bluuebunny/crossref_metadata_2025 huggingface dataset:
Trunk Fat and Blood Pressure in Children Through Puberty
Authors: He Qing , Horlick Mary , Fedun Barbara , Wang Jack , Pierson Richard N. , Heshka Stanley , Gallagher Dympna
Published: July 2002

Background
—

Fat distribution is well recognized as a cardiovascular risk factor in adults. The association between android fat distribution and cardiovascular risk factors, such as blood pressure (BP), was previously reported in an African-American and Caucasian pediatric population. The aim of the present study was to investigate the relationship between BP and body fat distribution in a large cross-sectional pediatric sample. The effects of race, sex, and puberty on this relationship were assessed.

Methods and Results
—

BP was measured in 920 healthy children and adolescents (African-American, Asian, and Caucasian, ages 5 to 18 years). Fat distribution was determined by skinfold thickness and dual-energy X-ray absorptiometry (DXA). Pubertal status was assessed by the criteria of Tanner. Regression analysis was used to explore the association between BP and fat distribution. Significant positive relationships between systolic and diastolic BP and trunk fat adjusted for total fat were seen in boys at all pubertal stages in all 3 races by both DXA and skinfold measurements. In girls, trunk fat was not a significant predictor of BP.

Conclusions
—

Our results demonstrate a sex difference in the relationship between BP and trunk fat in that a significant positive relationship was present in boys only. These findings, based on 2 independent measures of fat distribution, may help identify the specific features of individuals at risk, allow earlier intervention, and suggest sex-specific determinants for BP.
Norepinephrine Turnover Is Increased in Suprabulbar Subcortical Brain Regions and Is Related to Whole-Body Sympathetic Activity in Human Heart Failure
Authors: Aggarwal Anuradha , Esler Murray D. , Lambert Gavin W. , Hastings Jacqueline , Johnston Leonie , Kaye David M.
Published: July 2002

Background
—

Although it is established that heightened sympathetic drive exists in congestive heart failure (CHF), the reflex processes by which this may occur and the sites in the central nervous system that may be responsible for mediating this process are not yet fully elucidated.

Methods and Results
—

Eight patients with moderate to severe CHF and 8 healthy control subjects underwent simultaneous arterial and bilateral internal jugular venous blood sampling and cerebral venous blood pool scanning for anatomical determination of the origin of internal jugular venous blood flow. We estimated sympathetic nervous activity by measuring total body norepinephrine (NE) spillover using radiotracer methodology and determined brain NE turnover by measuring the internal jugular overflow of NE and its lipophilic metabolites, 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol. Suprabulbar subcortical turnover of NE was significantly greater in CHF patients than in the healthy group (2.77±0.75 versus 0.66±0.40 nmol/min,
P
<0.05). There was a significant positive correlation between suprabulbar subcortical turnover of NE and total body NE spillover (
r
=0.62,
P
=0.01).

Conclusions
—

This study, for the first time, demonstrates elevated suprabulbar subcortical noradrenergic activity in human CHF and identifies a positive correlation between this and the level of whole-body NE spillover. The findings suggest that the activation of noradrenergic neurons projecting rostrally from the brain stem mediates sympathetic nervous stimulation in CHF.
Tolerability of β-Blocker Initiation and Titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)
Authors: Gottlieb Stephen S. , Fisher Michael L. , Kjekshus John , Deedwania Prakash , Gullestad Lars , Vitovec Jiri , Wikstrand John
Published: July 2002

Background

—

β-Blockade improves survival when administered over a long period of time to patients with heart failure. However, the time course of any possible deterioration during the titration phase has not been reported.

Methods and Results

—

We looked at evidence of clinical deterioration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) by analyzing events and symptoms during the first 90 days. During titration, the Kaplan-Meier curves for the combined end point of all-cause mortality/all-cause hospitalization were similar in all patients randomized, with no significant difference in favor of placebo at any visit or in any of the analyzed subgroups (New York Heart Association class II, III/IV, or III/IV with ejection fraction <0.25, heart rate ≤76 bpm, and systolic blood pressure ≤120 mm Hg). The curves started to diverge in favor of β-blockade after 60 days. Low heart rate was the main factor that limited titration. In New York Heart Association class III/IV, 5.9% of the patients receiving placebo discontinued study medicine during the first 90 days compared with 8.1% of those receiving metoprolol CR/XL (
P
=0.037 unadjusted,
P
=NS adjusted); corresponding figures in those with New York Heart Association class III/IV and ejection fraction <0.25 were 7.1% and 8.0% (
P
=NS). From day 90 until the end of the study, more patients in the placebo group discontinued study medicine in all subgroups. There was no change in diuretic or ACE inhibitor dosing with β-blocker titration. Most patients reported no change in symptoms of breathlessness or fatigue during the titration phase.

Conclusions

—

When carefully titrated, metoprolol CR/XL can be given safely to the overwhelming majority of patients with stable mild to moderate heart failure, with minimal side effects or deterioration.
Functional and Biochemical Analysis of Endothelial (Dys)function and NO/cGMP Signaling in Human Blood Vessels With and Without Nitroglycerin Pretreatment
Authors: Schulz Eberhard , Tsilimingas Nikolaus , Rinze Ruth , Reiter Beate , Wendt Maria , Oelze Mathias , Woelken-Weckmüller Silke , Walter Ulrich , Reichenspurner Hermann , Meinertz Thomas , Münzel Thomas
Published: July 2002

Background

—

In experimental animal models, long-term in vivo treatment with nitroglycerin (NTG) induces both endothelial dysfunction and tolerance to nitrates. However, it is still controversial whether nitrate tolerance in humans is associated with both endothelial dysfunction and impaired vascular response to nitrovasodilator-derived NO.

