bluuebunny/crossref_metadata_2025 huggingface dataset:
Progression of Atherosclerosis Is Associated With Variation in the α
1
-Antitrypsin Gene
Authors: Talmud Philippa J. , Martin Steve , Steiner George , Flavell David M. , Whitehouse David B. , Nagl Sylvia , Jackson Richard , Taskinen Marja-Riitta , Frick M. Heikki , Nieminen Markku S. , Kesäniemi Y. Antero , Pasternack Amos , Humphries Steve E. , Syvänne Mikko
Published: April 2003

Objective—

α
1
-Antitrypsin (AAT) protects elastic tissue and may play a role in atherogenesis. The association of atherosclerosis progression with common AAT variants was considered in 2 clinical trials.

Methods and Results—

We examined the association of AAT V213A, S and Z deficiency alleles, and the functional 3′ UTR 11478G>A with change in minimal luminal diameter, a measure of focal disease, in the Lopid Coronary Angiography Trial gemfibrozil study of post-bypass men. S or Z carriers (n=14) showed strong progression of disease on placebo (11.5%) but responded well to treatment (3% regression). 11478A carriers treated with placebo or gemfibrozil showed significantly more disease progression (n=8, −14.5% and n=16, −4.0%, respectively) than 11478GG men (n=107, −7.0% and n=108, −1.4%, respectively; overall,
P
=0.003). VV213 men treated with gemfibrozil (n=68) showed −4.8% progression, whereas A213 carriers (n=55) showed +1.4% regression of disease (
P
=0.001). No V213A effect was seen on placebo (
P
=0.11). In the Diabetes Atherosclerosis Intervention Study fenofibrate trial of angiographic progression in type 2 diabetes, the association of 11478A with increased disease progression was confirmed in the treatment group, but not the gemfibrozil-treated A213 association with regression, suggesting a pharmacogenetic difference.

Conclusions—

Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis.
Systemic Arterial Expression of Matrix Metalloproteinases 2 and 9 in Acute Kawasaki Disease
Authors: Gavin Patrick J. , Crawford Susan E. , Shulman Stanford T. , Garcia Francesca L. , Rowley Anne H.
Published: April 2003

Objective—

Coronary artery aneurysms are the major complication of Kawasaki disease (KD). Matrix metalloproteinases (MMPs) regulate remodeling and degradation of the extracellular matrix. We hypothesized that MMP-9 expression is increased in acute KD aneurysms when compared with KD nonaneurysmal arteries and arteries from control children.

Methods and Results—

MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were immunolocalized in coronary arteries from children with fatal acute KD and controls. In KD coronary aneurysms, MMP-2 expression was prominent in the thickened neointima and in endothelial cells of new capillaries in areas of angiogenesis. MMP-9 was absent in control coronary arteries but was expressed in coronary artery aneurysms, nonaneurysmal coronary and noncoronary arteries, and cardiac nerves in acute KD, without an increase in TIMP-1 expression.

Conclusions—

MMP-2 likely participates in remodeling of the arterial wall in acute KD, particularly in the processes of neointimal proliferation and angiogenesis. MMP-9 may play a role in the development of coronary aneurysms, but its expression is not confined to aneurysmal arteries. Systemic arterial expression of MMP-9 in acute KD, even in the absence of inflammatory changes in the vessel, suggests induction by a circulating factor, or possibly by an infectious agent with tropism for arterial tissue.
C-Reactive Protein Is Independently Associated With Fasting Insulin in Nondiabetic Women
Authors: Pradhan Aruna D. , Cook Nancy R. , Buring Julie E. , Manson JoAnn E. , Ridker Paul M.
Published: April 2003

Objective—

Insulin resistance is associated with chronic subclinical inflammation, and both conditions are linked with increased risk for type 2 diabetes mellitus and atherothrombotic cardiovascular disease.

Methods and Results—

In a cross-sectional study conducted among participants in the Women’s Health Study, an ongoing US primary prevention trial of cardiovascular disease and cancer, we evaluated the correlates of elevated fasting insulin, a marker of insulin resistance, among 349 healthy, nondiabetic women who remained free from clinically diagnosed type 2 diabetes mellitus during a 4-year period from biomarker assessment. Fasting insulin was strongly associated with body mass index (BMI) (
r
=0.53,
P
<0.001), C-reactive protein (CRP) (
r
=0.38,
P
<0.001), and interleukin-6 (
r
=0.33,
P
<0.001). Physical activity level, alcohol consumption, and use of hormone replacement therapy were also related to fasting insulin. However, in multivariable linear regression analysis, BMI and CRP were the only independent correlates of log-normalized fasting insulin. Overall, the final model explained 32% of the variance in log insulin level. In multivariable logistic regression, the fully adjusted odds ratio (OR) for elevated fasting insulin (≥51.6 pmol/L) increased with tertile of BMI, CRP, and IL-6, such that the ORs in the highest versus lowest tertile of each parameter were 9.0 (95% confidence interval [CI], 4.4 to 18.7), 4.4 (95% CI, 1.9 to 10.1), and 2.0 (95% CI, 0.9 to 4.2), respectively. Furthermore, increasing levels of CRP were associated with a stepwise gradient in odds for elevated fasting insulin among both lean and overweight women.

