bluuebunny/crossref_metadata_2025 huggingface dataset:
Transactivation of lung lysozyme expression by Ets family member ESE-1
Authors: Lei Wanli , Jaramillo Richard J. , Harrod Kevin S.
Published: September 2007

Epithelial-specific Ets (ESE) transcription factors, consisting of ESE-1, ESE-2, and ESE-3, are constitutively expressed in distinct epithelia of mucosal tissues, including the lung. Each ESE member exhibits alternative splicing and yields at least two isoforms (a and b) with transcriptional targets largely unidentified. The studies described herein define a novel role for ESE transcription factors in transactivation of the human lysozyme gene ( LYZ), an essential component of innate defense in lung epithelia. Of the six ESE isoforms, ESE-1a and ESE-1b transactivated LYZ promoter in reporter gene assays, whereas only ESE-1b dramatically upregulated transcription of endogenous LYZ in both nonpulmonary and pulmonary epithelial cells. Importantly, ESE-1a and ESE-1b could transactivate the LYZ promoter in cultured primary airway epithelial cells. ESE-2 and ESE-3 isoforms were unable to substantially transactivate the lysozyme promoter or upregulate transcription of endogenous LYZ. Two functional consensus Ets sites located in the proximal 130-bp LYZ promoter were responsive to ESE-1b as identified by site-directed mutagenesis and DNA binding assays. Short hairpin RNA attenuation of endogenous ESE-1b mRNA levels in lung epithelia resulted in decreased LYZ transcription. Furthermore, ESE-1 antibody specifically enriched the 130-bp proximal LYZ promoter in chromatin immunoprecipitation analyses. These findings define a novel role for ESE transcription factors in regulating lung innate defense and suggest distinct regulatory functions for ESE family members.
Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle
Authors: Haus Jacob M. , Carrithers John A. , Trappe Scott W. , Trappe Todd A.
Published: September 2007

We examined intramuscular endomysial collagen, cross-linking, and advanced glycation end products, as well as the general and contractile protein concentration of 20 young (25 ± 3 yr) and 22 old (78 ± 6 yr, range: 70–93 yr) sedentary men and women to better understand the underlying basis of changes in skeletal muscle mass and function that occur with aging. The old individuals had an impaired ability (increased time) ( P < 0.05) to climb stairs (80%), rise from a chair (56%), and walk (44%), as well as lower ( P < 0.05) quadriceps muscle volume (−29%), muscle strength (−35%), muscle power (−48%), and strength (−17%) and power (−33%) normalized to muscle size. Vastus lateralis muscle biopsies revealed that intramuscular endomysial collagen (young: 9.6 ± 1.1, old: 10.2 ± 1.2 μg/mg muscle wet wt) and collagen cross-linking (hydroxylysylpyridinoline) (young: 395 ± 65, old: 351 ± 45 mmol hydroxylysylpyridinoline/mol collagen) were unchanged ( P > 0.05) with aging. The advanced glycation end product, pentosidine, was increased ( P < 0.05) by ∼200% (young: 5.2 ± 1.3, old: 15.9 ± 4.5 mmol pentosidine/mol collagen) with aging. While myofibrillar protein concentration was lower (−5%, P < 0.05), the concentration of the main contractile proteins myosin and actin were unchanged ( P > 0.05) with aging. These data suggest that the synthesis and degradation of proteins responsible for the generation (myosin and actin) and transfer (collagen and pyridinoline cross-links) of muscle force are tightly regulated in aging muscle. Glycation-related cross-linking of intramuscular connective tissue may contribute to altered muscle force transmission and muscle function with healthy aging.
Induction of Oral Tolerance to HSP60 or an HSP60-Peptide Activates T Cell Regulation and Reduces Atherosclerosis
Authors: van Puijvelde G.H.M. , van Es T. , van Wanrooij E.J.A. , Habets K.L.L. , de Vos P. , van der Zee R. , van Eden W. , van Berkel Th. J.C. , Kuiper J.
Published: September 2007

Objective—

HSP60-specific T cells contribute to the development of the immune responses in atherosclerosis. This can be dampened by regulatory T cells activated via oral tolerance induction, and we explored the effect of oral tolerance induction to HSP60 and the peptide HSP60 (253 to 268) on atherosclerosis.

Methods and Results—

HSP60 and HSP60 (253 to 268) were administered orally to LDLr
−/−
mice before induction of atherosclerosis and resulted in a significant 80% reduction in plaque size in the carotid arteries and in a 27% reduction in plaque size at the aortic root. Reduction in plaque size correlated with an increase in CD4
+
CD25
+
Foxp3
+
regulatory T cells in several organs and in an increased expression of Foxp3, CD25, and CTLA-4 in atherosclerotic lesions of HSP60-treated mice. The production of interleukin (IL)-10 and transforming growth factor (TGF)-β by lymph node cells in response to HSP60 was observed after tolerance induction.