Methods and Results

—

Patients undergoing elective bypass surgery were randomized to receive 48 hours of continuous NTG infusion (NTG group) or no nitrate therapy (control group). Segments of surgically removed arteria mammaria, vena saphena, and arteria radialis not required for the bypass procedure were used to examine (1) the vascular responsiveness to NTG and the endothelium-dependent vasodilator acetylcholine; (2) the expression of the NO target, the soluble guanylyl cyclase; (3) the expression of the soluble guanylyl cyclase/cGMP effector target, the cGMP-dependent protein kinase (cGK); and (4) the cGK activity as assessed by the phosphorylation state of its vascular substrate, the vasodilator-stimulated phosphoprotein at serine
239
(P-VASP). NTG treatment caused a marked degree of nitrate tolerance in all 3 vessel types studied and a significant cross-tolerance to the endothelium-dependent vasodilator acetylcholine in A. mammaria and A. radialis. Although soluble guanylyl cyclase, cGK-I, and VASP expression levels were not modified by NTG treatment, a marked decrease of P-VASP, a surrogate parameter for in-vivo cGK-I activity, was observed.

Conclusions

—

We conclude that long-term NTG treatment induces endothelial dysfunction and impaired vascular NO/cGMP signaling in humans, which can be monitored by measuring P-VASP levels.
Smoking a Single Cigarette Rapidly Reduces Combined Concentrations of Nitrate and Nitrite and Concentrations of Antioxidants in Plasma
Authors: Tsuchiya Masahiko , Asada Akira , Kasahara Emiko , Sato Eisuke F. , Shindo Mitsuo , Inoue Masayasu
Published: July 2002

Background

—

Cigarette smoking is a well-known risk factor for the development of cardiovascular disease, yet the mechanism of action involved is not completely understood. Because cigarette smoke contains superoxide and other reactive oxygen species, it has been hypothesized that some of the adverse effects of smoking may result from oxidative damage to endothelial cells, which results in nitric oxide (NO) shortage. However, little information is available regarding the acute effects of smoking on plasma concentrations of NO and antioxidants. We measured the changes in the combined plasma concentrations of nitrate and nitrite as an index of NO concentration, as well as changes in concentrations of major serum antioxidants (ascorbic acid, cysteine, methionine, and uric acid) in smokers after smoking a single cigarette.

Methods and Results

—

A randomized crossover study of the effects of smoking a single cigarette was performed in 20 smokers. Smoking a sham cigarette induced no significant changes in all assayed parameters. However, smoking a single cigarette significantly decreased nitrate and nitrite plasma concentrations by 3.5±1.2 and 3.4±1.1 μmol/L, compared with plasma concentrations at presmoking and sham smoking, respectively. The concentrations of ascorbic acid and other antioxidants were also significantly lower after smoking a single cigarette. These parameters returned to preexperimental levels 60 minutes after smoking cessation.

Conclusion

—

The present findings indicate that smoking a single cigarette temporarily decreases nitrate, nitrite, and serum antioxidant concentrations in the plasma. These transient changes may partially contribute to coronary vasoconstriction, which is routinely observed after smoking.
Propranolol Prevents the Development of Heart Failure by Restoring FKBP12.6-Mediated Stabilization of Ryanodine Receptor
Authors: Doi Masahiro , Yano Masafumi , Kobayashi Shigeki , Kohno Masateru , Tokuhisa Takahiro , Okuda Shinichi , Suetsugu Masae , Hisamatsu Yuhji , Ohkusa Tomoko , Kohno Michihiro , Matsuzaki Masunori
Published: July 2002

Background

—

In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca
2+
leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether β-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function.

Methods and Results

—

SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of rapid right ventricular pacing with or without propranolol [P(+) or P(−)]). End-diastolic and end-systolic diameters both increased less in P(+) than P(−), associated with a smaller decrease in fractional shortening in P(+). In SR from P(−), a prominent Ca
2+
leak was observed, and FK506 (which dissociates FKBP12.6 from RyR) did not induce an additional Ca
2+
leak. However, there was no appreciable Ca
2+
leak in SR from P(+), although FK506 induced a Ca
2+
leak as in normal SRs. In SR from P(+), an FK506-induced conformational change in RyR, which was virtually absent in SR from P(−), was observed as in normal SRs. Both the stoichiometry of FKBP12.6 versus RyR, assessed by [
3
H]FK506 and [
3
H]ryanodine binding assays, and the protein expression of FKBP12.6, assessed by Western blot analysis, were restored by propranolol toward the levels seen in normal SRs.

Conclusions

—

Low-dose propranolol corrects the defective interaction of FKBP12.6 with RyR (restoration of RyR conformational change and prevention of Ca
2+
leak from RyR), apparently resulting in an attenuation of intracellular Ca
2+
overload and hence preventing the development of left ventricular remodeling in heart failure.
PPARγ Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells
Authors: Oyama Yuko , Akuzawa Nobuhiro , Nagai Ryozo , Kurabayashi Masahiko
Published: July 2002

