bluuebunny/crossref_metadata_2025 huggingface dataset:
Ginkgo bilobaExtract Inhibits Tumor Necrosis Factor-α–Induced Reactive Oxygen Species Generation, Transcription Factor Activation, and Cell Adhesion Molecule Expression in Human Aortic Endothelial Cells
Authors: Chen Jaw-Wen , Chen Yung-Hsiang , Lin Feng-Yan , Chen Yuh-Lien , Lin Shing-Jong
Published: August 2003

Objective—This study was conducted to examination whetherGinkgo bilobaextract (GBE), a Chinese herb with antioxidant activity, could reduce cytokine-induced monocyte/human aortic endothelial cell (HAEC) interaction, a pivotal early event in atherogenesis.

Methods and Results—Pretreatment of HAECs with GBE (50 and 100 μg/mL for 18 hours) significantly suppressed cellular binding between the human monocytic cell line U937 and tumor necrosis factor-α (TNF-α)-stimulated HAECs by using in vitro binding assay (68.7% and 60.1% inhibitions, respectively). Cell enzyme–linked immunosorbent assay and immunoblot analysis showed that GBE (50 μg/mL for 18 hours) significantly attenuated TNF-α–induced cell surface and total protein expression of vascular cellular adhesion molecule-1 and intracellular adhesion molecule-1 (63.5% and 69.2%, respectively;P<0.05). However, pretreatment with probucol (5 μmol/L for 18 hours) reduced the expression of vascular cellular adhesion molecule-1 but not intracellular adhesion molecule-1. Preincubation of HAECs with GBE or probucol significantly reduced intracellular reactive oxygen species formation induced by TNF-α (76.8% and 68.2% inhibitions, respectively;P<0.05). Electrophoretic mobility shift assay demonstrated that both GBE and probucol inhibited transcription factor nuclear factor-κB activation in TNF-α–stimulated HAECs (55.2% and 65.6% inhibitions, respectively) but only GBE could inhibit the TNF-α–stimulated activator protein 1 activation (45.1% inhibition,P<0.05).

Conclusions—GBE could reduce cytokine-stimulated endothelial adhesiveness by downregulating intracellular reactive oxygen species formation, nuclear factor-κB and activator protein 1 activation, and adhesion molecule expression in HAECs, supporting the notion that the natural compoundGinkgo bilobamay have potential implications in clinical atherosclerosis disease.
Crucial Role of Type 2 Inositol 1,4,5-Trisphosphate Receptors for Acetylcholine-Induced Ca
2+
Oscillations in Vascular Myocytes
Authors: Morel Jean-Luc , Fritz Nicolas , Lavie Jean-Louis , Mironneau Jean
Published: August 2003

Objective—

The aim of this study was to correlate the expression of InsP
3
R subtypes in native vascular and visceral myocytes with specific Ca
2+
-signaling patterns.

Methods and Results—

By Western blot and immunostaining, we showed that rat portal vein expressed InsP
3
R1 and InsP
3
R2 but not InsP
3
R3, whereas rat ureter expressed InsP
3
R1 and InsP
3
R3 but not InsP
3
R2. Acetylcholine induced single Ca
2+
responses in all ureteric myocytes but only in 50% of vascular myocytes. In the remaining vascular myocytes, the first transient peak was followed by Ca
2+
oscillations. By correlating Ca
2+
signals and immunostaining, we revealed that oscillating vascular cells expressed both InsP
3
R1 and InsP
3
R2 whereas nonoscillating vascular cells expressed only InsP
3
R1. Acetylcholine-induced oscillations were not affected by inhibitors of ryanodine receptors, Ca
2+
-ATPases, Ca
2+
influx, and mitochondrial Ca
2+
uniporter but were inhibited by intracellular infusion of heparin. Using specific antibodies against InsP
3
R subtypes, we showed that acetylcholine-induced Ca
2+
oscillations were specifically blocked by the anti-InsP
3
R antibody. These data were supported by antisense oligonucleotides targeting InsP
3
R2, which selectively inhibited Ca
2+
oscillations.

