did not differ between the groups, but homozygous carriers of the rare MTP−493T variant showed a >100% greater increase in apoB-48 in the smallest (Svedberg flotation rate constant 20 to 60) triglyceride-rich lipoprotein fraction (
P
=0.005). These data support the notion that elevated transcriptional activity of MTP leads to an increased generation of the smallest triglyceride-rich lipoprotein from the intestine.
Interleukin-4 Deficiency Decreases Atherosclerotic Lesion Formation in a Site-Specific Manner in Female LDL Receptor−/− Mice
Authors: King Victoria L. , Szilvassy Stephen J. , Daugherty Alan
Published: July 2002

Activated lymphocytes and mast cells have been detected in human atherosclerotic lesions. Interleukin-4 (IL-4) is a prominent cytokine released during the activation of both these cell types, and its mRNA has been detected in human and mouse atherosclerotic lesions. To define the effects of IL-4 on atherogenesis, bone marrow stem cells from either IL-4−/− or IL-4+/+ mice were transplanted into lethally irradiated female low density lipoprotein (LDL) receptor−/− mice. After an interval sufficient to allow engraftment, mice were placed on a diet containing 21% saturated fat, 1.25% cholesterol, and 0.5% cholate. Hematopoietic engraftment was confirmed by the presence of the LDL receptor gene in bone marrow cells. The effect on IL-4 depletion was confirmed by quantifying cytokine release from splenocytes of reconstituted mice. The deficiency of IL-4 in bone marrow–derived cells had no effect on serum cholesterol concentrations or on the distribution of cholesterol among lipoproteins. Atherosclerotic lesion formation was not changed in the aortic root. However, deficiency of IL-4 led to reduced lesion size in the arch (9.1±1.1% versus 2.8±0.8% of intimal area,
P
<0.001) and the thoracic aorta (1.2±0.2% versus 0.4±0.1%,
P
<0.002). Therefore, IL-4 deficiency reduced atherosclerotic lesion formation in a site-specific manner in female LDL receptor−/− mice fed a high-fat diet.
Increased Plasmin and Serine Proteinase Activity During Flow-Induced Intimal Atrophy in Baboon PTFE Grafts
Authors: Kenagy Richard D. , Fischer Jens W. , Davies Mark G. , Berceli Scott A. , Hawkins Suzanne M. , Wight Thomas N. , Clowes Alexander W.
Published: July 2002

High blood flow causes intimal atrophy and loss of extracellular matrix in PTFE aortoiliac grafts. We have investigated whether matrix-degrading proteinases are altered in this baboon model of atrophy using zymography, western analysis, and a versican degradation assay. After four days of high flow, urokinase was increased and plasminogen activator inhibitor-1 was decreased in the intima. Plasminogen was increased after seven days. Pro-matrix metalloproteinase (MMP)-2, activated MMP-2, and proMMP-9 levels were modestly increased by high flow at 7 days, whereas MMP-3 and tissue inhibitor of metalloproteinases-1 were not altered. Extracts of 4-day high-flow intimas degraded more
35
S-methionine–labeled versican than low-flow intimal extracts, and this activity was inhibited by AEBSF, a serine proteinase inhibitor, and a plasmin antibody. In contrast, this activity was not inhibited by the MMP inhibitor, BB-94 (Batimastat). These data suggest that serine proteinases, including plasmin, may be largely responsible for extracellular matrix degradation in this primate model of flow-induced intimal atrophy.
Autosomal Genome-Wide Scan for Coronary Artery Calcification Loci in Sibships at High Risk for Hypertension
Authors: Lange Leslie A. , Lange Ethan M. , Bielak Lawrence F. , Langefeld Carl D. , Kardia Sharon L. , Royston Patrick , Turner Stephen T. , Sheedy Patrick F. , Boerwinkle Eric , Peyser Patricia A.
Published: July 2002

Abstract—

Coronary artery disease (CAD) is the leading cause of mortality in the developed world. Although several CAD risk factors, including measures of lipid metabolism, obesity, and blood pressure, have a genetic basis, many genes for CAD susceptibility have yet to be identified. Coronary atherosclerosis is the major cause of CAD, but many with coronary atherosclerosis lack symptoms. Thus, a major limitation of using symptomatic CAD endpoints (eg, sudden coronary death, myocardial infarction) as a study outcome is substantial disease misclassification. Coronary artery calcification (CAC) is part of the atherosclerotic process and is an independent predictor of CAD endpoints. In the present study, CAC was noninvasively quantified by electron beam computed tomography. We performed genome-wide multipoint mode-of-inheritance-free linkage analysis on affected sib pairs, defined as being ≥ the 70th sex- and age-specific percentile for CAC quantity, in a sample of 29 families enriched for hypertension. Almost 95% of participants were asymptomatic for CAD. Our LOD score (log
10
odds in favor of linkage) results provide evidence that chromosomal regions 6p21.3 (maximum LOD score=2.22,
P
=0.00070) and 10q21.3 (maximum LOD score=3.24,
P
=0.000057) may harbor genes associated with subclinical coronary atherosclerosis.
Cellular Redox State and Endothelial Dysfunction in Mildly Hyperhomocysteinemic Cystathionine β-Synthase–Deficient Mice
Authors: Weiss Norbert , Heydrick Stanley , Zhang Ying-Yi , Bierl Charlene , Cap André , Loscalzo Joseph
Published: July 2002