Conclusions—

CRP is independently associated with fasting hyperinsulinemia in nondiabetic women. These data provide additional support for previously reported associations between subclinical inflammation and the risk of type 2 diabetes and cardiovascular disease.
Factors Regulating Arteriogenesis
Authors: Schaper Wolfgang , Scholz Dimitri
Published: April 2003

Growth of collateral vessels is potentially able to preserve structure and a variable degree of function in subtended tissues in the presence of arterial occlusions. The process of transformation of a small arteriole into much larger conductance artery is called arteriogenesis. Small arterioles that interconnect side branches proximal from the arterial occlusion with distal ones experience increased fluid shear stress because of the increased blood flow velocity attributable to the pressure gradient along the bridging collaterals. This activates the endothelium and leads to monocyte adhesion and infiltration with the subsequent production of growth factors and proteases. Preexistent arterioles are essential. Their presence is genetically determined. Arteriogenesis is not organ- or species-specific; coronary or peripheral collateral vessels develop following the same design principles in mice, rats, rabbits, or dogs. In contrast to angiogenesis, arteriogenesis is not dependent on the presence of hypoxia/ischemia.
A Quantitative In Vitro Model of Smooth Muscle Cell Migration Through the Arterial Wall Using the Human Amniotic Membrane
Authors: Kallenbach Klaus , Fernandez Harold A. , Seghezzi Graziano , Baumann F. Gregory , Patel Sundeep , Grossi Eugene A. , Galloway Aubrey C. , Mignatti Paolo
Published: April 2003

Objective—

The development of intimal hyperplasia involves smooth muscle cell (SMC) migration into the intima and proliferation. Matrix metalloproteinases and their tissue inhibitors play important roles in this process. In this study, we describe a novel in vitro model for studying SMC migration through the vessel wall.

Methods and Results—

Human aortic SMCs (hASMCs) labeled with
125
I-iododeoxyuridine or unlabeled were grown on the stromal aspect of the human amniotic membrane. Mechanical damage to endothelial cells grown on the basement membrane and addition of growth factors or platelets were characterized for their effect on SMC migration into the stroma both by histological methods and by measuring the radioactivity associated with the membrane after removal of noninvasive SMCs. To assess the reliability of the model, the cells were infected with a recombinant adenovirus encoding the tissue inhibitor of metalloproteinase-1 (TIMP-1). Addition of a platelet-derived growth factor gradient stimulated hASMC infiltration into the stroma. This effect was abolished with TIMP-1-transduced hASMC, confirming that TIMP-1 overexpression blocks SMC invasion of the stroma.

Conclusions—

This in vitro model of SMC migration in the vessel wall provides an inexpensive, quantitative, and reliable tool to study the molecular and cellular mechanisms of intimal hyperplasia.
Extracellular Mediators in Atherosclerosis and Thrombosis
Authors: Major Christopher D. , Santulli Rosemary J. , Derian Claudia K. , Andrade-Gordon Patricia
Published: April 2003

It is well appreciated that thrombin as well as other proteases can act as signaling molecules that specifically regulate cells by cleaving and activating members of a novel class of protease-activated receptors (PARs). The utility of gene knockout strategies to define and better comprehend the physiological role of specific proteins is perhaps best exemplified in the field of thrombin receptors. The development of PAR knockout mice has provided the unique opportunity to identify and characterize new members of this novel family of GPCRs, evaluate the interaction of PARs jointly expressed in common cells and tissues, and better understand the role of PARs in thrombosis, restenosis, vascular remodeling, angiogenesis, and inflammation. Presently, 4 members of the PAR family have been cloned and identified. In this review, we examine experimental evidence gleaned from PAR−/−mouse models as well as how the use of PAR−/−mice has provided insights toward understanding the physiological role of thrombin in cells of the vascular system and vascular pathology.
Red Wine Polyphenolic Compounds Inhibit Vascular Endothelial Growth Factor Expression in Vascular Smooth Muscle Cells by Preventing the Activation of the p38 Mitogen-Activated Protein Kinase Pathway
Authors: Oak Min-Ho , Chataigneau Marta , Keravis Thérèse , Chataigneau Thierry , Beretz Alain , Andriantsitohaina Ramaroson , Stoclet Jean-Claude , Chang Soon-Jae , Schini-Kerth Valérie B.
Published: April 2003

Objective—

Moderate consumption of red wine has a beneficial effect on the cardiovascular system. This study examines whether red wine polyphenolic compounds (RWPCs) affect vascular endothelial growth factor (VEGF) expression, a major angiogenic and proatherosclerotic factor in vascular smooth muscle cells (VSMCs).

Methods and Results—

VEGF mRNA expression was assessed by Northern blot analysis and the release of VEGF by immunoassay in cultured VSMCs. Short-term and long-term exposure of VSMCs to RWPCs inhibited VEGF mRNA expression and release of VEGF in response to platelet-derived growth factor AB (PDGF
AB
), transforming growth factor-β
1
, or thrombin. The PDGF
AB
-induced expression of VEGF was markedly reduced by SB203580 (inhibitor of p38 mitogen-activated protein kinase [MAPK]), antioxidants, and diphenylene iodonium (inhibitor of flavin-dependent enzymes), slightly reduced by PD98059 (inhibitor of MEK), and not significantly affected by wortmannin (inhibitor of PI-3-kinase) and L-JNKI (inhibitor of JNK). Short-term and long-term treatment of VSMCs with RWPCs markedly reduced PDGF
AB
-induced production of reactive oxygen species and phosphorylation of p38 MAPK.