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily that acts as a key player in adipocyte differentiation, glucose metabolism, and macrophage differentiation. Osteopontin (OPN), a component of extracellular matrix, is elevated during neointimal formation in the vessel wall and is synthesized by macrophages in atherosclerotic plaques. In the present study, we investigated the molecular mechanisms regulating OPN gene expression by PPARγ in THP-1 cells, a cell line derived from human monocytic leukemia cells. Northern and Western blot analyses showed that exposure of THP-1 cells to PMA (phorbol 12-myristate 13-acetate) increases OPN mRNA and protein levels in a time-dependent manner. PMA-induced OPN expression was significantly decreased by troglitazone (Tro) and other PPARγ ligands. Transient transfection assays of the human OPN promoter/luciferase construct showed that PPARγ represses OPN promoter activity, and the PPARγ-responsive region within the OPN promoter lies between −1000 and −970 relative to the transcription start site. Site-specific mutation analysis and electrophoretic mobility shift assays indicated that a homeobox-like A/T-rich sequence between −990 and −981, which functions as a binding site for PMA-induced nuclear factors other than PPARγ, mediates the repression of OPN expression by Tro. Furthermore, concatenated A/T-rich sequences conferred the PPARγ responsiveness on the heterologous promoter. Taken together, these data suggest that PPARγ ligand inhibits OPN gene expression through the interference with the binding of nuclear factors to A/T-rich sequence in THP-1 cells.
Regression of Atherosclerosis in Monkeys Reduces Vascular Superoxide Levels
Authors: Hathaway Christopher A. , Heistad Donald D. , Piegors Donald J. , Miller Francis J.
Published: July 2002

Superoxide (O
2
·−
) in arteries may contribute to atherosclerosis in part by inactivation of nitric oxide. We hypothesized that regression of atherosclerosis in nonhuman primates is associated with a decrease in vascular NAD(P)H oxidase, decreased O
2
·−
levels, and improved endothelium-dependent relaxation. Cynomolgus monkeys (n=28) were fed an atherogenic diet for 47±10 (mean±SE) months. In carotid arteries (containing advanced lesions), femoral arteries (moderate lesions), and saphena arteries (minimal lesions), we examined O
2
·−
levels and vasomotor function. Compared with vessels from normal monkeys (n=8), O
2
·−
levels (measured by lucigenin-enhanced chemiluminescence) were 3.3-fold higher in carotid, 1.7-fold higher in femoral, and not different in saphena arteries from atherosclerotic monkeys. Dihydroethidium staining also demonstrated increased O
2
·−
levels throughout the vessel wall in femoral and carotid arteries from atherosclerotic monkeys. Components of the NAD(P)H oxidase (p22
phox
and p47
phox
) were increased in atherosclerotic arteries, and immunohistochemistry demonstrated colocalization primarily to areas of macrophage infiltration. Relaxation to acetylcholine was impaired in carotid and femoral, but not saphena, arteries from atherosclerotic monkeys. After 8 months of regression diet (n=9), serum cholesterol decreased to normal, and O
2
·−
levels (basal and NAD(P)H-stimulated), as well as expression of NAD(P)H oxidase, returned toward normal. Relaxation to acetylcholine improved in femoral arteries, but not in the more diseased carotid arteries. We conclude that, in a primate model of moderately severe atherosclerosis and regression of atherosclerosis, changes in endothelial function are inversely related to O
2
·−
and NAD(P)H oxidase levels. Reduction in vascular O
2
·−
during regression of atherosclerosis may contribute to improvement in vasomotor function.
Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes
Authors: Li Yanxia , Kranias Evangelia G. , Mignery Gregory A. , Bers Donald M.
Published: July 2002

Ryanodine receptor (RyR) phosphorylation by protein kinase A (PKA) may be important in modulating resting sarcoplasmic reticulum (SR) Ca
2+
release, especially in heart failure. However, clear cellular data on PKA-dependent modulation of cardiac RyRs is limited because of difficulty in distinguishing between PKA effects on RyR, phospholamban (PLB), and Ca
2+
current. To clarify this, we measured resting Ca
2+
sparks in streptolysin-O permeabilized ventricular myocytes from wild-type (WT) and PLB knockout (PLB-KO) mice and transgenic mice expressing only double-mutant PLB (PLB-DM) that lacks the regulatory phosphorylation sites (S16A/T17A). In WT myocytes, cAMP dramatically increased Ca
2+
spark frequency (CaSpF) by 2- and 3-fold when [Ca
2+
] was clamped at 50 and 10 nmol/L (and the SR Ca
2+
content also rose by 40% and 50%). However, in PLB-KO and PLB-DM, neither CaSpF nor SR Ca
2+
load was changed by the addition of 10 μmol/L cAMP (even with phosphatase inhibition). PKA activation also increased Ca
2+
spark amplitude, duration, and width in WT, but not in PLB-KO or PLB-DM. RyR phosphorylation was confirmed by measurements of
32
P incorporation on immunoprecipitated RyR. In intact resting myocytes, PKA activation increased CaSpF 2.8-fold in WT, but not in PLB-KO, confirming results in permeabilized myocytes. We conclude that the PKA-dependent increase in myocyte CaSpF and size is entirely attributable to PLB phosphorylation and consequent enhanced SR Ca
2+
load. PKA does not seem to have any appreciable effect on resting RyR function in these ventricular myocytes. Moreover, the data provide compelling evidence that elevated intra-SR [Ca
2+
] increases RyR gating independent of cytosolic [Ca
2+
] (which was clamped).
A Structural and Dynamic Investigation of the Facilitating Effect of Glycoprotein IIb/IIIa Inhibitors in Dissolving Platelet-Rich Clots
Authors: Collet J.Ph. , Montalescot G. , Lesty C. , Weisel J.W.
Published: July 2002

Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors were shown recently to facilitate the rate and the extent of pharmacological thrombolysis. However, their synergistic potential with rtPA in dissolving thrombotic vaso-occlusions is not fully understood. We have therefore developed a dynamic and structural approach for analysis of fibrinolysis to assess the inhibiting effect of platelets and the facilitating effect of GPIIb/IIIa inhibitors in dissolving platelet-rich clots (PRCs). Fluorescent rtPA was used to study the architecture of PRCs, to follow the progression of the rtPA binding front, and to measure the lysis-front velocity using confocal microscopy. Fibrinolysis resistance of PRCs was related to a reduction of both rtPA binding and lysis-front velocities of platelet-rich areas compared with platelet-poor areas (2.4±0.2 versus 3.5±0.4 μm/min for rtPA binding velocity,
P
=0.04, and 1.2±0.6 versus 2.8±0.2 μm/min for lysis-front velocity,
P
=0.008, in platelet-rich and platelet-poor areas, respectively). Fibrinolysis appeared heterogeneous, leaving platelet-rich areas un-lysed. Adding pharmacological concentrations of abciximab (0.068 μmol/L) or eptifibatide (1 μmol/L) before clotting decreased the average surface of platelet-rich areas by 64% (
P
=0.0005) and 72% (
P
=0.0007), respectively. The resulting equalization of rtPA binding rate and rtPA binding-front velocity between platelet-rich and platelet-poor areas led to a 3-fold increase of the lysis-front velocity in platelet-rich areas of either abciximab-PRC (
P
=0.006) or eptifibatide-PRC (
P
=0.03). The overall lysis rate of treated-PRC was increased by 74% compared with control-PRC (
P
<0.01). These results demonstrate that fibrinolysis resistance of PRCs is related primarily to the heterogeneity in the clot structure between platelet-rich and platelet-poor areas. GP IIb/IIIa inhibitors facilitate the rate and the extent of fibrinolysis by improving rtPA binding velocity and, subsequently, the lysis rate in platelet-rich areas. These findings provide new insights on the synergistic potential of GP IIb/IIIa inhibitors and fibrinolytic agents.
Applied Proteomics
Authors: Lopez Mary F. , Melov Simon
Published: July 2002

The identification of a majority of the polypeptides in mitochondria would be invaluable because they play crucial and diverse roles in many cellular processes and diseases. The endogenous production of reactive oxygen species (ROS) is a major limiter of life as illustrated by studies in which the transgenic overexpression in invertebrates of catalytic antioxidant enzymes results in increased lifespans. Mitochondria have received considerable attention as a principal source—and target—of ROS. Mitochondrial oxidative stress has been implicated in heart disease including myocardial preconditioning, ischemia/reperfusion, and other pathologies. In addition, oxidative stress in the mitochondria is associated with the pathogenesis of Alzheimer’s disease, Parkinson’s disease, prion diseases, and amyotrophic lateral sclerosis (ALS) as well as aging itself. The rapidly emerging field of proteomics can provide powerful strategies for the characterization of mitochondrial proteins. Current approaches to mitochondrial proteomics include the creation of detailed catalogues of the protein components in a single sample or the identification of differentially expressed proteins in diseased or physiologically altered samples versus a reference control. It is clear that for any proteomics approach prefractionation of complex protein mixtures is essential to facilitate the identification of low-abundance proteins because the dynamic range of protein abundance within cells has been estimated to be as high as 10
7
. The opportunities for identification of proteins directly involved in diseases associated with or caused by mitochondrial dysfunction are compelling. Future efforts will focus on linking genomic array information to actual protein levels in mitochondria.
Mechanical Stress Regulates Syndecan-4 Expression and Redistribution in Vascular Smooth Muscle Cells
Authors: Li Lei , Chaikof Elliot L.
Published: July 2002

Syndecan-4 is a unique membrane-associated heparan sulfate proteoglycan that colocalizes with integrin heterodimers in focal adhesion complexes. Because focal adhesions serve as a putative mechanotransduction system, we postulated that physical forces that are sensed by focal adhesions may regulate the expression and intracellular distribution of syndecan-4 and thereby modulate cell movement and orientation. In this report, syndecan-4 was identified as a transcriptionally regulated, immediate-early gene in response to the application of oscillatory stress. This fluctuation was associated with coordinate changes in the concentration and compartmentalization of syndecan-4 proteins. Specifically, syndecan-4 was lost from the dorsal aspect of the cell membrane and translocated from its intracellular pool to the ventral cell surface. Dissociation of syndecan-4 and vinculin from focal adhesions may contribute to promoting cell motility, because overexpression of syndecan-4, in part, blocked this dissociation and also retarded mechanical stretch-induced cell migration. These studies suggest that mechanical stress induces cell locomotion, in part, by the dynamic regulation of syndecan-4 expression and relocation.
Experimental Rupture of Atherosclerotic Lesions Increases Distal Vascular Resistance
Authors: Taylor Andrew J. , Bobik Alex , Berndt Michael C. , Ramsay Debra , Jennings Garry
Published: July 2002