Previous in vitro experiments have shown that hyperhomocysteinemia leads to oxidative inactivation of nitric oxide, in part by inhibiting the expression of cellular glutathione peroxidase (GPx-1). To elucidate the role of intracellular redox status on homocysteine-induced endothelial dysfunction and oxidant stress, heterozygous cystathionine β-synthase–deficient (CBS
−/+
) and wild-type (CBS
+/+
) mice were treated with the cysteine donor
l
-2-oxothiazolidine-4-carboxylic acid (OTC). CBS
−/+
mice had significantly lower GPx-1 activity compared with their CBS
+/+
littermates, and OTC treatment led to a modest increase in tissue GPx-1 activity and significant increases in total thiols and in reduced glutathione levels in both CBS
+/+
and CBS
−/+
mice. Superfusion of the mesentery with β-methacholine or bradykinin produced dose-dependent vasodilation of mesenteric arterioles in CBS
+/+
mice and in CBS
+/+
mice treated with OTC. In contrast, mesenteric arterioles from CBS
−/+
mice manifested dose-dependent vasoconstriction in response to both agonists. OTC treatment of CBS
−/+
mice restored normal microvascular vasodilator reactivity to β-methacholine and bradykinin. These findings demonstrate that mild hyperhomocysteinemia leads to endothelial dysfunction in association with decreased bioavailable nitric oxide. Increasing the cellular thiol and reduced glutathione pools and increasing GPx-1 activity restores endothelial function. These findings emphasize the importance of intracellular redox balance for nitric oxide bioactivity and endothelial function.
Native LDL Upregulation of ATP-Binding Cassette Transporter-1 in Human Vascular Endothelial Cells
Authors: Liao Hailing , Langmann Thomas , Schmitz Gerd , Zhu Yi
Published: July 2002

ATP-binding cassette transporter-1 (ABCA1) mediates the lipid efflux from cells to apolipoproteins. In studying the gene expression and regulation of ABCA1 in human vascular endothelial cells (ECs), we found that native low density lipoprotein (LDL) elevates ABCA1 in both protein and mRNA levels in a time- and dose-dependent fashion. Transfection of full-length human ABCA1 in ECs lowers cellular cholesterol content and increases apolipoprotein (apo) A-I–mediated cholesterol efflux. Transfection of the ABCA1 promoter–luciferase reporter results in a 2-fold induction after LDL exposure. The responsive element was mapped within −116 to −54 of the promoter region with use of promoter deletion constructs, as reported in other cells. A mutation of the DR4 site greatly diminished the LDL effect. Results showing that LDL increases the liver X receptor responsive element (LXRE)–driven luciferase activity demonstrate the effect of LDL on LXR activation. Furthermore, ligands of the retinoid X receptor and LXR activate ABCA1 in ECs at levels of both promoter activation and mRNA induction. Therefore, ABCA1 is expressed in vascular ECs and is transcriptionally upregulated by LDL. Overexpression of ABCA1 in these cells prevents overloading of cholesterol by increasing the efflux of cholesterol. Thus, ABCA1 plays an important role in the homeostasis of cholesterol in the vascular endothelium.
Basilar Vasospasm Diagnosis
Authors: Soustiel Jean F. , Shik Venyamin , Shreiber Reuven , Tavor Yonit , Goldsher Dorith
Published: July 2002

Background and Purpose

—

Numerous studies have shown that cerebral vasospasm is one of the leading causes of death and neurological disability after subarachnoid hemorrhage. Most of these studies, however, have focused on anterior circulation vessels. Since the introduction of the transcranial Doppler (TCD), increasing attention has been given to basilar artery (BA) vasospasm, especially in traumatic subarachnoid hemorrhage. As shown for the anterior circulation, however, the significance of elevated flow velocities (FVs) in the posterior vessels may be ambiguous, so vasospasm may not be reliably differentiated from hyperemia. The purpose of the present study was to evaluate the potential additional value of an intracranial/extracranial FV ratio in the posterior circulation to cope with this shortcoming of the TCD in the diagnosis of BA vasospasm.