Conclusions—

These data indicate that RWPCs strongly inhibit growth factor–induced VEGF expression in VSMCs by preventing the redox-sensitive activation of the p38 MAPK pathway. The potential antiangiogenic and antiatherosclerotic properties of RWPCs are likely to contribute to cardiovascular protection by preventing the development of atherosclerotic lesions.
Baroreflex Buffering Is Reduced With Age in Healthy Men
Authors: Jones Pamela Parker , Christou Demetra D. , Jordan Jens , Seals Douglas R.
Published: April 2003

Background—

Baroreflex buffering is an important mechanism in arterial blood pressure control. The effect of healthy (physiological) aging on tonic baroreflex buffering in humans is unknown.

Methods and Results—

Baroreflex buffering was determined in 27 young (aged 25±1 years) and 16 older (aged 65±1 years) healthy normotensive men by measuring the potentiation of the systolic blood pressure (SBP) responses to a phenylephrine bolus (BRB
bolus
) and incremental infusion (BRB
slope
) during compared with before ganglionic blockade with trimethaphan. The SBP responses to phenylephrine either were not different or greater in the older men before ganglionic blockade, but smaller during ganglionic blockade. BRB
bolus
(2.1±0.4 versus 5.1±0.7,
P
<0.001) and BRB
slope
(1.6±0.2 versus 3.5±0.4,
P
<0.0001) were ≈115% smaller in the older men. Baroreflex buffering was not consistently related to mean levels or variability of blood pressure or heart rate, or to cardiovagal baroreflex sensitivity, but correlated with muscle sympathetic nerve activity (BRB
bolus
:
r
=−0.55, BRB
slope
:
r
=−0.69,
P
<0.005) and the SBP responses to phenylephrine during ganglionic blockade (BRB
bolus
:
r
=0.53; BRB
slope
:
r
=0.98,
P
<0.0001). BRB
bolus
was also inversely related to the SBP response to phenylephrine before ganglionic blockade (
r
=−0.78,
P
<0.0001).

Conclusions—

Physiological aging in men is associated with a marked reduction in baroreflex buffering. The decrease in baroreflex buffering with aging is related to increases in basal sympathetic nerve activity and reductions in systemic α
1
–adrenergic vascular responsiveness. These findings are helpful for interpreting changes in baroreflex buffering in older patients with cardiovascular disease, as well as changes in responsiveness to vasoactive drugs with aging.
Prolonged QTc Interval and High B-Type Natriuretic Peptide Levels Together Predict Mortality in Patients With Advanced Heart Failure
Authors: Vrtovec Bojan , Delgado Reynolds , Zewail Aly , Thomas Cynthia D. , Richartz Barbara M. , Radovancevic Branislav
Published: April 2003

Background—

The role of QTc interval prolongation in heart failure remains poorly defined. To better understand it, we analyzed the QTc interval duration in patients with heart failure with high B-type natriuretic peptide (BNP) levels and analyzed the combined prognostic impact of prolonged QTc and elevated BNP.

Methods and Results—

QTc intervals were measured in 241 patients with heart failure who had BNP levels >400 pg/mL. QT interval duration was determined by averaging 3 consecutive beats through leads II and V
4
on a standard 12-lead ECG and corrected by using the Bazett formula. QTc intervals were prolonged (>440 ms) in 122 (51%) patients and normal in 119 (49%). The BNP levels in these 2 groups were not significantly different (786±321 pg/mL in the prolonged QTc group versus 733±274 pg/mL in the normal QTc group,
P
=0.13). During 6 months of follow-up, 46 patients died, 9 underwent transplantation, and 17 underwent left ventricular assist device implantation. The deaths were attributed to pump failure (n=24, 52%), sudden cardiac death (n=18, 39%), or noncardiac causes (n=4, 9%). Kaplan-Meier survival rates were 3 times higher in the normal QTc group than in the prolonged QTc group (
P
<0.0001). On multivariate analysis, prolonged QTc interval was an independent predictor of all-cause death (
P
=0.0001), cardiac death (
P
=0.0001), sudden cardiac death (
P
=0.004), and pump failure death (
P
=0.0006).

Conclusions—

Prolonged QTc interval is a strong, independent predictor of adverse outcome in patients with heart failure with BNP levels >400 pg/mL.
Relationships Between Low-Density Lipoprotein Particle Size, Plasma Lipoproteins, and Progression of Coronary Artery Disease
Authors: Vakkilainen Juha , Steiner George , Ansquer Jean-Claude , Aubin Francois , Rattier Stephanie , Foucher Christelle , Hamsten Anders , Taskinen Marja-Riitta
Published: April 2003

Background—

The Diabetes Atherosclerosis Intervention Study showed that treatment with fenofibrate decreases progression of coronary atherosclerosis in subjects with type 2 diabetes. We determined whether on-treatment plasma lipid concentrations and LDL particle size contribute to the favorable effect of fenofibrate on the progression of coronary artery disease (CAD).

Methods and Results—

A total of 418 subjects with type 2 diabetes were randomly assigned to 200 mg micronized fenofibrate daily or placebo. The mean follow-up time was 39.6 months. LDL peak particle diameter (LDL size) was determined by polyacrylamide gradient gel electrophoresis from 405 subjects at baseline and at the end of the study. Progression of CAD was measured with quantitative coronary angiography. LDL size increased significantly more in the fenofibrate group than in the placebo group (0.98±1.04 versus 0.32±0.92 nm,
P
<0.001). In the combined group, small LDL size was significantly associated with progression of CAD measured as the increase of percentage diameter stenosis (
r
=−0.16,
P
=0.002) and decreases in minimum (
r
=−0.11,
P
=0.030) and mean (
r
=−0.10,
P
=0.045) lumen diameter. High on-treatment LDL cholesterol, apolipoprotein B, and triglyceride concentrations were also associated with the progression of CAD. In regression analyses, small LDL size added to the effect of LDL cholesterol and apolipoprotein B on the progression of CAD. Similar associations were observed in the fenofibrate group, whereas in the placebo group, lipoprotein variables were not significantly correlated with the progression of CAD.