Conclusions—

Our results suggest that in native smooth muscle cells, a differential expression of InsP
3
R subtypes encodes specific InsP
3
-mediated Ca
2+
responses and that the presence of the InsP
3
R2 subtype is required for acetylcholine-induced Ca
2+
oscillations in vascular myocytes.
Ets Motifs Are Necessary for Endothelial Cell–Specific Expression of a 723-bp Tie-2 Promoter/Enhancer in
Hprt
Targeted Transgenic Mice
Authors: Minami Takashi , Kuivenhoven Jan Albert , Evans Valerie , Kodama Tatsuhiko , Rosenberg Robert D. , Aird William C.
Published: August 2003

Objective—

Tie-2 is an endothelial cell–specific receptor tyrosine kinase that is involved in the remodeling of blood vessels and angiogenesis. Our goal was to characterize Tie-2 promoter function as a means of providing insight into the mechanisms of endothelial cell–specific gene regulation.

Methods and Results—

When targeted to the
Hprt
locus of mice, a small Tie-2 promoter fragment (containing a 300-bp intronic enhancer coupled upstream to a 423-bp core promoter) (T-short) directed widespread endothelial cell expression in vivo. The T-short promoter contains 2 clusters of Ets sites, one in the first exon, the other in the intronic enhancer. In cultured endothelial cells, a combined mutation of the Ets motifs resulted in a significant reduction in promoter activity. Consistent with these results, the same Ets mutations resulted in a loss of detectable expression of the T-short promoter in all vascular beds with the notable exception of the brain.

Conclusions—

These results suggest that the T-short promoter contains information for widespread expression in the vascular tree, Ets sites are necessary for in vivo promoter activity, and the shorter Tie-2 fragment may be useful as a tool to direct heterologous gene expression within the intact endothelium.
Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury
Authors: Sata Masataka , Tanaka Kimie , Ishizaka Nobukazu , Hirata Yasunobu , Nagai Ryozo
Published: August 2003

Objective—

It has been suggested that deregulated expression of the tumor suppressor protein p53 may play a role in the pathogenesis of occlusive vascular remodeling. However, the role of p53 in cell proliferation and apoptosis in vascular lesions has been controversial.

Methods and Results—

We tested the potential involvement of p53-mediated molecular signaling in lesion formation using a mouse model of vascular injury that may resemble balloon angioplasty. A large wire was inserted into the femoral artery of p53
+/+
and p53
−/−
mice. There was no significant difference in the occurrence of rapid-onset apoptosis, that is, 4 hours after injury. At 2 weeks, the number of proliferating cells in the lesion of p53
−/−
mice was significantly higher than that observed in p53
+/+
mice. The frequency of apoptotic cells was significantly lower in p53
−/−
mice than in p53
+/+
mice. At 4 weeks, the neointimal hyperplasia of p53
−/−
mice was greater than that of p53
+/+
mice. There was no significant difference in the frequency of apoptosis in the lesions.

Conclusions—

These results indicate a crucial role of p53 in pathological vascular remodeling after mechanical injury and provide the basis for the development of new therapies targeting p53 for a prophylactic treatment of vascular diseases.
Effects of Intravenous Apolipoprotein A-I/Phosphatidylcholine Discs on LCAT, PLTP, and CETP in Plasma and Peripheral Lymph in Humans
Authors: Kujiraoka Takeshi , Nanjee M. Nazeem , Oka Tomoichiro , Ito Mayumi , Nagano Makoto , Cooke C. Justin , Takahashi Sadao , Olszewski Waldemar L. , Wong Jinny S. , Stepanova Irina P. , Hamilton Robert L. , Egashira Tohru , Hattori Hiroaki , Miller Norman E.
Published: August 2003

Objective—

We have previously shown that intravenous apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) discs increase plasma pre-β HDL concentration and stimulate reverse cholesterol transport (RCT) in humans. We have now investigated the associated changes in the following 3 HDL components that play key roles in RCT: lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP).