Conclusion—

Oral tolerance induction to HSP60 and a small HSP60-peptide leads to an increase in the number of CD4
+
CD25
+
Foxp3
+
regulatory T cells, resulting in a decrease in plaque size as a consequence of increased production of IL-10 and TGF-β. We conclude that these beneficial results of oral tolerance induction to HSP60 and HSP60 (253 to 268) may provide new therapeutic approaches for the treatment of atherosclerosis.
Soluble CD40 Ligand Predicts Ischemic Stroke and Myocardial Infarction in Patients With Nonvalvular Atrial Fibrillation
Authors: Ferro Domenico , Loffredo Lorenzo , Polimeni Licia , Fimognari Filippo , Villari Paolo , Pignatelli Pasquale , Fuster Valentin , Violi Francesco
Published: September 2007

Objective—

Atrial fibrillation (AF) is associated with a high incidence of vascular disease that may be related to a prothrombotic and inflammatory state. Soluble CD40 ligand (sCD40L), which stems essentially from platelet activation, possesses inflammatory and prothrombotic properties. The aim of the study was to assess whether sCD40L is a predictor of stroke or myocardial infarction (MI) in patients with nonvalvular AF.

Methods and Results—

Plasma levels of sCD40L were measured in 231 patients (177 [77%] had permanent or persistent AF, and 54 [23%] had paroxysmal AF). Patients were followed for a mean period of 27.8±8.8 months, and cardiovascular events such as fatal and nonfatal stroke and MI were recorded. AF population was divided in 2 groups according to sCD40L level above or below the median (4.76 ng/mL). The 2 patients’ groups had similar distribution of cardiovascular risk factors, age, gender, medications, or serum C-reactive protein levels. During the follow-up period, vascular events occurred in 6 (2 nonfatal MI and 4 nonfatal ischemic strokes) of 116 patients with low levels of sCD40L (5.1%) and in 29 (11 fatal and 3 nonfatal MI; 3 fatal and 12 nonfatal ischemic strokes) of 115 patients with high levels (25.2%) (log-rank test:
P
<0.001). Using the COX proportional Hazards model, patients with sCD40L above the median were 4.63 times more likely to experience a vascular event (95% C.I.: 1.92 to 11.20).

Conclusions—

This study shows that enhanced soluble CD40L level is a predictor of vascular events in patients with nonvalvular AF, thus suggesting that enhanced platelet activation may play a role in its clinical progression.
Dose-Response Study of Recombinant Factor VIIa/Tissue Factor Inhibitor Recombinant Nematode Anticoagulant Protein c2 in Prevention of Postoperative Venous Thromboembolism in Patients Undergoing Total Knee Replacement
Authors: Lee Agnes , Agnelli Giancarlo , Büller Harry , Ginsberg Jeffrey , Heit John , Rote William , Vlasuk George , Costantini Lorrie , Julian Jim , Comp Philip , van der Meer Jan , Piovella Franco , Raskob Gary , Gent Michael
Published: September 2007

Background
—With the best prophylactics now available, venous thromboembolism after total knee replacement remains substantial (25% to 27%). Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of factor VIIa/tissue factor complex that has the potential to reduce this risk. The present study was performed to determine an efficacious and safe dose of rNAPc2 for prevention of venous thromboembolism after elective, unilateral total knee replacement.

Methods and Results
—This open-label, sequential dose-ranging study was conducted in 11 centers in Canada, Europe, and the United States. Five regimens were tested. Injections were administered subcutaneously on the day of surgery (day 1) and days 3, 5, and optionally, day 7. Primary efficacy outcome was a composite of overall deep vein thrombosis based on mandatory unilateral venography (day 7±2) and confirmed symptomatic venous thromboembolism recorded ≤48 hours after the last dose of rNAPc2. Primary safety outcome was major bleeding ≤72 hours after the last dose. An independent, blinded Central Adjudication Committee assessed all outcome events. Of 293 patients studied, 251 (86%) could be evaluated for primary efficacy analysis. A dosage of 3.0 μg/kg administered within 1 hour after surgery provided the best observed results, with an overall deep vein thrombosis rate of 12.2%, a proximal deep vein thrombosis rate of 1.3%, and a major bleeding rate of 2.3%.

Conclusions
—A randomized, double-blind trial that compared rNAPc2 with current best prophylactics is warranted based on encouraging, first-reported clinical results for a factor VIIa/tissue factor inhibitor evaluated for thrombosis prophylaxis.
Sexual Dimorphism in the Electrocardiographic Dynamics of Human Ventricular Repolarization
Authors: Lehmann Michael H. , Yang Hua
Published: September 2007

Background—Previous characterizations of sex differences in ST-T waveform voltages have largely focused on amplitudes at selected time points during repolarization, subject to potential distortions from variations in heart rate (HR) or reliance on a JT-normalized time scale.

Methods and Results—Using digitized 12-lead ECGs from 553 normal adults (426 males) with HRs confined to 60±1, 70±1, or 80±1 bpm, we derived X, Y, and Z lead voltages and then generated, for each HR category by sex, summary (population mean) resultant spatial vector amplitudes (ST-TXYZ) and instantaneous slopes (dV/dtXYZ) at successive 4-ms intervals following the J point. Within each HR category, there was an early intersex divergence of ST-TXYZtrajectories (95% CIs nonoverlapping), with men exhibiting 2- to 3-fold greater dV/dtXYZvalues during the ST segment and achieving greater maximum TXYZand dV/dtXYZvalues than women; descending TXYZlimbs were relatively more concordant between sexes but still steeper in men. The early sex differences in repolarization dynamics persisted in multiple regression analyses that took into account age and a morphometric index of left ventricular mass. In men, absolute values of extrema of TXYZand dV/dtXYZvaried inversely with HR.