Conclusions—

Changes in LDL size and plasma lipid levels account for part of the antiatherogenic effect of fenofibrate in type 2 diabetes.
Effect of Chronic Right Atrial Stretch on Atrial Electrical Remodeling in Patients With an Atrial Septal Defect
Authors: Morton Joseph B. , Sanders Prashanthan , Vohra Jitendra K. , Sparks Paul B. , Morgan John G. , Spence Steven J. , Grigg Leeanne E. , Kalman Jonathan M.
Published: April 2003

Background—

Adults with an atrial septal defect (ASD) frequently develop late atrial arrhythmias. We sought to characterize the pattern and persistence of atrial electrical remodeling caused by chronic right atrial (RA) stretch in this group.

Methods and Results—

Thirteen ASD patients without atrial arrhythmia (42±10 years old; RA volume, 65±16 mL) and 17 normal control subjects (44±11 years old; RA volume, 38±8 mL) had electrophysiological study to measure (1) atrial effective refractory period (AERP) from the low lateral/high lateral/high septal RA and distal coronary sinus (CS), (2) dispersion of AERP, (3) lateral-RA and CS conduction time during constant pacing, (4) conduction delay across the crista terminalis measuring the number of crista catheter bipoles (0–10) recording discrete double potentials during pacing, (5) corrected sinus node recovery time, and (6) P-wave duration. After ASD closure (8.3±5.6 months), follow-up echo studies (n=12) and electrophysiological study (n=4) were performed. The low-lateral AERP, P-wave duration, sinus node recovery time, and extent of conduction delay across the crista terminalis were significantly greater in ASD patients. No differences were found for other measured electrophysiological study parameters. At follow-up, there was incomplete resolution of RA volume (47±12 mL;
P
<0.01 versus before surgery), a trend toward shortening of the AERP at the lateral RA and an increase at the distal CS and high septal RA, but persisting extensive, widely split crista double potentials.

Conclusions—

Chronic RA stretch because of ASD causes electrical remodeling with modest increases in RA ERP, conduction delay at the crista terminalis, and sinus node dysfunction. Conduction delay at the crista terminalis persists beyond ASD closure and may contribute to the long-term atrial arrhythmia substrate in this condition.
Protein S Confers Neuronal Protection During Ischemic/Hypoxic Injury in Mice
Authors: Liu Dong , Guo Huang , Griffin John H. , Fernández Jose A. , Zlokovic Berislav V.
Published: April 2003

Background—

Protein S is an antithrombotic factor that also exhibits mitogenic activity. Thus, we hypothesized that protein S may control cerebrovascular thrombosis in stroke and protect brain tissue from ischemic injury.

Methods and Results—

We studied protein S in a murine in vivo model of stroke and an in vitro model of neuronal hypoxia/reoxygenation injury. Animals received purified human plasma–derived protein S or vehicle intravenously 10 minutes after initiation of middle cerebral artery occlusion followed by reperfusion. Protein S at 0.2 to 2 mg/kg significantly improved the motor neurological deficit by 3.8- to 3.2-fold and reduced infarction and edema volumes by 45% to 54% and 45% to 62%, respectively. Protein S at 2 mg/kg improved postischemic cerebral blood flow by 21% to 26% and reduced brain fibrin deposition and infiltration with neutrophils by 40% and 53%, respectively. Intracerebral bleeding was not observed with protein S. Protein S protected ischemic neurons in vivo and cultured neurons from hypoxia/reoxygenation-induced apoptosis in a time- and dose-dependent manner. Recombinant human protein S exerted protective effects from hypoxia-induced damage similar to the plasma-derived protein S both in vivo and in vitro.

Conclusions—

Protein S is a significant neuroprotectant during ischemic brain injury with direct effects on neurons and antithrombotic effects. Thus, protein S could be a prototype of a new class of agents for clinical stroke with combined direct neuronal protective effects and systemic antithrombotic and antiinflammatory activities.
Arrhythmogenic Substrate of the Pulmonary Veins Assessed by High-Resolution Optical Mapping
Authors: Arora Rishi , Verheule Sander , Scott Luis , Navarrete Antonio , Katari Vikram , Wilson Emily , Vaz Dev , Olgin Jeffrey E.
Published: April 2003

Background—

It has recently been recognized that atrial fibrillation can originate from focal sources in the pulmonary veins (PVs). However, the mechanisms of focal atrial fibrillation have not been well characterized. We assessed the electrophysiological characteristics of the PVs using high-resolution optical mapping.

Methods and Results—

Coronary-perfused, isolated whole-atrial preparations from 33 normal dogs were studied. Programmed electrical stimulation was performed, and a 4-cm
2
area of the PV underwent optical mapping of transmembrane voltage to obtain 256 simultaneous action potentials. Marked conduction slowing was seen at the proximal PV, compared with the rest of the vein, on both the epicardial (31.3±4.47 versus 90.2±20.7 cm/s,
P
=0.001) and endocardial (45.8±6.90 versus 67.6±10.4 cm/s,
P
=0.012) aspects. Pronounced repolarization heterogeneity was also noted, with action potential duration at 80% repolarization being longest at the PV endocardium. Nonsustained reentrant beats were induced with single extrastimuli, and the complete reentrant loop was visualized (cycle length, 155±30.3 ms); reentrant activity could be sustained with isoproterenol. Sustained focal discharge (cycle length, 330 to 1100 ms) was seen from the endocardial surface in the presence of isoproterenol; each focus was localized near the venous ostium.