Rupture of atherosclerotic lesions, resulting in localized thrombi and marked falls in distal blood flow, is a pivotal event in unstable coronary syndromes. We tested the hypothesis that after lesion rupture, vasoconstrictor mechanisms are major contributors to a marked rise in distal microvascular resistance, which is responsible for much of the interruption in blood flow. Cholesterol-fed rabbits underwent endothelial denudation of their left iliac arteries to induce angiographically severe, fatty, American Heart Association type IV-like atherosclerotic lesions. After lesion disruption with a stiff wire, we measured distal blood flow and pressure, capillary patency in the distal vascular bed, and the response to the vasodilators adenosine, nitroprusside, and glyceryl trinitrate. Morphology of the lesions and of the associated thrombi was also examined to assess lumen restriction at the site of rupture. Disruption of atherosclerotic lesions reduced mean flow from 5.04±1.21 to 1.23±0.37 mL/min (
P
<0.005), and calculated distal vascular resistance rose rapidly, from 17.5±2.9 to 37.9±6.4 mm Hg · min/mL (
P
<0.005). Lesion rupture did not significantly affect capillary patency in the distal muscle vascular bed, and although nonocclusive thrombi were present at the site of nearly all ruptured lesions, embolized thrombi were rare in capillaries (<1%). The early rise in distal microvascular resistance could be normalized with intra-arterially administered adenosine or the NO donor nitroprusside, but not glyceryl trinitrate, an organonitrate possessing large muscular artery-selective vasodilator characteristics. Thus, rupture of atherosclerotic lesions induces rapid and marked increases in distal vascular resistance, which is the consequence of severe microvascular vasoconstriction. Therapeutic targeting of the microvasculature should improve reperfusion in acute coronary syndromes.
Physical Activity May Modulate Effects of
ApoE
Genotype on Lipid Profile
Authors: Bernstein Martine S. , Costanza Michael C. , James Richard W. , Morris Michael A. , Cambien François , Raoux Ségolène , Morabia Alfredo
Published: July 2002

Increased levels of physical activity may improve the lipid profile, but is this effect identical across apolipoprotein E (
apoE
) genotypes? A population-based cross-sectional survey conducted from 1999 to 2000 included 1708 randomly selected men and women aged 35 to 74 years. A validated physical activity questionnaire measured, for each participant, the total energy expenditure and its percentage used in high-intensity activities (%high-intensity activity), eg, brisk walking and sports. The effects of the
apoE×
%high-intensity activity interaction on the lipid profile were investigated by using multiple linear regression models. Among men, increased %high-intensity activity had greater protective effects in the
apoE4
group regarding (1) high density lipoprotein (HDL) cholesterol (
P
<0.001), compared with either the
apoE2
(interaction
P
=0.05) or
apoE3
(interaction
P
<0.03) groups, and (2) triglycerides (
P
<0.03), compared with the
apoE3
group (interaction
P
=0.07). A 10% increase of %high-intensity activity by an
apoE4
man would correspond with a 0.07-mmol/L increase in HDL cholesterol and a −0.15-mmol/L decrease in triglycerides. Among women, only the protective effects of physical activity on HDL cholesterol in the
apoE4
group versus the
apoE2
group was statistically significant. Spending a larger fraction of the total energy expenditure in high-intensity activities may counteract the atherogenic effects of the ε
4
allele on the lipid profile.
Altered Pattern of Vascular Connexin Expression in Atherosclerotic Plaques
Authors: Kwak Brenda R. , Mulhaupt Flore , Veillard Niels , Gros Daniel B. , Mach François
Published: July 2002

Paracrine cell-to-cell interactions are crucial events during atherogenesis. However, little is known about the role of direct intercellular communication via gap junctions during this process. We have investigated the expression pattern of 3 vascular gap junction proteins (connexins) in mouse and human atherosclerotic plaques. Low density lipoprotein receptor–deficient mice were fed a high-fat diet for 0, 6, 10, or 14 weeks to induce different stages of atherosclerosis. Connexin37 (Cx37) and Cx40 were detected in the endothelium, and Cx43 was detected in the media of nondiseased aortas. In early atheromas, endothelial and medial connexin expression remained unchanged, and “islets” of Cx43 in smooth muscle cells and Cx37 in macrophages were observed in the neointima. In advanced atheromas, Cx37 was detected in medial smooth muscle cells and in macrophages in the lipid core but not in the endothelium covering the plaques. Cx40 could also no longer be detected in the endothelium covering the plaques. Cx43, on the other hand, was detected in the endothelium covering the shoulder of the plaques and also sparsely in neointimal smooth muscle cells. Similar results were obtained for human carotid arteries. In conclusion, vascular connexins are differentially expressed by atheroma-associated cells within lesions. These observations suggest a role for gap junctional intercellular communication during atherogenesis.
Atorvastatin Preferentially Reduces LDL-Associated Platelet-Activating Factor Acetylhydrolase Activity in Dyslipidemias of Type IIA and Type IIB
Authors: Tsimihodimos Vasilis , Karabina Sonia-Athena P. , Tambaki Afroditi P. , Bairaktari Eleni , Goudevenos John A. , Chapman M. John , Elisaf Moses , Tselepis Alexandros D.
Published: July 2002

Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is a phospholipase A
2
that is primarily associated with low density lipoprotein (LDL). PAF-AH activity has also been found in high density lipoprotein (HDL), although it has recently been indicated that there is no PAF-AH protein in HDL. Plasma paraoxonase 1 (PON1) is an HDL-associated esterase, which also exhibits PAF-AH–like activity. The effect of atorvastatin (20 mg per day for 4 months) on PAF-AH and PON1 activities in patients with dyslipidemia of type IIA (n=55) or type IIB (n=21) was studied. In both patient groups, atorvastatin significantly reduced plasma PAF-AH activity because of the decrease in LDL plasma levels and the preferential decrease in PAF-AH activity on dense LDL subfractions (LDL-4 and LDL-5). Drug therapy did not affect HDL-associated PAF-AH activity or serum PON1 activities toward paraoxon and phenylacetate in either patient group. However, because of the reduction in LDL cholesterol levels, the ratios of HDL-associated PAF-AH and serum PON1 activities to LDL cholesterol levels were significantly increased after drug administration. The reduction of the LDL-associated PAF-AH activity and the elevation in the ratios of HDL-associated PAF-AH and PON1 activities to LDL plasma levels may represent a new dimension in the antiatherogenic effect of atorvastatin.
Beneficial Effects of NO-Releasing Derivative of Flurbiprofen (HCT-1026) in Rat Model of Vascular Injury and Restenosis
Authors: Maffia Pasquale , Ianaro Angela , Sorrentino Raffella , Lippolis Laura , Maiello Francesco M. , del Soldato Piero , Ialenti Armando , Cirino Giuseppe
Published: July 2002