Conclusions—At physiological resting HRs, the spatial ST-T vector voltage time trajectory is steeper in men than in women, beginning virtually from the J point. In addition to its mechanistic implications, the demonstration of marked sensitivity of ST-TXYZand especially dV/dtXYZto sex raises the possibility that these time-based, ECG-derived parameters might be informative in pathophysiological studies of ventricular repolarization.
Respiratory Modulation of Muscle Sympathetic Nerve Activity in Patients With Chronic Heart Failure
Authors: Goso Yukiko , Asanoi Hidetsugu , Ishise Hisanari , Kameyama Tomoki , Hirai Tadakazu , Nozawa Takashi , Takashima Shutaro , Umeno Katsumi , Inoue Hiroshi
Published: September 2007

Background

Sympathoexcitation and respiratory instability are closely related to worsening of chronic heart failure. To elucidate the dynamic nature of respiratory modulation of sympathetic activity in patients with heart failure, we studied within-breath variation of muscle sympathetic nerve activity (MSNA) under various ventilatory volumes.

Methods and Results

MSNA, blood pressure, and respiratory flow were recorded in 23 patients with left ventricular ejection fraction ≤45%. Within-breath suppression of MSNA (neural silence) was found in 11 patients (MSNA bursts: 71±10/100 heartbeats) but not in the remaining 12 patients (MSNA bursts: 88±8/100 heartbeats). Patients without neural silence had a smaller tidal volume (391±70 versus 267±75 mL/m
2
,
P
<0.01) and a higher respiratory rate (15±2 versus 19±4 breaths/min,
P
<0.01) during spontaneous respiration than those with neural silence. The relationship between tidal volume and minimal amplitude of MSNA bursts in each breath was obtained during random-interval breathing and fitted by an exponential function. The curve of patients without neural silence was shifted to the right and upward, which suggests that a greater tidal volume was required to suppress MSNA (227±70 versus 437±195 mL/m
2
,
P
<0.01).

Conclusions

Sympathoexcitation in patients with chronic heart failure is closely related to both a decrease in resting tidal volume and an attenuated sympathoinhibitory effect of lung inflation reflex.
Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension
Authors: Zhao L. , Mason N.A. , Morrell N.W. , Kojonazarov B. , Sadykov A. , Maripov A. , Mirrakhimov M.M. , Aldashev A. , Wilkins M.R.
Published: September 2007

Background

This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice.

Methods and Results

In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O
2
for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean±SD mm Hg]: normoxia 16.0±2.1 versus hypoxia 25.0±4.8) was almost abolished by sildenafil (normoxia 16.0±2.1 versus hypoxia 18.0±3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg · kg
−1
· d
−1
) throughout 3 weeks of exposure to hypoxia (10% O
2
) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3±9.9 versus 29.9±9.7 mm Hg,
P
<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling.

Conclusions

Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.
Pharmacodynamics and Pharmacokinetics of Eptifibatide in Patients With Acute Coronary Syndromes
Authors: Tardiff Barbara E. , Jennings Lisa K. , Harrington Robert A. , Gretler Daniel , Potthoff Richard F. , Vorchheimer David A. , Eisenberg Paul R. , Lincoff A. Michael , Labinaz Marino , Joseph Diane M. , McDougal Mark F. , Kleiman Neal S. ,   for the PERIGEE Investigators
Published: September 2007

Background

Platelet deposition and aggregation are central to the pathogenesis of ischemic complications of acute coronary syndromes (ACS). Pharmacodynamic effects of the platelet glycoprotein IIb/IIIa antagonist eptifibatide have been delineated in healthy subjects but not in patients with ACS. We assessed effects of eptifibatide on ex vivo platelet aggregation in patients enrolled in the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy (PURSUIT) trial of ACS.

Methods and Results

Patients were randomly assigned to an intravenous bolus (180 μg/kg) and 72-hour infusion of eptifibatide (2.0 μg/kg per minute, n=48) or placebo (n=50). We assessed correlations of plasma eptifibatide levels with receptor occupancy and inhibition of ex vivo platelet aggregation at 5 minutes and 1, 4, 24, 48, and 72 hours during treatment and 4 and 8 hours after termination of infusion. Blood was collected in buffered citrate and
d
-phenylalanyl-
l
-prolyl-
l
-arginine chloromethylketone anticoagulants. Although eptifibatide produced profound, prolonged inhibition of platelet aggregation during therapy, aggregation appeared to recover partially by 4 hours after the bolus. The aggregation response was greater with thrombin receptor agonist peptide versus ADP stimulation; inhibition of platelet aggregation was greater in blood samples anticoagulated with citrate versus
d
-phenylalanyl-
l
-prolyl-
l
-arginine chloromethylketone (PPACK). Plasma eptifibatide levels correlated significantly with receptor occupancy but not with inhibition of platelet aggregation.

Conclusions

A bolus and infusion of eptifibatide inhibits platelet aggregation profoundly in patients with ACS and is followed by brief, partial recovery. These results enhance our understanding of the relation between pharmacodynamic and clinical effects of eptifibatide in such patients and may have important implications for its use in percutaneous interventions.
Cerivastatin, a Hydroxymethylglutaryl Coenzyme A Reductase Inhibitor, Improves Endothelial Function in Elderly Diabetic Patients Within 3 Days
Authors: Tsunekawa Taku , Hayashi Toshio , Kano Hatsuyo , Sumi Daigo , Matsui-Hirai Hisako , Thakur Navin Kumar , Egashira Kensuke , Iguchi Akihisa
Published: September 2007

Background

The short-term effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on endothelial function at doses that do not affect plasma lipid levels are not known.