Methods

—

FV in the extracranial vertebral artery (VA) was measured in 20 healthy volunteers. Normative values of an intracranial/extracranial VA FV ratio (IVA/EVA) and a BA/extracranial VA FV ratio (BA/EVA) were calculated. Thirty-four patients with subarachnoid hemorrhage were then evaluated with TCD and CT angiography (CTA). The value of the IVA/EVA and BA/EVA ratios in the diagnosis and assessment of vertebrobasilar vasospasm was investigated.

Results

—

The extracranial VA could be insonated in all subjects at depths ranging from 45 to 55 mm. The average FV for the extracranial VA was 26 cm/s. The ratios between intracranial and extracranial VA FVs were 1.6 on both sides, whereas the ratio between the BA FVs and the mean extracranial VA FVs was slightly higher at 1.7. Fourteen patients (41.2%) had CTA evidence of BA vasospasm. Vasospasm was severe in 7 patients, moderate in 1, and mild in the remaining. An FV threshold of 80 cm/s was indicative of BA vasospasm in 92.8% with 3 false-positive results that could be related to vertebrobasilar hyperemia. Comparative analysis between CTA and TCD findings showed that BA/EVA was >2 in all patients with BA vasospasm (100% sensitivity) and <2 in all but 1 patient without BA vasospasm (95% specificity). Furthermore, the BA/EVA ratio showed a close correlation with BA diameter (
r
=−0.8139,
P
<0.0001) and was >3 in all patients with severe vasospasm.

Conclusions

—

The results of the present study showed that the BA/EVA ratio may contribute to an improved discrimination between BA vasospasm and vertebrobasilar hyperemia and enhance the accuracy and reliability of TCD in the diagnosis of BA vasospasm. Our data further suggest that the BA/EVA ratio may provide an approximation of vasospasm severity and help in identifying patients who are likely to suffer from hemodynamically significant vasospasm.
Tumor Necrosis Factor Receptor Levels Are Associated With Carotid Atherosclerosis
Authors: Elkind Mitchell S. , Cheng Jianfeng , Boden-Albala Bernadette , Rundek Tanja , Thomas Joyce , Chen Hong , Rabbani LeRoy E. , Sacco Ralph L.
Published: July 2002

Background and Purpose

—

Recent evidence suggests that atherosclerosis is an inflammatory condition. Serum levels of inflammatory markers may serve as measures of the severity of atherosclerosis and risk of stroke. We sought to determine whether tumor necrosis factor-α (TNF-α) and TNF receptor levels are associated with carotid plaque thickness.

Methods

—

The Northern Manhattan Stroke Study is a community-based study of stroke risk factors. For this cross-sectional analysis, inflammatory marker levels, including TNF-α and TNF receptors 1 and 2, were measured by immunoassay in stroke-free community subjects undergoing carotid duplex Doppler ultrasound. Maximal carotid plaque thickness (MCPT) was measured for each subject. Analyses were stratified by age <70 and ≥70 years. Simple and multiple linear regression analyses were used to calculate the association between marker levels and MCPT. Multiple logistic regression was used to calculate odds ratios and 95% CIs for the association of inflammatory markers with MCPT ≥1.5 mm (>75th percentile), after adjustment for demographic and potential medical confounding factors.

Results

—

The mean age of the 279 subjects was 67.6±8.5 years; 49% were men; 63% were Hispanic, 17% black, and 17% white. Mean values for TNF-α and its receptors were as follows: TNF-α, 1.88±3.97 ng/mL; TNF receptor 1, 2.21±0.99 ng/mL; and TNF receptor 2, 4.85±2.23 ng/mL. Mean MCPT was elevated in those in the highest quartiles compared with lowest quartiles of TNF receptor 1 and 2 (1.24 versus 0.79 mm and 1.23 versus 0.80 mm, respectively). Among those aged <70 years, TNF receptor 1 and 2 were associated with an increase in MCPT (mean difference=0.36 mm,
P
=0.01 for TNF receptor 1 and mean difference=0.10 mm,
P
=0.04 for TNF receptor 2). After adjustment for sex, race-ethnicity, hypertension, diabetes mellitus, LDL cholesterol, smoking, and body mass index, associations remained (mean difference=0.36 mm,
P
=0.001 for TNF receptor 1 and mean difference=0.09 mm,
P
=0.051 for TNF receptor 2). There was no association for TNF receptors in those aged ≥70 years old and no association for TNF-α in either age group. Among those aged <70 years, each unit increase in TNF receptor level increased the odds of the participant’s having MCPT ≥1.5 mm (adjusted odds ratio=4.7; 95% CI, 1.7 to 15.4 for TNF receptor 1; odds ratio=1.9; 95% CI, 1.3 to 2.9 for TNF receptor 2).