One of the major problems related to the percutaneous transluminal coronary angioplasty technique is the renarrowing of the vessel, a phenomenon known as restenosis. NO and nonsteroidal anti-inflammatory drugs have been shown to play a role in this pathology. The main problem with the use of conventional NO donors is that they affect blood pressure and flow, and for these reasons, they cannot be used safely in clinical practice. The aim of this study was to evaluate, with the use of a rat model of balloon angioplasty, whether a structural derivative of flurbiprofen, containing an added NO-releasing moiety (HCT-1026), is able to reduce or prevent neointimal formation. Rats were treated for 14 days with equimolar doses of flurbiprofen (2, 7, and 21 mg/kg) or HCT-1026 (3, 10, and 30 mg/kg). After this 14-day treatment, HCT-1026 but not flurbiprofen significantly modified the neointima/media ratio. The reduction in the neointimal proliferation obtained with HCT-1026 was well correlated with an increase in nitrite/nitrate plasma levels and a reduced cell proliferation. Neither HCT-1026 nor flurbiprofen affected inducible NO synthase induction in injured vessels. In conclusion, HCT-1026 caused a significant reduction in restenosis that appears to be directly related to NO release. HCT-1026 may prove to be beneficial in preventing or delaying restenosis in humans.
Hepatic Fatty Acid Synthesis Is Suppressed in Mice With Fatty Livers Due to Targeted Apolipoprotein B38.9 Mutation
Authors: Lin Xiaobo , Schonfeld Gustav , Yue Pin , Chen Zhouji
Published: July 2002

Humans and genetically engineered mice with hypobetalipoproteinemia due to truncation-producing mutations of the apolipoprotein B (apoB) gene frequently have fatty livers, because the apoB defect impairs the capacity of livers to export triglycerides (TGs). We assessed the adaptation of hepatic lipid metabolism in our apoB-38.9-bearing mice. Hepatic TG contents were 2- and 4-fold higher in heterozygous and homozygous mice, respectively, compared with wild-type mice. Respective in vivo hepatic fatty acid synthetic rates were reduced to 40% and 15% of the wild-type rate. Hepatic mRNAs for sterol regulatory element-binding protein (SREBP)-1c, fatty acid synthase (FAS), and stearoyl coenzyme A desaturase-1 were coordinately decreased. FAS and SREBP-1c mRNA levels were strongly and positively correlated with each other and inversely correlated with hepatic TGs, suggesting that impaired TG export is a potent inhibitor of fatty acid synthesis. In contrast, levels of plasma β-hydroxybutyrate and of hepatic carnitine palmitoyl transferase and peroxisome proliferator-activated receptor-α mRNAs were not altered, implying that β-oxidation was not affected. Fasting followed by refeeding increased hepatic fatty acid synthesis 56-fold over fasting in normal and heterozygous mice but only 24-fold in homozygous mice. Parallel changes occurred in FAS and SREBP-1c mRNAs. Thus, impairment of very low density lipoprotein export downregulates hepatic fatty acid synthesis, but the adaptation is incomplete, resulting in fatty livers. The signals mediating suppression of FAS and SREBP-1c levels remain to be identified.
Activation of Big Mitogen-Activated Protein Kinase-1 Regulates Smooth Muscle Cell Replication
Authors: Luo Honglin , Reidy Michael A.
Published: July 2002

This study examined the activation of big mitogen-activated protein (MAP) kinase-1 (BMK1) in rat carotid smooth muscle cells (SMCs). Platelet-derived growth factor, fibroblast growth factor-2, sorbitol, and serum all increased the activation of BMK1 in rat carotid SMCs, whereas angiotensin II, phorbol esters, and tumor necrosis factor-α had only slight effects. With the exception of tumor necrosis factor-α, all these factors phosphorylated extracellular signal–regulated kinase (ERK)1/2. The MAPK kinase inhibitor (MEKI), U0126 (1 μmol/L), blocked ERK1/2 phosphorylation and at higher doses (5 μmol/L) blocked BMK1 phosphorylation. This inhibitor also blocked SMC DNA synthesis in a dose-dependent manner. When SMCs were transfected with an adenoviral construct expressing dominant mutant BMK1 and stimulated with fibroblast growth factor-2, a significantly smaller increase in cyclin D1 and cyclin A expression and in retinoblastoma factor phosphorylation was detected compared with the increase in cells transfected with an adenoviral construct expressing green fluorescent protein (GFP). SMC DNA synthesis was significantly blocked in the cells transfected with the dominant mutant BMK1. These data support the suggestion that BMK1 is important and necessary for mitogen-induced SMC proliferation.
A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding
Authors: Refino Canio J. , Jeet Surinder , DeGuzman Leo , Bunting Stuart , Kirchhofer Daniel
Published: July 2002