Methods and Results

We investigated the short-term effects of cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, on endothelial function and endothelium-related products in elderly diabetic patients. Twenty-seven elderly diabetic patients (aged 69.3±3.4 years), with or without mild hypercholesterolemia, were enrolled in this study, which tested cerivastatin treatment (0.15 mg/d) for 3 days. Endothelium-dependent flow-mediated dilatation, endothelium-independent dilatation by nitroglycerin in the brachial artery, nitric oxide-related products (nitrite/nitrate and cGMP), endothelium-related products (von Willebrand Factor, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecule-1), and a marker of oxidant stress (8-isoprostane) were assessed. Levels of plasma lipids were not changed before and after treatment with cerivastatin. Flow-mediated dilatation was significantly increased by cerivastatin treatment, as were plasma nitrite/nitrate levels (from 16.9±3.4 to 22.0±3.7 μmol/L,
P
<0.05) and cGMP values. The percent of nitroglycerin-induced dilatation was not changed. Plasma concentrations of 8-isoprostane decreased, and levels of soluble vascular cell adhesion molecule also tended to decrease with cerivastatin.

Conclusions

Improvement of endothelial function was in line with antiatherosclerotic effects. Cerivastatin improved impaired endothelial function in the short-term without affecting lipid profiles in elderly diabetic patients. This effect may be partly due to upregulation of endothelial nitric oxide synthase.
Eplerenone Suppresses Constrictive Remodeling and Collagen Accumulation After Angioplasty in Porcine Coronary Arteries
Authors: Ward Michael R. , Kanellakis Peter , Ramsey Debra , Funder John , Bobik Alex
Published: September 2007

Background

Coronary artery angioplasty triggers healing that causes constrictive remodeling. Because collagen accumulation correlates with constrictive remodeling and aldosterone has been implicated in collagen accumulation, we examined how aldosterone and the mineralocorticoid receptor antagonists spironolactone and eplerenone affect remodeling and collagen in porcine coronary and iliac arteries after angioplasty.

Methods and Results

Twenty-four pigs were allocated into 4 treatment groups: oral eplerenone (100 mg/d), oral spironolactone (200 mg/d), subcutaneous aldosterone (400 μg/d), or no treatment. Twenty-eight days after angioplasty of the coronary arteries, eplerenone increased total vessel area by 30% (
P
<0.05) and luminal area by nearly 60% (
P
<0.05) compared with the no-treatment group, without affecting neointima size. These effects were accompanied by a 65% reduction in neointimal and medial collagen density (both
P
<0.05). Spironolactone was less effective, and aldosterone tended to exert opposite effects on coronary artery structure after angioplasty. These effects were not observed in angioplastied iliac arteries.

Conclusions

Eplerenone attenuates constrictive remodeling after coronary artery angioplasty by mechanisms involving reduction in collagen accumulation, which thus appears to be an important contributor to constrictive remodeling of angioplastied coronary arteries.
Prospective Multicenter Study of Pregnancy Outcomes in Women With Heart Disease
Authors: Siu Samuel C. , Sermer Mathew , Colman Jack M. , Alvarez A. Nanette , Mercier Lise-Andree , Morton Brian C. , Kells Catherine M. , Bergin M. Lynn , Kiess Marla C. , Marcotte Francois , Taylor Dylan A. , Gordon Elaine P. , Spears John C. , Tam James W. , Amankwah Kofi S. , Smallhorn Jeffrey F. , Farine Dan , Sorensen Sheryll ,   on behalf of the Cardiac Disease in Pregnancy (CARPREG) Investigators
Published: September 2007

Background

The maternal and neonatal risks associated with pregnancy in women with heart disease receiving comprehensive prenatal care have not been well defined.

Methods and Results

We prospectively enrolled 562 consecutive pregnant women with heart disease and determined the outcomes of 599 pregnancies not ending in miscarriage. Pulmonary edema, arrhythmia, stroke, or cardiac death complicated 13% of pregnancies. Prior cardiac events or arrhythmia, poor functional class or cyanosis, left heart obstruction, and left ventricular systolic dysfunction independently predicted maternal cardiac complications; the cardiac event rate can be predicted using a risk index incorporating these predictors. Neonatal complications (20% of pregnancies) were associated with poor functional class or cyanosis, left heart obstruction, anticoagulation, smoking, and multiple gestations.

Conclusions

Pregnancy in women with heart disease is associated with significant cardiac and neonatal complications, despite state-of-the-art obstetric and cardiac care. Maternal cardiac risk can be predicted with the use of a risk index.
Relationship Between Sinus Rhythm Activation and the Reentrant Ventricular Tachycardia Isthmus
Authors: Ciaccio Edward J. , Tosti Alexis C. , Scheinman Melvin M.
Published: September 2007

Background

In canine hearts with inducible reentry, the isthmus tends to form along an axis from the area of last to first activity during sinus rhythm. It was hypothesized that this phenomenon could be quantified to predict reentry and the isthmus location.