Methods and Results—

apoA-I/PC discs (40 mg/kg over 4 hours) were infused into 8 healthy men. Samples of blood and prenodal peripheral lymph were collected for 24 to 48 hours. At 12 hours, plasma LCAT concentration had increased by 0.40±0.90 mg/L (+7.8%; mean±SD;
P
<0.05), plasma cholesterol esterification rate by 29.0±9.0 nmol/mL per h (+69.5%;
P
<0.01), plasma CETP concentration by 0.5±0.2 mg/L (+29.7%;
P
<0.01), and plasma PLTP activity by 1.45±0.67 μmol/mL per h (+23.9%;
P
<0.01). In contrast, plasma PLTP concentration had decreased by 4.4±2.7 mg/L (−44.8%;
P
<0.01). The changes in PLTP were accompanied by alterations in the relative proportions of large lipoproteins containing inactive PLTP and small particles containing PLTP of high specific activity. No changes were detected in peripheral lymph.

Conclusions—

Nascent HDL secretion may induce changes in PLTP, LCAT, and CETP that promote RCT by catalyzing pre-β HDL production, cholesterol esterification in HDLs, and cholesteryl ester transfer from HDLs to other lipoproteins.
Serum Chitotriosidase Activity Is Increased in Subjects With Atherosclerosis Disease
Authors: Artieda Marta , Cenarro Ana , Gañán Alberto , Jericó Ivonne , Gonzalvo Carmen , Casado Juan M. , Vitoria Isabel , Puzo José , Pocoví Miguel , Civeira Fernando
Published: August 2003

Objective—

This study was undertaken to analyze the relation between serum activity of chitotriosidase enzyme, a protein synthesized exclusively by activated macrophages, and atherosclerotic lesion extent in subjects with atherothrombotic stroke (ATS) and in subjects with ischemic heart disease (IHD).

Methods and Results—

We assayed the serum chitotriosidase activity and a common chitotriosidase gene polymorphism that causes deficiency in chitotriosidase activity in 3 Spanish populations, ATS (n=153), IHD (n=124), and control (n=148) subjects. Statistical differences were found in serum chitotriosidase activity between ATS (88.1±4.6 nmol/mL · h,
P
<0.0001) and IHD subjects (79.0±6.3,
P
=0.002) versus control group (70.9±5.2). These observed differences were not attributable to a distinct allelic or genotype distribution. The extension of the atherosclerotic lesion in carotids of ATS subjects was measured by duplex sonography. Chitotriosidase activities were 66.9±9.6, 88.7±8.3, and 107.7±11.8 for subjects with carotid stenosis ≤30%, 31% to 60%, and >60%, respectively. Statistical differences were observed between subjects with major and intermediate stenosis grade compared with subjects with minor stenosis,
P
=0.005 and
P
=0.016, respectively.

Conclusions—

Serum chitotriosidase activity is significantly increased in individuals suffering from atherosclerosis disease and is related to the severity of the atherosclerotic lesion, suggesting a possible role as atherosclerotic extent marker.
Mechanisms Involved in Adenosine Triphosphate–Induced Platelet Aggregation in Whole Blood
Authors: Stafford Nicholas P. , Pink Andrew E. , White Ann E. , Glenn Jacqueline R. , Heptinstall Stan
Published: August 2003

Objective—

Effects on platelet aggregation of adenosine triphosphate (ATP) released from damaged cells and from platelets undergoing exocytosis have not been clearly established. In this study we report on the effects of ATP on platelet aggregation in whole blood.

Methods and Results—

Aggregation, measured using a platelet-counting technique, occurred in response to ATP and was maximal at 10 to 100 μmol/L. It was abolished by MRS2179, AR-C69931, and creatine phosphate/creatine phosphokinase, implying that conversion to adenosine diphosphate (ADP) is required. ATP did not induce aggregation in platelet-rich plasma, but aggregation did occur when apyrase or hexokinase was added. Aggregation also occurred after addition of leukocytes to platelet-rich plasma (as a source of ecto-ATPase), and this was potentiated on removal of adenosine by adenosine deaminase, indicating that adenosine production modulates the response. Dipyridamole, which inhibits adenosine uptake into erythrocytes, inhibited aggregation induced by ATP in whole blood, and adenosine deaminase reversed this. DN9693 and forskolin synergized with dipyridamole to inhibit ATP-induced aggregation.