Conclusions—

The normal PV seems to have the necessary substrate to support reentry as well as focal activity. Although reentry occurred more distally in the vein, focal activity seemed to occur more proximally.
Intracellular Chloride Accumulation and Subcellular Elemental Distribution During Atrial Fibrillation
Authors: Akar Joseph G. , Everett Thomas H. , Ho Ruoya , Craft Joseph , Haines David E. , Somlyo Andrew P. , Somlyo Avril V.
Published: April 2003

Background—

Ion channel remodeling occurs during atrial fibrillation (AF); however, the extent of alteration in the subcellular distribution of elements (Na, K, Cl, Ca, Mg, P) is unknown. Electron probe microanalysis was used to determine the total (free+bound) in vivo subcellular concentration of these elements during AF.

Methods and Results—

The left atrial appendage (LAA) was snap-frozen in situ after pacing (640 bpm) for 3 minutes (n=5 dogs), 30 minutes (n=3), or 48 hours (n=5). Dogs in sinus rhythm (n=3) served as controls. Whole-cell, cytosolic, and mitochondrial elemental concentrations were measured in cryosections. LAA effective refractory period (ERP) was measured before and after pacing. LAA ERP decreased significantly after 48 hours (116±3 to 88±10 ms,
P
=0.02). Whole-cell Cl increased by 9.0 mmol/L and 17 mmol/L after 3 and 30 minutes of pacing, respectively (
P
<0.0001), without a concomitant increase in Na. However, at 48 hours, whole-cell Na was reduced by 51% (
P
<0.01). Cytosolic Ca increased by 1.1 mmol/kg dry wt after 3 minutes (
P
<0.005), but mitochondrial Ca remained low and unchanged. Cell size measured in transverse cryosections increased after 3 minutes of pacing (75±5 to 109±11 μm
2
,
P
=0.007) but returned to baseline by 30 minutes (66±5 μm
2
).

Conclusions—

Intracellular Cl accumulation induced by rapid pacing is a novel finding and may play a role in AF pathogenesis by causing resting membrane depolarization and ERP reduction. There was no evidence of cellular or mitochondrial Ca overload despite the development of electrical remodeling and transient increase in cytoplasmic Ca.
Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation
Authors: Ayoub Iyad M. , Kolarova Julieta , Yi Zhong , Trevedi Atul , Deshmukh Hanumant , Lubell David L. , Franz Michael R. , Maldonado Frank A. , Gazmuri Raúl J.
Published: April 2003

Background—

Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation.

Methods and Results—

Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0±0.2 to 1.5±0.3 cm with NaCl,
P
<0.001 versus 0.9±0.1 to 1.1±0.3 cm with cariporide,
P
=NS), maintained the coronary perfusion pressure above resuscitability thresholds (10±8 versus 19±3 mm Hg before attempting defibrillation,
P
<0.05), and increased resuscitability (2 of 8 versus 8 of 8,
P
<0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD
60
at 2 minutes after resuscitation; 75±29 versus 226±16 ms,
P
<0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction.

Conclusions—

NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.
Intramural Coronary Vasculature Prevents Transmural Radiofrequency Lesion Formation
Authors: Fuller Ithiel A. , Wood Mark A.
Published: April 2003

Background—

Blood flow near a radiofrequency (RF) lesion can reduce lesion size by convective cooling. It is unknown whether blood flow through small vasculature within an RF lesion can prevent transmural lesion formation.

Methods and Results—

In 40 rabbit right ventricle preparations, 2 epicardial RF lesions were created straddling a selectively perfused (0 to 12 mL/min) marginal artery (diameter, 0.34±0.1 mm). RF lesions were created at either 60°C or 80°C and delivered either sequentially or simultaneously. Conduction through the lesion area was measured. The lesions were analyzed histologically. At a perfusion rate of 0 mL/min, all RF lesions were transmural and without conduction. As little as 1 mL of flow through the artery during RF delivery could prevent transmural lesion formation by preserving a cuff of tissue along the length of the vessel. High-energy delivery (45 W) and very high tissue temperatures (93°C) were needed to overcome the protective effect of vascular perfusion at 12 mL/min. The volume of preserved myocardium was related to arterial perfusion rate, artery diameter, and lesion temperature but not to the sequence of RF delivery (sequential versus simultaneous). Conduction persisted through the RF lesion in 20 experiments. Conduction through the lesion was related to the arterial perfusion rate and volume or cross-sectional area of preserved myocardium.

Conclusions—

Flow through even small intramyocardial vessels can prevent transmural lesion formation and preserve conduction through an RF lesion. These findings may represent an unrecognized obstacle to the creation of linear RF lesions in the clinical setting.
Stent-Induced Expression and Activation of the Leukocyte Integrin Mac-1 Is Associated With Neointimal Thickening and Restenosis
Authors: Inoue Teruo , Uchida Toshihiko , Yaguchi Isao , Sakai Yoshihiko , Takayanagi Kan , Morooka Shigenori
Published: April 2003

Background—

Increased expression of the β
2
integrin Mac-1 (CD11b/CD18, α
M
β
2
), which is responsible for firm leukocyte adhesion to platelets and fibrinogen at injured vessels, is found in association with neointimal hyperplasia after coronary interventions. The role of Mac-1 in the pathophysiology of restenosis is incompletely defined. To clarify further the role of Mac-1, we determined whether coronary stenting induced activation of Mac-1, which is required for high-affinity receptor-ligand interactions.