Methods and Results

An in situ canine model of reentrant ventricular tachycardia occurring in the epicardial border zone was used in 54 experiments (25 canine hearts in which primarily long monomorphic runs of figure-8 reentry were inducible, 11 with short monomorphic or polymorphic runs, and 18 lacking inducible reentry). From the sinus rhythm activation map for each experiment, the linear regression coefficient and slope were calculated for the activation times along each of 8 rays extending from the area of last activation. The slope of the regression line for the ray with greatest regression coefficient (called the primary axis) was used to predict whether or not reentry would be inducible (correct prediction in 48 of 54 experiments). For all 36 experiments with reentry, isthmus location and shape were then estimated on the basis of site-to-site differences in sinus rhythm electrogram duration. For long and short runs of reentry, estimated isthmus location and shape partially overlapped the actual isthmus (mean overlap of 71.3% and 43.6%, respectively). On average for all reentry experiments, a linear ablation lesion positioned across the estimated isthmus would have spanned 78.2% of the actual isthmus width.

Conclusions

Parameters of sinus rhythm activation provide key information for prediction of reentry inducibility and isthmus location and shape.
Oxidized Low-Density Lipoprotein Downregulates Endothelial Basic Fibroblast Growth Factor Through a Pertussis Toxin-Sensitive G-Protein Pathway
Authors: Chang Po-Yuan , Luo Sherry , Jiang Tao , Lee Yuan-Teh , Lu Shao-Chun , Henry Philip D. , Chen Chu-Huang
Published: September 2007

Background

Oxidized LDL (oxLDL) inhibits angiogenesis in part by downregulating endothelial basic fibroblast growth factor (bFGF). To determine the mechanism of the downregulation, we investigated the signal transduction pathway involving potential phospholipid mediators.

Methods and Results

Cultured bovine aortic endothelial cells were incubated with PBS (lipoprotein-free control), LDL, or copper oxLDL under serum-free conditions. At 24 hours, oxLDL (50 μg/mL) decreased bFGF mRNA (Northern blot), bFGF protein (Western blot and ELISA), and concomitant DNA synthesis, all by 40% to 50% compared with PBS. LDL had no effect. Pretreating the cells with 100 ng/mL pertussis toxin (PTX) for 18 hours before oxLDL exposure almost completely blocked the inhibitory effects of oxLDL. In contrast, inhibiting other major cellular signal transduction pathways with PD-98059 (mitogen-activated protein kinase kinase inhibitor), HA-1004 (inhibitor of cGMP- and cAMP-dependent protein kinase), or Ro-31-8220 (protein kinase C inhibitor) or chelating intracellular Ca
2+
with BAPTA-AM failed to attenuate any of the oxLDL effects assayed. Addition to the cultures of WEB 2086, a specific antagonist of the PTX-sensitive G protein–coupled platelet-activating factor (PAF) receptor, blocked the action of oxLDL. Whereas PAF dispersed in the culture medium failed to produce oxLDL-like effects, degradation of PAF and PAF-like phospholipids accumulated in oxLDL with a recombinant human PAF acetylhydrolase eliminated the inhibitory effects of oxLDL on bFGF expression and DNA synthesis.

Conclusions

OxLDL suppresses endothelial bFGF expression and DNA synthesis through a PTX-sensitive heterotrimeric G-protein pathway involving mediator phospholipids similar, but not identical, to PAF.
Admission Troponin T Level Predicts Clinical Outcomes, TIMI Flow, and Myocardial Tissue Perfusion After Primary Percutaneous Intervention for Acute ST-Segment Elevation Myocardial Infarction
Authors: Giannitsis Evangelos , Müller-Bardorff Margit , Lehrke Stephanie , Wiegand Uwe , Tölg Ralph , Weidtmann Britta , Hartmann Franz , Richardt Gert , Katus Hugo A.
Published: September 2007

Background

—

In ST-segment elevation myocardial infarction, a troponin T ≥0.1 μg/L on admission indicates poorer prognosis despite early reperfusion. To evaluate the underlying reason, we studied the value of cardiac troponin T (cTnT) for prediction of outcomes, epicardial blood flow, and myocardial reperfusion after primary percutaneous intervention.

Methods and Results

—

Patients (n=140) admitted within 12 hours after onset of symptoms were stratified by admission cTnT. Epicardial and myocardial reperfusion were graded by the TIMI score and by measurement of relative increases of myoglobin, cTnT, and creatine kinase (CK)-MB 60 minutes after recanalization, respectively. cTnT was positive in 64 patients (45.7%) and was associated with longer median time intervals to admission (5.5 versus 3.5 hours,
P
<0.001) and higher mortality rates after 30 days (12.5% versus 3.9%,
P
=0.06) and 9 months (14% versus 3.9%,
P
=0.005). cTnT independently predicted a 3.2-fold risk for incomplete epicardial reperfusion (
P
=0.03). In addition, cTnT ≥0.1 μg/L was associated with more severely impaired myocardial perfusion despite normal epicardial flow, as indicated by lower 60-minute ratios of myoglobin (2.6 versus 7.6,
P
=0.007), cTnT (6.6 versus 29.2,
P
<0.001), and CK-MB (3.5 versus 21.4,
P
=0.002) and a tendency for less resolution of ST-segment elevations (54% versus 60%,
P
=0.08).