Conclusions—

ATP induces aggregation in whole blood via conversion of ATP to ADP by ecto-ATPases on leukocytes. This is inhibited by agents that prevent adenosine removal. Reduced aggregation at high concentrations of ATP (>100 μmol/L) may be a consequence of inhibition by ATP of ADP action at ADP receptors.
Hypercholesterolemia Blunts Forearm Vasorelaxation and Enhances the Pressor Response During Acute Systemic Hypoxia
Authors: Barreto-Filho José Augusto S. , Consolim-Colombo Fernanda Marciano , Guerra-Riccio Grazia Maria , Santos Raul D. , Chacra Ana Paula , Lopes Heno Ferreira , Teixeira Sandra H. , Martinez Tânia , Krieger José Eduardo , Krieger Eduardo Moacyr
Published: August 2003

Objective—

During hypoxia, active substances released by the endothelium play a key role in the cardiovascular and respiratory responses elicited to optimize oxygen delivery. As hypercholesterolemia is a major cause of endothelial dysfunction, it may interfere with these responses.

Methods and Results—

We studied cardiovascular and ventilatory responses to acute systemic hypoxia in 14 patients with hypercholesterolemia (HC) and 13 control (CO) subjects. Oxygen saturation decreased similarly in both groups. Diastolic blood pressure increased only in the HC group (
P
=0.0002) and, despite systolic blood pressure increases both in the HC group, 140±4 (95% confidence interval [CI],131 to 149 mm Hg) to 154±4 mm Hg (95% CI,145 to 164 mm Hg), and in the CO group, 133±3 (95% CI,126 to 140 mm Hg) to 140±4 mm Hg (95% CI,132 to 148 mm Hg), the HC group showed an enhanced pressor response (
P
=0.03, group comparison). Both groups had increased forearm blood flow, but the decrease in forearm vascular resistance in the CO group, 40±5 (95% CI, 30 to 51 UR) to 31±4 UR (95% CI,23 to 39 UR) (
P
=0.0001) was not seen in the HC group, 29±3 (95% CI, 22 to 37 UR) to 26±3 UR (95% CI, 20 to 33 UR), (
P
=0.03, group comparison).

Conclusions—

Hypercholesterolemic patients demonstrate a hyperreactive pressor response and absence of forearm vasodilation during acute systemic hypoxia.
Human Cytomegalovirus Seropositivity Is Associated With Impaired Vascular Function
Authors: Grahame-Clarke Cairistine , Chan Norman N. , Andrew Dawn , Ridgway Geoff L. , Betteridge D. John , Emery Vincent , Colhoun Helen M. , Vallance Patrick
Published: August 2003

Background—

Herpesvirus infection is a possible risk factor for atherogenesis, and diabetics may be at particular risk. Endothelial dysfunction is an early marker for atherosclerosis, and the present study tests the hypotheses that (1) prior infection with cytomegalovirus (CMV) and herpes simplex virus (HSV) is associated with endothelial dysfunction and (2) this may be more marked in diabetics.

Methods and Results—

Serum samples were tested for anti-IgG antibodies to CMV and HSV from 400 subjects (mean age for diabetics and nondiabetics, 37.8±4.3 and 37.9±3.7 [SD]). We also assessed
Helicobacter pylori
and
Chlamydia pneumoniae
serology. Coronary atheroma was quantified by means of electron beam computed tomography. Subjects (n=157) underwent venous occlusion plethysmography with acetylcholine, bradykinin, glyceryl trinitrate, norepinephrine, and
l
-
N
G
-monomethyl-
l
-arginine. Individuals who were seropositive for CMV had reduced responses to bradykinin (
P
=0.005) and glyceryl trinitrate (
P
=0.006). The reduced response to bradykinin remained significant (
P
=0.045) after adjusting for the response to glyceryl trinitrate and was independent of conventional risk factors. Positive serology for the other organisms did not have an independent effect on reactivity. There was a weaker association between CMV and coronary artery calcification (
P
=0.09). Positive serology for each of the other pathogens did not affect reactivity, but there was a relation between total pathogen burden and impaired vascular reactivity. No significant differences were found between diabetics and nondiabetics.