Methods and Results—

Expression of CD11b (α-subunit of Mac-1) and binding of 8B2 (monoclonal antibody against an activation-dependent neoepitope of Mac-1) on the surface of polymorphonuclear leukocytes were analyzed in 62 patients undergoing coronary stenting using flow cytometric analysis of whole blood obtained from the coronary sinus and femoral vein. Transcardiac CD11b expression increased significantly at 24 hours and maximally at 48 hours after stenting; 8B2 began to increase at 10 minutes and was maximally increased at 48 hours after stenting. These changes were more prominent in patients with subsequent restenosis. Multiple regression analysis showed that the late lumen loss by quantitative coronary angiographic analysis was independently correlated with the CD11b increase (
R
=0.42,
P
<0.01) and the 8B2 increase (
R
=0.55,
P
<0.001) 48 hours after the procedure. Mac-1 activation, as assessed by 8B2 binding, was the most powerful predictor of late lumen loss.

Conclusion—

Coronary stenting produced upregulation and early activation of the leukocyte integrin Mac-1, which is associated with late lumen loss and restenosis. These data support a role for inflammation in neointimal thickening and suggest the validity of targeting leukocyte recruitment for preventing clinical restenosis.
Intracoronary Radiation Therapy Improves the Clinical and Angiographic Outcomes of Diffuse In-Stent Restenotic Lesions
Authors: Waksman Ron , Cheneau Edouard , Ajani Andrew E. , White R. Larry , Pinnow Ellen , Torguson Rebecca , Deible Regina , Satler Lowell F. , Pichard Augusto D. , Kent Kenneth M. , Teirstein Paul S. , Lindsay Joseph
Published: April 2003

Background—

The Washington Radiation for In-Stent Restenosis Trial for long lesions (Long WRIST) was designed to determine the safety and efficacy of vascular brachytherapy for the treatment of diffuse in-stent restenosis.

Methods and Results—

A total of 120 patients with diffuse in-stent restenosis in native coronary arteries (lesion length, 36 to 80 mm) were randomized for either radiation with
192
Ir with 15 Gy at 2 mm from the source axis or placebo. After enrollment, 120 additional patients with the same inclusion criteria were treated with
192
Ir with 18 Gy and included in the Long WRIST High Dose registry. Antiplatelet therapy was initially prescribed for 1 month and was extended to 6 months in the last 60 patients of the Long WRIST High Dose registry. At 6 months, the binary angiographic restenosis rate was 73%, 45%, and 38% in the placebo, 15 Gy, and 18 Gy radiated groups, respectively (
P
<0.05). At 1 year, the primary clinical end point of major cardiac events was 63% in the placebo group and 42% in the radiated group with 15 Gy (
P
<0.05). The major cardiac event rate was further reduced with 18 Gy (22%;
P
<0.05 versus 15 Gy). Late thrombosis was 12%, 15%, and 9% in the placebo group, 15 Gy group with 1 month of antiplatelet therapy, and 18 Gy group with 6 months of antiplatelet therapy, respectively.

Conclusions—

Vascular brachytherapy with
192
Ir is safe and reduces the rate of recurrent restenosis in diffuse in-stent restenosis. The efficacy of vascular brachytherapy on angiographic and clinical outcomes is enhanced with a radiation dose of 18 Gy and prolonged antiplatelet therapy.
Relation of Inflammation and Benefit of Statins After Percutaneous Coronary Interventions
Authors: Chan Albert W. , Bhatt Deepak L. , Chew Derek P. , Reginelli Joel , Schneider Jakob P. , Topol Eric J. , Ellis Stephen G.
Published: April 2003

Background—

Beyond lipid lowering, statins are known to possess antiinflammatory and antithrombotic properties. Recent studies suggested an association between statins and early reduction in death or myocardial infarction (MI) after percutaneous coronary interventions (PCIs). We sought to examine the interrelationship between inflammation, statin use, and PCI outcomes.

Methods and Results—

In the year 2000, 1552 consecutive United States residents underwent elective or urgent PCI at the Cleveland Clinic and were prospectively followed for 1 year. Preprocedural serum high-sensitivity C-reactive protein (hsCRP) levels were routinely measured. Patients who had statins initiated before the procedure (39.6%) had a lower median hsCRP level (0.40 versus 0.50 mg/dL,
P
=0.012) independent of the baseline cholesterol levels and had less frequent periprocedural MI (defined by CKMB ≥3×upper limit of normal, 5.7% versus 8.1%,
P
=0.038). At 1 year, statin pretreatment was predictive of survival predominantly among patients within the highest hsCRP quartile (mortality rate with statin pretreatment versus no pretreatment when hsCRP ≥1.11 mg/dL, 5.7% versus 14.8%,
P
=0.009). Using multivariate analysis, preprocedural hsCRP level remained an independent predictor for 1-year death or MI only in patients without statin therapy (hazard ratio, 1.32/quartile;
P
=0.001). After adjusting for the propensity of receiving statins, statin pretreatment was an independent predictor for 1-year survival within the highest hsCRP quartile (hazard ratio, 0.44;
P
=0.039).