Conclusions

—

cTnT predicts poorer clinical outcomes, lower rates of postprocedural TIMI 3 flow, and more severely compromised myocardial perfusion despite normal epicardial flow. Thus, a cTnT-positive patient may require more aggressive adjunctive therapy when treated by percutaneous coronary intervention. The impact of preexisting or evolving microvascular dysfunction and the effect of therapies that target myocardial perfusion require further prospective evaluation.
Lumen Loss in Transplant Coronary Artery Disease Is a Biphasic Process Involving Early Intimal Thickening and Late Constrictive Remodeling
Authors: Tsutsui Hiroshi , Ziada Khaled M. , Schoenhagen Paul , Iyisoy Atila , Magyar William A. , Crowe Timothy D. , Klingensmith Jon D. , Vince D. Geoffrey , Rincon Gustavo , Hobbs Robert E. , Yamagishi Masakazu , Nissen Steven E. , Tuzcu E. Murat
Published: September 2007

Background

—

Coronary artery disease is the major cause of late cardiac allograft failure. However, few data exist regarding the natural history of changes in intimal and external elastic membrane (EEM) areas after heart transplantation.

Methods and Results

—

In 38 transplant recipients, serial intravascular ultrasound examinations were performed 3.7±2.2 weeks after transplantation and annually thereafter for 5 years. In 59 coronary arteries, we compared 135 matched segments among serial studies. In each segment, intravascular ultrasound images were digitized at 1-mm intervals, and mean values of EEM and lumen and intimal areas were analyzed. In the first year after transplantation, the intimal area increased significantly from 1.8±1.6 to 3.0±2.1 mm
2
(
P
<0.001). Subsequently, the annual increase in intimal area decreased. EEM area did not change during the first year; however, between years 1 and 3, significant expansion of EEM area occurred (15.4±4.6 to 17.2±5.4 mm
2
,
P
<0.001). Thereafter, EEM area decreased significantly from 17.2±5.4 mm
2
(year 3) to 15.1±4.9 mm
2
(year 5,
P
=0.01). Different mechanisms of lumen loss were observed during 2 phases after transplantation: early lumen loss primarily caused by intimal thickening and late lumen loss caused by EEM area constriction.

Conclusions

—

This serial ultrasound study revealed that most of the intimal thickening occurred during the first year after heart transplantation. Changes in the EEM area showed a biphasic response, consisting of early expansion and late constriction. Thus, different mechanisms of lumen loss were observed during the early and late phases after transplantation.
Reduced Myocardial Sarcoplasmic Reticulum Ca
2+
-ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy
Authors: Somura Fuji , Izawa Hideo , Iwase Mitsunori , Takeichi Yasushi , Ishiki Ryoji , Nishizawa Takao , Noda Akiko , Nagata Kohzo , Yamada Yoshiji , Yokota Mitsuhiro
Published: September 2007

Background

—

The relationship between left ventricular (LV) contractile functional reserve and gene expression of Ca
2+
-handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified.

Methods and Results

—

We calculated the maximum first derivative of LV pressure (LV dP/dt
max
) and the LV pressure half-time (T
1/2
) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction >55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca
2+
-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na
+
/Ca
2+
exchanger were quantified by use of a real-time quantitative reverse transcription—polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dt
max
with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate—LV dP/dt
max
relation was biphasic at physiological pacing rates. Both the mean maximal wall thickness and the LV hypertrophy score in group B were greater than in group A (20±5 versus 15±3 mm and 7±1 versus 5±2 points, respectively). SERCA2 mRNA levels were significantly lower in group B (SERCA2/GAPDH ratio 0.34±0.15) compared with group A (0.72±0.27) and control subjects (0.85±0.47), whereas the mRNA expression of ryanodine receptor-2, phospholamban, calsequestrin, and Na
+
/Ca
2+
exchanger were similar in all groups.

Conclusions

—

These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca
2+
handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction.
Circulating Nonesterified Fatty Acid Level as a Predictive Risk Factor for Sudden Death in the Population
Authors: Jouven Xavier , Charles Marie-Aline , Desnos Michel , Ducimetière Pierre
Published: September 2007

Background

In ischemic conditions, concentration of circulating nonesterified fatty acids (NEFA) is increased and has a proarrhythmic effect that is responsible for ventricular tachyarrhythmias. In nonischemic patients, high NEFA plasma concentration has been shown to be associated with frequent premature ventricular complexes and increased familial risk of cardiovascular disease, but its relation to sudden death has not been studied. We assessed the role of circulating NEFA in sudden death in asymptomatic men in a long-term cohort study.

Methods and Results

A total of 5250 men employed by the city of Paris, aged 42 to 53 in 1967 to 1972, free of known ischemic cardiac disease, and included in the Paris Prospective Study I, completed a second annual examination and had fasting plasma circulating NEFA measured. Each subject underwent a physical examination and ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers. Vital status was obtained for each subject from specific inquiries until he retired; after retirement, it was obtained from death certificates. Body mass index, systolic and diastolic blood pressures, tobacco consumption, parental history of sudden death, fasting cholesterol level, and circulating NEFA concentration were independent factors associated with sudden death during follow up (average, 22 years). When adjusted for confounding factors, circulating NEFA concentration remained an independent risk factor for sudden death (relative risk, 1.70; 95% confidence interval, 1.21 to 2.13) but not for fatal myocardial infarction.