Conclusions—

This study shows that CMV-seropositive individuals have endothelial dysfunction and impaired responses to NO. This association was independent of conventional risk factors and may be associated with increased atherosclerosis burden.
Role of Cyclooxygenase-2 in the Generation of Vasoactive Prostanoids in the Rat Pulmonary and Systemic Vascular Beds
Authors: Baber Syed R. , Champion Hunter C. , Bivalacqua Trinity J. , Hyman Albert L. , Kadowitz Philip J.
Published: August 2003

Background—

Prostanoid synthesis by the cyclooxygenase (COX)-2 pathway plays an important role in inflammation, and recent studies have shown the presence of COX-2 in the normal rat lung. However, the role of COX-2 in the generation of vasoactive prostanoids in the rat is uncertain. In the present study, the hypothesis that synthesis of vasoactive prostanoids via the COX-2 pathway can alter pulmonary and systemic vascular resistance was investigated, and the effects of selective COX-2 inhibitors on pulmonary and systemic responses to the prostanoid precursor arachidonic acid were examined in the anesthetized rat with a recently developed right-heart catheterization technique.

Methods and Results—

Injections of arachidonic acid caused dose-related increases in pulmonary vascular resistance and decreases in systemic vascular resistance. These responses were attenuated by selective COX-2 inhibitors and a selective COX-1 inhibitor, whereas responses to exogenous prostanoids were not altered. Nimesulide or NS-398 did not alter arachidonic acid–induced platelet aggregation in rat platelet-rich plasma. Western blot analysis and immunostaining showed the expression of both COX isoforms in the rat lung.

Conclusions—

The results of these experiments suggest that arachidonic acid is converted into vasoactive prostanoids by the COX-2 and COX-1 pathway in the pulmonary and peripheral vascular beds in the rat and that TXA
2
is a major prostanoid formed in the normal rat lung.
Effects of Unilateral and Bilateral Carotid Baroreflex Stimulation on Cardiac and Neural Sympathetic Discharge Oscillatory Patterns
Authors: Furlan Raffaello , Diedrich André , Rimoldi Alexandra , Palazzolo Laura , Porta Cesare , Diedrich Laura , Harris Paul A. , Sleight Peter , Biagioni Italo , Robertson David , Bernardi Luciano
Published: August 2003

Background—

Left and right carotid baroreflex afferents participate in generating the spontaneous variability of heart rate (HR), arterial pressure (AP), and muscle sympathetic nerve activity (MSNA), but the relative contribution of each side is unclear. Pathophysiological conditions unilaterally affecting carotid baroreceptor function might result in abnormal changes of HR, AP, and MSNA variability, thus markedly affecting prognosis. We tested the hypothesis that unilateral carotid baroreceptor perturbation might differentially affect HR, AP, and MSNA variability compared with stimulation of the opposite side.

Methods and Results—

In 12 healthy volunteers, 4 sinusoidal neck suction procedures (0.1 Hz, from 0 to −50 mm Hg) were applied at the right, left, and combined right and left sides of the neck, in concordance or with phase opposition. Respiration was controlled at 0.25 Hz. Power spectrum analysis assessed the changes in the 0.1-Hz oscillatory component of the R-R interval, systolic AP (SAP), and MSNA variability induced by rhythmic baroreceptor stimulation. Mean R-R interval, SAP, and MSNA were unchanged during all procedures. The increase of the 0.1-Hz component of R-R and SAP variability during right and combined right and left carotid baroreceptor stimulation was greater than the changes induced by left-sided stimulation. The increase in the 0.1-Hz oscillatory component of MSNA variability was similar during all neck suction procedures.