10C12, a human antibody F(ab′)
2
, which specifically binds to the γ-carboxyglutamic acid domain of factor IX/factor IXa (F.IX/IXa), interferes with all known coagulation processes in which F.IX/IXa is involved. In a rabbit model of carotid artery injury, intravenous administration of 10C12 or heparin decreased thrombosis dose dependently. The dose that resulted in a 90% reduction of thrombus mass (ED
90
) was a 30-μg/kg bolus of 10C12 or a 100-U/kg bolus plus 1.0 U · kg
−1
· min
−1
infusion of heparin. Heparin, at and below the ED
90
, significantly prolonged coagulation times and cuticle bleeding times. In contrast, 10C12 had no effect on coagulation or bleeding times at doses up to 4 times the ED
90
. To further evaluate the effect of 10C12 on bleeding, it was compared with heparin in a novel model of blood loss. At the ED
90
of heparin, blood loss induced by a standardized injury to the vasculature of the rabbit tibia increased to more than 2 times that of saline controls. In contrast, the dose of 10C12 required to produce a similar increase in blood loss was more than 30 times the ED
90
. The antithrombotic potency and relative safety of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.
Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice
Authors: Aiello Robert J. , Bourassa Patricia-Ann , Lindsey Saralyn , Weng Weifan , Freeman Ann , Showell Henry J.
Published: July 2002

Leukotriene B4 (LTB4) is a potent chemotactic agent that activates monocytes through the LTB4 receptor (BLTR). We tested the hypothesis that LTB4 receptor blockade would slow atherosclerotic progression by inhibiting monocyte recruitment. Homozygous low-density receptor knockout (LDLr
−/−
) mice and apolipoprotein E deficient (apoE
−/−
) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days. In apoE
−/−
mice, treatment with the LTB4 antagonist did not affect plasma lipid concentrations but significantly reduced CD11b levels both in vascular lesions and whole blood. Compared with age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE
−/−
mice at all time points tested. Lesion area reduction was also demonstrated in LDLr
−/−
mice maintained on a high-fat diet. LTB4 antagonism had no significant effect on lesion size in mice possessing the null alleles for another chemotactic agent, monocyte chemoattractant protein-1 (MCP-1
−/−
×apoE
−/−
), suggesting MCP-1 and LTB4 may either interact or exert their effects by a common mechanism. These results demonstrate that in a preclinical model of atherosclerosis LTB4 receptor blockade reduces lesion progression and further suggest a previously unrecognized role for LTB4 or other oxidized lipids recognized by the BLTR receptor in the pathogenesis of this disease.
Extending Tissue Plasminogen Activator Use to Community and Rural Stroke Patients
Authors: Merino José G. , Silver Brian , Wong Edward , Foell Blaine , Demaerschalk Bart , Tamayo Arturo , Poncha Fali , Hachinski Vladimir
Published: July 2002

Background and Purpose

—

Guidelines for intravenous tissue plasminogen activator (tPA) use in stroke emphasize the importance of limiting its use to facilities with imaging capabilities and stroke expertise. This prospective case series set out to evaluate the safety of tPA use in patients referred from rural communities to a tertiary center.

Methods

—

Prospective data of 82 consecutive patients treated with tPA in London, Ontario, were reviewed.

Results

—

Twenty-three patients were transferred to London from a rural hospital (non-London patients); 49 were first evaluated in a London emergency room (London ER); and 10 were inpatients in a London hospital at the time of stroke onset. Mean transfer time and distance to London for non-London patients were 89 minutes and 41 miles. Although symptom onset to London ER times were longer for non-London than for London ER patients (123 versus 53 minutes), the door to needle times were significantly shorter for the former (49 versus 95 minutes,
P
<0.005). Imaging to needle times were longer for London inpatients compared with London ER patients (55 versus 36 minutes,
P
=0.16). The proportion of patients with >4-point improvement on the NIH Stroke Scale or cure at 24 hours was 57%, with no difference among groups (
P
=0.46). The overall symptomatic hemorrhage rate at 36 hours was 2%. No significant differences in outcomes were observed at 3 months.

Conclusions

—

This prospective study suggests that it is feasible and safe to treat rural patients referred to a tertiary care center with tPA, thus extending the benefits of thrombolysis for acute stroke to a wider population.
Risk of Hospitalized Stroke in Men Enrolled in the Honolulu Heart Program and the Framingham Study
Authors: Rodriguez Beatriz L. , D’Agostino Ralph , Abbott Robert D. , Kagan Abraham , Burchfiel Cecil M. , Yano Katsuhiko , Ross G. Webster , Silbershatz Halit , Higgins Millicent W. , Popper Jordan , Wolf Philip A. , Curb J. David
Published: July 2002

Background and Purpose

—

Risk of death due to stroke in Japan is more than double the risk in the United States. It remains unknown why some ethnic groups are more prone to stroke than others.

Our purpose was to compare the 20-year incidence of hospitalized stroke between Japanese-American men in the Honolulu Heart Program and white men in the Framingham Study.

Methods

—

This was a 20-year follow-up study beginning around 1965, a population-based study on the island of Oahu, Hawaii, and in Framingham, Mass. Participants were 7589 men in Honolulu and 1216 men in Framingham without prevalent coronary heart disease and stroke. Subjects were 45 to 68 years old when follow-up began. Main outcome measures were incident thromboembolic and hemorrhagic stroke.

Results

—

Framingham men had a 40% excess of thromboembolic stroke compared with Honolulu men after adjustment for age and other risk factors (62/1000 versus 45/1000, respectively,
P
<0.001), whereas incidence of hemorrhagic stroke was nearly identical (14.8/1000). In both cohorts, each stroke type was consistently elevated in the presence of hypertension and cigarette smoking. Diabetes and body mass index increased the risk of thromboembolic stroke in both samples, and diabetes increased the risk of hemorrhagic events in Framingham. Alcohol intake and low total cholesterol were associated with hemorrhagic events in Honolulu but not in Framingham. Despite occasional differences in risk factor effects, none were significantly different between cohorts.