Conclusions

Circulating NEFA concentration is an independent risk factor for sudden death in middle-aged men. Some form of primary prevention could be envisaged in subjects at high risk of sudden death.
Altered Growth Responses of Pulmonary Artery Smooth Muscle Cells From Patients With Primary Pulmonary Hypertension to Transforming Growth Factor-β
1
and Bone Morphogenetic Proteins
Authors: Morrell Nicholas W. , Yang Xudong , Upton Paul D. , Jourdan Karen B. , Morgan Neal , Sheares Karen K. , Trembath Richard C.
Published: September 2007

Background

Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-β (TGF-β) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-β superfamily members.

Methods and Results

For studies of
3
H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-β
1
(10 ng/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng/mL) inhibited basal and serum-stimulated
3
H-thymidine incorporation, and TGF-β
1
and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-β
1
stimulated
3
H-thymidine incorporation (200%;
P
<0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary hypertension. In addition, BMPs failed to suppress DNA synthesis and proliferation in PASMCs from PPH patients. Reverse transcription–polymerase chain reaction of PASMC mRNA detected transcripts for type I (TGF-βRI, Alk-1, ActRI, and BMPRIB) and type II (TGF-βRII, BMPR-II, ActRII, ActRIIB) receptors. Receptor binding and cross-linking studies with
125
I-TGF-β
1
confirmed that the abnormal responses in PPH cells were not due to differences in TGF-β receptor binding. Mutation analysis of PASMC DNA failed to detect mutations in TGF-βRII and Alk-1 but confirmed the presence of a mutation in BMPR-II in 1 of 5 PPH isolates.

Conclusions

We conclude that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-β
1
and BMPs and that altered integration of TGF-β superfamily growth signals may contribute to the pathogenesis of PPH.
Effect of Aging on the Prognostic Significance of Ambulatory Systolic, Diastolic, and Pulse Pressure in Essential Hypertension
Authors: Khattar Rajdeep S. , Swales John D. , Dore Caroline , Senior Roxy , Lahiri Avijit
Published: September 2007

Background

This study compared the relative prognostic significance of 24 hour intra-arterial ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) parameters in middle-aged versus elderly hypertensives.

Methods and Results

A total of 546 subjects aged <60 years and 142 subjects aged ≥60 years who had undergone baseline pretreatment 24-hour intra-arterial ambulatory blood pressure monitoring were followed for 9.2±4.1 years. Multivariate analysis showed that in younger subjects, 24-hour, daytime, and nighttime DBP, MAP, and SBP, when considered individually, were positively related to morbid events; DBP parameters provided the best predictive values. In the group ≥60 years (elderly group), 24-hour, daytime, and nighttime PP and SBP were the most predictive parameters, whereas ambulatory DBP and MAP measurements failed to provide any prognostic value. When 24-hour values of SBP and DBP were jointly included in the baseline model, DBP (z=2.02,
P
=0.04) but not SBP (z=−0.43,
P
=0.67) was related to outcome in younger subjects, whereas in the elderly group, SBP (z=3.33,
P
=0.001) was positively and DBP (z=−1.75,
P
=0.07) was negatively related to outcome. Clinic blood pressure measurements failed to provide any independent prognostic value in either age group.

Conclusions

The relative prognostic significance of ambulatory blood pressure components depends on age; DBP parameters provided the best prognostic value in middle-aged individuals, whereas PP parameters were the most predictive in the elderly. This may reflect differing underlying hemodynamic mechanisms of hypertension in these age groups.
Adenovirus-Mediated Gene Transfer of VEGF
121
Improves Lower-Extremity Endothelial Function and Flow Reserve
Authors: Rajagopalan Sanjay , Shah Manan , Luciano Ann , Crystal Ronald , Nabel Elizabeth G.
Published: September 2007

Background

Vascular endothelial growth factor (VEGF) currently is being evaluated in clinical angiogenesis trials involving patients with peripheral arterial disease. We hypothesized that delivery of VEGF to the skeletal muscle of the lower extremity using an adenoviral vector (Ad
GV
VEGF
121.10
) would improve peripheral endothelial function. Accordingly, we investigated lower-extremity endothelial function in patients enrolled in a Phase I adenovirus-mediated gene delivery trial of VEGF
121.10
.

Methods and Results

Blood flow to the index extremity was measured by thermodilution at baseline and 30 days after administration of Ad
GV
VEGF
121.10
, in response to the infusion of endothelium-dependent and -independent agonists (acetylcholine and nitroglycerin, respectively) into the ipsilateral femoral artery. There was no difference in basal flow before or after treatment with Ad
GV
VEGF
121.10
. In response to acetylcholine (150 μg/min and 300 μg/min), there was a 0.9-fold (0.33±0.03 to 0.32±0.03 L/min) and 1.2-fold (0.33±0.03 to 0.490±0.02 L/min) change in flow before Ad
GV
VEGF
121.10
treatment. After Ad
GV
VEGF
121.10
treatment, flow increased 2.4-fold (0.310±0.04 to 0.730±0.10 L/min) and 2.3-fold (0.31±0.04 to 0.7±0.08 L/min), respectively (
P
<0.05 before Ad
GV
VEGF
121.10
treatment versus after Ad
GV
VEGF
121.10
for both doses). Infusion of nitroglycerin resulted in a 1.8-fold increase in flow before Ad
GV
VEGF
121.10
(0.33±0.03 to 0.58±0.06 L/min) compared with a 2.4-fold increase (0.31±0.04 to 0.73±0.09 L/min) after Ad
GV
VEGF
121.10
(
P
=NS before Ad
GV
VEGF
121.10
versus after Ad
GV
VEGF
121.10
). Lower-extremity flow reserve increased in all patients in response to at least 1 dose of acetylcholine. Peak walking times increased concomitant with improvement in endothelial function.