Conclusions—

Right carotid baroreflex loading was as efficient as bilateral stimulation and more effective than left carotid suction in modulating R-R and SAP variability. There was no asymmetry in neural sympathetic discharge responses after single-sided carotid baroreceptor stimulation.
Detectable Serum Cardiac Troponin T as a Marker of Poor Prognosis Among Patients With Chronic Precapillary Pulmonary Hypertension
Authors: Torbicki Adam , Kurzyna Marcin , Kuca Paweł , Fijałkowska Anna , Sikora Jarosław , Florczyk Michał , Pruszczyk Piotr , Burakowski Janusz , Wawrzyńska Lilianna
Published: August 2003

Background—

Right ventricular failure is a leading cause of death in patients with chronic pulmonary hypertension (PH). We checked whether detection of cardiac troponin T (cTnT), a specific marker of myocyte injury, could be useful in prognostic stratification of those patients.

Methods and Results—

Initial evaluation of 56 clinically stable patients (age 41±15 years) with pulmonary arterial (51 patients) or inoperable chronic thromboembolic (5 patients) PH (mean pulmonary arterial pressure 60±18 mm Hg) included cTnT test, allowing detection of its serum levels ≥0.01 ng/mL [cTnT(+)]. cTnT was detectable in 8 of 56 (14%) patients (mean±SD, 0.034±0.022; range, 0.010 to 0.077 ng/mL). Despite similar pulmonary hemodynamics, they had higher heart rate (92±15 versus 76±14 bpm,
P
=0.004), lower mixed venous oxygen saturation (50±10% versus 57±9%,
P
=0.04), and higher serum N-terminal pro-B–type natriuretic peptide (4528±3170 versus 2054±2168 pg/mL,
P
=0.03) and walked less during the 6-minute walk test (298±132 versus 396±101 m,
P
=0.02). Cumulative survival estimated by Kaplan-Meier curves was significantly worse at 24 months in cTnT(+) compared with cTnT(−) (29% versus 81%, respectively, log-rank test
P
=0.001). Multivariate analysis revealed cTnT status (hazard ratio, 4.89; 95% CI, 1.18 to 20.29;
P
=0.03), 6-minute walk test (hazard ratio, 0.93 for each 10 m;
P
=0.01), and pulmonary vascular resistance (hazard ratio, 1.13;
P
=0.01) as independent markers of mortality. All 3 cTnT(+) patients who survived the follow-up period converted to cTnT(−) during treatment.

Conclusions—

Detectable cTnT is a so-far ignored independent marker of increased mortality risk in patients with chronic precapillary PH, supporting the role of progressive myocyte injury in the vicious circle leading to hemodynamic destabilization.
Cost Effectiveness of Defibrillation by Targeted Responders in Public Settings
Authors: Nichol G. , Valenzuela T. , Roe D. , Clark L. , Huszti E. , Wells G.A.
Published: August 2003

Background—

Out-of-hospital cardiac arrest is frequent and has poor outcomes. Defibrillation by trained targeted nontraditional responders improves survival versus historical controls, but it is unclear whether such defibrillation is a good value for the money. Therefore, this study estimated the incremental cost effectiveness of defibrillation by targeted nontraditional responders in public settings by using decision analysis.

Methods and Results—

A Markov model evaluated the potential cost effectiveness of standard emergency medical services (EMS) versus targeted nontraditional responders. Standard EMS included first-responder defibrillation followed by advanced life support. Targeted nontraditional responders included standard EMS supplemented by defibrillation by trained lay responders. The analysis adopted a US societal perspective. Input data were derived from published or publicly available data. Future costs and effects were discounted at 3%. Monte Carlo simulation and sensitivity analyses assessed the robustness of results. Standard EMS had a median of 0.47 (interquartile range [IQR]=0.32 to 0.69) quality-adjusted life years and a median of $14 100 (IQR=$8600 to $21 900) costs per arrest. Targeted nontraditional responders in casinos had an incremental cost of a median $56 700 (IQR=$44 100 to $77 200) per additional quality-adjusted life year. The results were sensitive to changes in time to defibrillation, incidence of arrest, and number of devices required to implement rapid defibrillation.