Conclusions—

Statin therapy before PCI is associated with a marked reduction in mortality among patients with high hsCRP levels. A hsCRP-guided strategy may improve targeting of statin therapy and clinical outcome among patients undergoing PCI.
Noninvasive Determination of Coronary Blood Flow Velocity With Cardiovascular Magnetic Resonance in Patients After Stent Deployment
Authors: Nagel Eike , Thouet Thomas , Klein Christoph , Schalla Simon , Bornstedt Axel , Schnackenburg Bernhard , Hug Jürgen , Wellnhofer Ernst , Fleck Eckart
Published: April 2003

Background—

In patients with coronary artery stents, no direct noninvasive coronary artery imaging is possible with magnetic resonance (MR). A well-established method for the assessment of the functional significance of a coronary lesion is the measurement of coronary flow reserve by invasive intracoronary Doppler. The purpose of the study was to determine coronary flow velocity reserve (CFVR) with MR after stent deployment.

Methods and Results—

Thirty-eight patients after successful PTCA and stent deployment were included. CFVR was measured perpendicular to the artery distal to the stent using phase-contrast velocity quantification at rest and during adenosine-stimulated hyperemia with a 1.5T MR tomograph (ACS NT, Philips). Measurements were repeated after 3 months and compared with invasive coronary angiography. In 18 patients, additional invasive Doppler flow measurements were obtained. CFVR could be determined in 29 of 38 (76%) of the patients. After 3 months, significant differences were obtained between coronary arteries with and without restenosis. Using a threshold of 1.2, a sensitivity of 83% with a specificity of 94% was achieved for ≥75% stenoses. CFVR with CMR was similar to Doppler results (
r
=0.87), with a mean relative difference of 7.5%.

Conclusions—

In patients with preserved coronary microcirculating vasoreactivity that are suitable for MR coronary angiography and flow assessments, CMR measures of coronary blood flow velocities reserve may be used to detect in-stent restenosis.
C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle
Authors: Wang Chao-Hung , Li Shu-Hong , Weisel Richard D. , Fedak Paul W.M. , Dumont Aaron S. , Szmitko Paul , Li Ren-Ke , Mickle Donald A.G. , Verma Subodh
Published: April 2003

Background—

Accumulating evidence suggests that C-reactive protein (CRP), in addition to predicting vascular disease, may actively facilitate lesion formation by inciting endothelial cell activation. Given the central importance of angiotensin type 1 receptor (AT
1
-R) in the pathogenesis of atherosclerosis, we examined the effects of CRP on AT
1
-R expression and kinetics in vascular smooth muscle (VSM) cells. In addition, the effects of CRP on VSM migration, proliferation, and reactive oxygen species (ROS) production were evaluated in the presence and absence of the angiotensin receptor blocker, losartan. Lastly, the effects of CRP (and losartan) on neointimal formation were examined in vivo in a rat carotid angioplasty model.

Methods and Results—

The effects of human recombinant CRP (0 to 100 μg/mL) on AT
1
-R transcript, mRNA stability, and protein expression were studied in cultured human VSM cells. AT
1
-R binding was assessed with
125
I-labeled angiotensin II (Ang II). VSM migration was assessed with wound cell migration assays, whereas VSM proliferation was determined with [
3
H]-incorporation and cell number. The effects of CRP (and losartan) on Ang II–induced ROS production were evaluated by 2′,7′-dichlorofluorescein fluorescence. Lastly, the effects of CRP (and losartan) on neointimal formation, VSM cell migration, proliferation, and matrix formation were studied in vivo in a rat carotid artery balloon injury model. CRP markedly upregulated AT
1
-R mRNA and protein expression and increased AT
1
-R number on VSM cells. CRP promoted VSM migration and proliferation in vitro and increased ROS production. Furthermore, CRP potentiated the effects of Ang II on these processes. In the rat carotid artery angioplasty model, exposure to CRP resulted in an increase in cell migration and proliferation, collagen and elastin content, and AT
1
-R expression, as well as an increase in neointimal formation; these effects were attenuated by losartan.

Conclusions—

CRP, at concentrations known to predict cardiovascular events, upregulates AT
1
-R–mediated atherosclerotic events in vascular smooth muscle in vitro and in vivo. These data lend credence to the notion that CRP functions as a proatherosclerotic factor as well as a powerful risk marker.
Interaction Between Soluble Thrombomodulin and Intercellular Adhesion Molecule-1 in Predicting Risk of Coronary Heart Disease
Authors: Wu Kenneth K. , Aleksic Nena , Ballantyne Christie M. , Ahn Chul , Juneja Harinder , Boerwinkle Eric
Published: April 2003

Background—

Results from previous ARIC (Atherosclerosis Risk In Communities) analyses indicate that soluble intercellular adhesive molecule-1 (sICAM) and soluble thrombomodulin (sTM) levels are associated with risk of coronary heart disease (CHD) in an opposite direction. A high sICAM level increases the risk of CHD, whereas a high level of sTM has a lower risk of CHD. It was unclear whether there was an interaction between sTM and sICAM.

Methods and Results—

Using a nested case-cohort design, we measured sTM and sICAM in 317 incident CHD cases and 726 non-cases from the ARIC participants. Consistent with our previous reports, sICAM values in the upper versus the lower tertile increased the risk of CHD event by ≈2-fold (95% confidence interval [CI], 1.46 to 2.87) whereas sTM values in the lower versus the upper tertile increased CHD risk by ≈4-fold (95% CI, 2.80 to 5.74). Interaction between these 2 parameters was determined by weighted Cox proportional hazard regression. A significant interaction (
P
=0.038) was noted. Combinatorial analysis shows a significant increase in CHD risk ratio (RR) (4.66, 95% CI, 1.89 to 11.46) of the lower sTM/upper sICAM group versus the upper sTM/lower sICAM group. Individuals whose sTM values were in the upper tertile had a RR below 1, even when sICAM were in the upper tertile. The RR of lower tertile sTM was increased by sICAM in a tertile-dependent manner.