Conclusions

Adenoviral gene transfer of VEGF
121.10
appears to modulate endothelial function and lower-extremity flow reserve in patients with peripheral arterial disease.
Development and Testing of the Helex Septal Occluder, a New Expanded Polytetrafluoroethylene Atrial Septal Defect Occlusion System
Authors: Zahn Evan M. , Wilson Neil , Cutright Warren , Latson Larry A.
Published: September 2007

Background

—

A variety of transcatheter atrial septal defect (ASD) occluders are currently in use around the world. Although for the most part effective, all of these devices lack features that would be desirable in a “perfect” device. The Helex septal occluder is a new type of device designed to improve the results of transcatheter ASD closure. This study was designed to examine the effectiveness and safety of this occluder in an animal model.

Methods and Results

—

The Helex was implanted into 24 dogs with surgically created ASDs. Procedural details focusing on deployment, removal, and early closure rates were examined. Follow-up consisted of sequential transesophageal echocardiography and fluoroscopy as well as epicardial contrast echocardiography and angiography at the time of death. Specimens were examined grossly and histologically, and devices were tested for metal fatigue. All animals had successful ASD closure. Implantation was uncomplicated (mean fluoroscopy time 11.7 minutes), and removal or repositioning was always possible. Closure rate as judged by transesophageal echocardiography was 88% initially and 100% at 2-week follow-up. Devices rapidly became infiltrated with connective tissue without inflammation and were endothelialized over time. There were no instances of thromboembolism. A single wire-frame fracture occurred secondary to a prototype delivery system malfunction.

Conclusions

—

The Helex septal occluder proved safe and effective for ASD closure. Several advantages over currently available devices were evident in this model. Controlled prospective clinical trials are needed.
Abciximab Readministration
Authors: Tcheng James E. , Kereiakes Dean J. , Lincoff A. Michael , George Barry S. , Kleiman Neal S. , Sane David C. , Cines Douglas B. , Jordan Robert E. , Mascelli Mary Ann , Langrall Mary Ann , Damaraju Lakshmi , Schantz Allen , Effron Mark B. , Braden Gregory A. ,   for the ReoPro Readministration Registry Investigators
Published: September 2007

Background

—

Platelet glycoprotein IIb/IIIa blockade with abciximab (ReoPro) improves the clinical outcomes of percutaneous coronary intervention. This registry was conducted to characterize the effects of repeated administration of abciximab during intervention.

Methods and Results

—

We recruited 500 consecutive patients at 22 centers in the United States who were receiving abciximab for at least a second time during percutaneous coronary intervention. Safety was measured as the incidence of hypersensitivity reactions, major bleeding, and thrombocytopenia. Efficacy was assessed as event-free clinical success. Human antichimeric antibody (HACA) responses were also characterized. There were no cases of hypersensitivity (95% upper confidence bound, 0.3%), major bleeding, or death. Clinical success was 94.4%. Thrombocytopenia occurred in 23 patients (4.6%; 95% CI, 2.8% to 6.4%), including 12 (2.4%; 95% CI, 1.1% to 3.7%) who developed profound thrombocytopenia (<20×10
9
cells/L). In 2 patients (0.4%), profound thrombocytopenia did not develop until after hospital discharge; in 4 (0.8%), profound thrombocytopenia recurred despite platelet transfusion. Before a first readministration, a positive HACA titer was present in 22 of 454 patients (4.8%); after a first readministration, an additional 82 of 432 (19.0%) became HACA-positive. HACA did not neutralize the in vitro inhibition of platelet aggregation by abciximab or correlate with clinical events.

Conclusions

—

The results, including overall rates of thrombocytopenia, were consistent with randomized clinical trials of first abciximab treatment. However, there was a shift from mild to profound thrombocytopenia, and cases of delayed presentation and of recurrent thrombocytopenia were seen. These findings suggest that indications and guidelines for first-time use apply to retreatment, particularly the systematic monitoring for thrombocytopenia.
Density and Kinetics of
I
Kr
and
I
Ks
in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of
I
Ks
Blockade at High Heart Rate in Guinea Pig and Rabbit
Authors: Lu Zhibo , Kamiya Kaichiro , Opthof Tobias , Yasui Kenji , Kodama Itsuo
Published: September 2007

Background

—

Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K
+
current (
I
K
) may help to develop agents effective at high heart rate.

Methods and Results

—

We assessed the density and kinetics of the 2 components of the delayed rectifier K
+
current,
I
Kr
and
I
Ks
, in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for
I
Ks
and E-4031 for
I
Kr
) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques. In guinea pig ventricular myocytes only, blockade of
I
Ks
causes APD prolongation in a frequency-independent manner, whereas blockade of
I
Ks
in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of
I
Kr
in both species. This result can be explained primarily by the higher density of
I
Ks
in guinea pig ventricle and by its slow deactivation kinetics, which allows
I
Ks
to accumulate at high heart rate because little time is available for complete deactivation of it during diastole.

Conclusions

—

Density and kinetics of components of
I
K
explain why blockade of
I
Ks
is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.