Conclusions—

Where cardiac arrest is frequent and response time intervals are short, rapid defibrillation by targeted nontraditional responders may be a good value for the money compared with standard EMS. The incidence of arrest should be considered when choosing locations to implement public access defibrillation.
Quality of Life of Children After Repair of Transposition of the Great Arteries
Authors: Culbert Erin L. , Ashburn David A. , Cullen-Dean Geraldine , Joseph Jay A. , Williams William G. , Blackstone Eugene H. , McCrindle Brian W. ,   the Congenital Heart Surgeons Society
Published: August 2003

Background—

We sought to assess quality of life of children with transposition of the great arteries (TGA) enrolled during transition in management strategy from atrial to arterial switch operation.

Methods and Results—

Neonates enrolled by the Congenital Heart Surgeons Society in a prospective study of TGA between 1985 and 1989 were eligible. A Child Health Questionnaire was sent for completion by the child between February and June 2000. Data were compared with published normative values. Child Health Questionnaires were completed by 306 of 708 survivors at a mean age of 13±1 years. Diagnosis included TGA (n=202, 66%), TGA/ventricular septal defect (VSD) (n=84, 27%), and TGA/VSD/pulmonary stenosis (n=20, 7%). Repair type was arterial switch (n=189, 62%), atrial switch (n=105, 34%; Senning=58, Mustard=47), or Rastelli (n=12, 4%). Children with TGA scored significantly higher than published norms in all categories except self-esteem. TGA/VSD/pulmonary stenosis was associated with lower scores than TGA and TGA/VSD in physical functioning (
P
=0.002), general health perceptions (
P
=0.012), and mental health (
P
=0.048). Arterial repair was associated with higher scores than atrial or Rastelli repair in physical functioning (
P
<0.001), pain (
P
=0.004), mental health (
P
=0.019), self-esteem (
P
=0.004), and general health perceptions (
P
<0.001). By multivariable analyses, the most common independent factors impacting scores were repair type, perfusion parameters, and gender.

Conclusions—

Quality of life and health status as perceived by children 11 to 15 years after TGA repair is excellent when compared with published normative data and is better after arterial switch operation than after atrial repair.
Mechanism of Complement Activation and Its Role in the Inflammatory Response After Thoracoabdominal Aortic Aneurysm Repair
Authors: Fiane Arnt E. , Videm Vibeke , Lingaas Per S. , Heggelund Lars , Nielsen Erik W. , Geiran Odd R. , Fung Michael , Mollnes Tom E.
Published: August 2003

Background—

Complement activation contributes to ischemia-reperfusion injury. Patients undergoing thoracoabdominal aortic aneurysm (TAAA) repair suffer extensive ischemia-reperfusion and considerable systemic inflammation.

Methods and Results—

The degree and mechanism of complement activation and its role in inflammation were investigated in 19 patients undergoing TAAA repair. Patients undergoing open infrarenal aortic surgery (n=5) or endovascular descending aortic aneurysm repair (n=6) served as control subjects. Substantial complement activation was seen in TAAA patients but not in controls. C1rs-C1-inhibitor complexes increased moderately, whereas C4bc, C3bBbP, C3bc, and the terminal SC5b-9 complex (TCC) increased markedly after reperfusion, reaching a maximum 8 hours after reperfusion. Interleukin (IL)-1β, tumor necrosis factor α (TNF-α), and IL-8 increased significantly in TAAA patients but not in controls, peaking at 24 hours postoperatively and correlating closely with the degree of complement activation. IL-6 and IL-10 increased to a maximum 8 hours after reperfusion in the TAAA patients, were not correlated with complement activation, and increased moderately in the control subjects. Myeloperoxidase and lactoferrin increased markedly before reperfusion in all groups, whereas sICAM-1, sP-selectin, and sE-selectin were unchanged. No increase was observed in complement activation products, IL-1β, TNF-α, or IL-8 in a mannose-binding lectin (MBL)–deficient TAAA patient, whereas IL-6, IL-10, myeloperoxidase, and lactoferrin increased as in the controls. Two other MBL-deficient TAAA patients receiving plasma attained significant MBL levels and showed complement and cytokine patterns identical to the MBL-sufficient TAAA patients.