Conclusions

—

The incidence of thromboembolic stroke requiring hospitalization is markedly less in Honolulu than in Framingham. The difference in stroke incidence rates observed cannot be explained by the traditional risk factors. Further studies are needed to identify factors that protect Japanese-American men in Honolulu from stroke.
Creatine Kinase-MB Elevation After Stroke Is Not Cardiac in Origin
Authors: Ay Hakan , Arsava Ethem Murat , Sarıbaş Okay
Published: July 2002

Background and Purpose

—

Creatine kinase-MB (CK-MB) increases in some patients with stroke, with no clear evidence of an acute coronary syndrome. Its elevations have been suggested to represent a biological marker for stroke-related myocardial injury. Troponin T has superior sensitivity and specificity to CK-MB in revealing minor myocardial injury. Therefore, we studied troponin T levels after stroke to determine whether troponin T increases in parallel to CK-MB.

Methods

—

We made daily measurements of CK-MB, myoglobin, total creatine kinase (total CK), and troponin T levels up to day 5 in 32 patients with large hemispheric infarction and with no history of coronary heart disease. The daily enzyme levels were compared with those of a control group of 22 patients with neurological diseases other than stroke.

Results

—

Serum CK-MB, myoglobin, and total CK levels were elevated above the cutoff value in 11, 26, and 20 patients with stroke, respectively. These enzyme levels gradually increased within the first 3 days and declined afterward. Troponin T did not exceed the reference range in any patients. One patient had elevated myoglobin and 3 had elevated total CK in the control group. The difference between groups was significant for CK-MB, myoglobin, and total CK at various time points.

Conclusions

—

Troponin T, a more specific biochemical marker of myocardial injury, does not increase after stroke. Normal troponin T along with elevated CK-MB signifies that CK-MB is not the biological marker for myocytolysis. CK-MB elevations in stroke patients are likely to be noncardiac in origin.
The Association Between Trait Anger and Incident Stroke Risk
Authors: Williams Janice E. , Nieto F. Javier , Sanford Catherine P. , Couper David J. , Tyroler Herman A.
Published: July 2002

Background and Purpose

—

This study examined the relation between trait anger and incident stroke risk among participants without a history of stroke at the first follow-up examination of the Atherosclerosis Risk in Communities (ARIC) study.

Methods

—

The study sample included 13 851 black and white men and women, aged 48 to 67 years, who completed the Spielberger Trait Anger Scale. Median follow-up time was 77.3 months.

Results

—

In the full cohort, Cox proportional hazards regression analyses showed a modest increase in the risk for stroke among individuals with high trait anger, though the association did not remain statistically significant after multivariate adjustment. Participants ≤60 years of age who reported having high trait anger had a 2.82 (95% CI, 1.65 to 4.80) times greater risk for hemorrhagic and ischemic strokes combined (any) and a 2.93 (95% CI, 1.64 to 5.22) times greater risk for ischemic strokes alone than their counterparts who reported having low trait anger (hazard rate ratios adjusted for sex and race/ethnicity). Similarly, among participants with HDL cholesterol levels >47, the risk for any stroke was 2.86 (95% CI, 1.56 to 5.25) times greater for those who reported having high trait anger, whereas the risk for ischemic strokes alone was 2.98 (95% CI, 1.58 to 5.61) times greater (hazard rate ratios adjusted for age, sex, and race/ethnicity). These associations remained strong and statistically significant after further adjustment for several established biological and sociodemographic risk factors for stroke and were absent among older participants and those with lower HDL cholesterol values.

Conclusions

—

Trait anger was associated with an increased risk for incident stroke in the ARIC study among younger participants and those with higher HDL cholesterol levels.
Prevalence and Risk Factors of Silent Brain Infarcts in the Population-Based Rotterdam Scan Study
Authors: Vermeer Sarah E. , Koudstaal Peter J. , Oudkerk Matthijs , Hofman Albert , Breteler Monique M.B.
Published: July 2002

Background and Purpose

—

Silent brain infarcts are commonly seen on magnetic resonance imaging (MRI) both in patients with a first stroke and in healthy elderly persons. These infarcts seem associated with an increased risk of stroke. It is unclear whether risk factors for silent infarcts differ from those for symptomatic stroke. We investigated the prevalence of, and cardiovascular risk factors for, silent brain infarcts.

Methods

—

The Rotterdam Scan Study is a population-based cohort study among 1077 participants 60 to 90 years of age. Participants underwent cerebral MRI. We assessed cardiovascular risk factors by interview and physical examination. Associations between risk factors and presence of infarcts were analyzed by logistic regression and adjusted for age, sex, and relevant confounders.

Results

—

For 259 participants (24%) 1 or more infarcts on MRI were seen; 217 persons had only silent and 42 had symptomatic infarcts. The prevalence odds ratio (OR) of both silent and symptomatic infarcts increased with age by 8% per year (95% CI, 1.06 to 1.10 and 1.04 to 1.13, respectively). Silent infarcts were more frequent in women (age-adjusted OR, 1.4; 95% CI, 1.0 to 1.8). Hypertension was associated with silent infarcts (age- and sex-adjusted OR, 2.4; 95% CI, 1.7 to 3.3), but diabetes mellitus and smoking were not.

Conclusions

—

Silent brain infarcts are 5 times as prevalent as symptomatic brain infarcts in the general population. Their prevalence increases with age and seems higher in women. Hypertension is associated with silent infarcts, but other cardiovascular risk factors are not.