Conclusions

—

Relative elevation in TNF receptor levels, but not TNF-α, is associated with carotid atherosclerosis among individuals aged <70 years in this multiethnic, urban population. Chronic subclinical infection or inflammation may account for this association, and modification of these inflammatory pathways may provide a novel approach to stroke prevention.
Different Measures for Assessing Stroke Outcome
Authors: Celani Maria Grazia , Cantisani Teresa Anna , Righetti Enrico , Spizzichino Lorenzo , Ricci Stefano
Published: July 2002

Background and Purpose

—

We sought to assess the relationship between 2 simple questions on recovery (question 1: do you feel that you have made a complete recovery from your stroke?) and dependency (question 2: do you require help from another person for everyday activities?) and the Barthel Index (BI) and Oxford Handicap Scale (OHS), as well as the relationship between BI and OHS, in a large number of Italian stroke survivors who participated in the International Stroke Trial (IST).

Methods

—

We used data from 2423 patients interviewed by telephone at 6 months after the event. The κ statistic, sensitivity, and specificity were calculated for several comparisons. Internal consistency for BI was calculated.

Results

—

The reliability of the dependency question compared with BI=20 (κ=0.93) and the reliability of the recovery question compared with OHS=0 (κ=0.89) were good. Sensitivity of the dependency question in predicting whether patients scored BI >18 was 0.98; sensitivity of the recovery question in predicting whether patients scored OHS=0 was 0.99. The reliability of BI=20 compared with OHS <3 was good (κ=0.87). Internal consistency of BI was very high (Cronbach’s α=0.96).

Conclusions

—

The 2 simple questions are a good means of evaluating outcome from a patient’s view and of dichotomizing the stroke survivor in a time-effective and reliable way.
CT Angiography in Acute Ischemic Stroke
Authors: Verro Piero , Tanenbaum Lawrence N. , Borden Neil M. , Sen Souvik , Eshkar Noam
Published: July 2002

Background and Purpose

—

We sought to evaluate the ability of CT angiography (CTA) to determine vessel occlusion before acute stroke treatment and to predict its impact on patient outcome.

Methods

—

Consecutive patients with acute focal neurological deficits received immediate brain CTA. Occlusion on CTA was correlated with other neuroimaging studies and clinical outcome.

Results

—

Diagnostic CTA was obtained in 54 patients: catheter angiography (digital subtraction angiography) confirmed the CTA findings in 12 of 14 patients (86%). CTA results were consistent with at least 1 other neuroimaging study in 40 of 50 patients (80%). Patients with occlusion on CTA had significantly worse discharge National Institutes of Health Stroke Scale (NIHSS) score (mean 14.3 versus 4.5,
P
=0.0023). In multivariate analysis, both CTA-determined presence of occlusion and admission NIHSS score were independent predictors of clinical outcome.

Conclusions

—

In our study there was good agreement between acute CTA interpretation and subsequent imaging studies. CTA evidence of occlusion correlated strongly and independently with poor clinical outcome. CTA provides relevant data regarding vessel patency in acute stroke, which may be of value in selecting patients for aggressive treatment.
Effect of Age on Functional Outcomes After Stroke Rehabilitation
Authors: Bagg Stephen , Pombo Alicia Paris , Hopman Wilma
Published: July 2002

Background and Purpose

—

The incidence of stroke and the demand for stroke rehabilitation services continues to increase, and it has been proposed that age be used in combination with severity of stroke to determine type of rehabilitation. It is important to identify the impact of age on functional outcome before embracing a system that limits access to rehabilitation on the basis of age.

Methods

—

This prospective study includes all patients admitted to an inpatient stroke rehabilitation program for 6 years. Demographic and clinical data were extracted by means of chart review. Functional status at admission and discharge was evaluated by means of the FIM
TM
instrument. Multivariate regression techniques were used to assess the relationships between age, functional outcome, and other predictive variables. Particular attention was paid to the
r
2
values to assess the amount of variation accounted for by the predictors.

Results

—

Age alone was a significant predictor of total FIM score and Motor FIM score at discharge, but not FIM change. For both total FIM score and Motor FIM score at discharge, age alone accounted for only 3% of the variation in outcome. For all the models, age explained at the most 1.3% of the variation in functional outcome after adjustment for other factors, such as admission FIM score.

Conclusions

—

The small amount of variation that can be explained by age alone and the questionable clinical relevance of such a small effect suggest that there is no justification to deny patients access to rehabilitation solely because of advanced age.