Conclusion—

Weighted Cox proportional hazard analysis shows a significant interaction between sTM and sICAM in predicting risk of CHD event. Combinatorial analysis reveals that an upper tertile sICAM had a significant increase in the risk of a CHD event only when sTM was in the lower tertile.
Pilot Trial of Oral Rapamycin for Recalcitrant Restenosis
Authors: Brara Prabhtej S. , Moussavian Mehran , Grise Mark A. , Reilly John P. , Fernandez Mindy , Schatz Richard A. , Teirstein Paul S.
Published: April 2003

Background—

Sirolimus-coated stents are a promising new therapy for restenosis. We treated a select group of patients at especially high risk for restenosis with oral sirolimus.

Methods and Results—

Patients were treated with an oral sirolimus-loading dose of 6 mg after coronary angioplasty, followed by 2 mg/d for 4 weeks. Serum electrolytes, lipid profile, renal panel, and complete blood cell count were measured at 1, 3, and 5 weeks after drug initiation. Oral sirolimus was prescribed to 22 patients who had a total of 28 lesions and were at high risk for restenosis. Of the 22 study patients, 11 (50%) discontinued oral sirolimus early because of side effects or laboratory abnormalities. Hypertriglyceridemia and leukopenia were the most frequent adverse events, occurring in 3 patients each. All adverse drug effects were reversible after discontinuation. Follow-up was obtained in 100% of patients at a mean of 9.9±1.8 months, ranging from 6.5 to 11.8 months. Target lesion revascularization (TLR) occurred in 15 of 28 lesions (53.6%) and 13 of 22 patients (59.1%). There was no difference in TLR for patients receiving a complete course of sirolimus (n=8; 72.7%) compared with patients who terminated treatment prematurely (n=5; 45.5%;
P
=NS). Clinically driven repeat cardiac catheterization was obtained in 15 (68.2%) patients; restenosis (>50% diameter stenosis at follow-up) was present in 13 (86.7%).

Conclusion—

Oral sirolimus does not appear to provide benefit to patients with recalcitrant restenosis. Adverse drug effects are frequent, underscoring the importance of local drug delivery to achieve high tissue concentrations without systemic adverse drug effects.
Functional Consequences of Endothelial Nitric Oxide Synthase Uncoupling in Congestive Cardiac Failure
Authors: Dixon Lana J. , Morgan David R. , Hughes Sinead M. , McGrath Lawrence T. , El-Sherbeeny Naglaa A. , Plumb Rick D. , Devine Adrian , Leahey William , Johnston G. Dennis , McVeigh Gary E.
Published: April 2003

Background—

Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O
2
·−
), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O
2
·−
. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF.

Methods and Results—

We employed the platelet as a compartmentalized ex-vivo model to examine O
2
·−
and NO production. When eNOS is functioning normally, incorporation of N
ω
-Nitro-
l
-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O
2
·−
detection, as inhibition of NO production prevents NO scavenging of O
2
·−
. This was observed in controls and 9 of the CCF patients, in whom O
2
·−
detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O
2
·−
production by 39%, indicating O
2
·−
production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8±1.4 versus 0.9±0.4 pmol/10
8
platelets,
P
=0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling.

Conclusions—

This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.
Evaluating China's research performance: how do SCI and Chinese indexes compare?
Authors: Liang Liming
Published: April 2003

The aim of this paper is to compare the value of SCI (the Science Citation Index) and two domestic Chinese databases of scientific papers and citations, Chinese Scientific and Technical Papers and Citations (CSTPC) and the Chinese Science Citation Database (CSCD), as measures of China's research output and performance. The two main results of the study are (i) that the number of papers indexed in SCI is more sensitive as an indicator of research activity than numbers of citations or papers indexed in CSCD or CSTPC, and (ii) that the number of papers indexed in SCI is also a much more volatile indicator than measures derived from the Chinese databases. Related to these findings is the fact that there is now fierce competition among different regions of China for the top research rankings as defined by papers indexed in SCI.
Science and research in Iran: A scientometric study
Authors: Wilson Concepción S. , Osareh Farideh
Published: April 2003

Indicators of science and technology (S&T) activity often disadvantage developing countries, due, in part, to incomplete compilation of statistics or to the examination of indicators in isolation. Among the major indicators of S&T activity are research and development (R&D) expenditures and their relationship to gross domestic product, numbers of personnel involved in S&T research, scientific publication output and rankings by scientific discipline, and numbers of patents registered in the international patent systems. A ‘composite index of S&T capacity’ developed by researchers at the Rand Corporation is described and applied comparatively. We have compiled data on Iranian S&T activity under the following headings: R&D expenditure, population and educational profile, academic personnel, R&D personnel. A scientometric analysis of Iranian S&T publications using the Science Citation Index is presented, and possible shortcomings of this approach discussed. All findings are reported, analysed, and discussed with reference to the various compilations of S&T indicators and to our earlier studies on Iranian scientific publications. In particular we analyse annual distributions of world and Iranian S&T publications, international collaboration of Iranian scientists, journals where Iranian scientists publish and journals they cite, the most productive Iranian scientists and the extent of their influence nationally and internationally, and S&T subject areas in which Iranian scientists excel. We conclude with comments and suggestions for the continued development of Iran's S&T capacity.