Conclusions—

The data suggest that complement activation during TAAA repair is MBL mediated, amplified through the alternative pathway, and responsible in part for the inflammatory response.
Effect of Lower Dose of Oral Conjugated Equine Estrogen on Size and Oxidative Susceptibility of Low-Density Lipoprotein Particles in Postmenopausal Women
Authors: Wakatsuki Akihiko , Okatani Yuji , Ikenoue Nobuo , Shinohara Koichi , Watanabe Kazushi , Fukaya Takao
Published: August 2003

Background—

Estrogen replacement therapy (ERT) has an antioxidant effect that opposes the oxidation of LDL. Oral ERT-induced increases in plasma triglyceride, however, are associated with decreased LDL size, which may counteract this antioxidant effect. Because lower doses of oral estrogen do not affect plasma triglyceride concentrations, LDL size might not change, and the antioxidant effect of estrogen might be preserved. We investigated whether a lower dose of oral estrogen could eliminate the adverse effects of high-dose oral ERT on the size and oxidative susceptibility of LDL in postmenopausal women.

Methods and Results—

Postmenopausal women received no treatment or were treated with oral conjugated equine estrogen (CEE) 0.625 or 0.3125 mg/d for 3 months. CEE at a dose of 0.625 mg/d significantly increased plasma triglyceride concentrations and decreased LDL diameter, but the concentrations of LDL-derived thiobarbituric acid reactive substances (TBARS) and lag time for conjugated diene formation did not change. In contrast, 0.3125 mg of CEE did not affect plasma triglyceride concentrations or LDL diameter and significantly decreased LDL-derived TBARS concentrations and significantly prolonged LDL lag time. Estrogen-induced changes in LDL diameter correlated negatively with changes in plasma triglyceride (
r
=−0.44,
P
<0.01) and LDL-derived TBARS (
r
=−0.57,
P
<0.001) but positively with changes in LDL lag time (
r
=0.42,
P
<0.01).

Conclusions—

Because oral CEE at a dose of 0.3125 mg/d does not elevate plasma triglyceride, resulting in unchanged size of LDL particles that are resistant to oxidation, the antioxidant effect of estrogen can be preserved.
Systemic Delivery of Bone Marrow–Derived Mesenchymal Stem Cells to the Infarcted Myocardium
Authors: Barbash Israel M. , Chouraqui Pierre , Baron Jack , Feinberg Micha S. , Etzion Sharon , Tessone Ariel , Miller Liron , Guetta Esther , Zipori Dov , Kedes Laurence H. , Kloner Robert A. , Leor Jonathan
Published: August 2003

Background—

Systemic delivery of bone marrow–derived mesenchymal stem cells (BM-MSCs) is an attractive approach for myocardial repair. We aimed to test this strategy in a rat model after myocardial infarction (MI).

Methods and Results—

BM-MSCs were obtained from rat bone marrow, expanded in vitro to a purity of >50%, and labeled with
99m
Tc exametazime, fluorescent dye,
LacZ
marker gene, or bromodeoxyuridine. Rats were subjected to MI by transient coronary artery occlusion or to sham MI.
99m
Tc-labeled cells (4×10
6
) were transfused into the left ventricular cavity of MI rats either at 2 or 10 to 14 days after MI and were compared with sham-MI rats or MI rats treated with intravenous infusion. Gamma camera imaging and isolated organ counting 4 hours after intravenous infusion revealed uptake of the
99m
Tc-labeled cells mainly in the lungs, with significantly smaller amounts in the liver, heart, and spleen. Delivery by left ventricular cavity infusion resulted in drastically lower lung uptake, better uptake in the heart, and specifically higher uptake in infarcted compared with sham-MI hearts. Histological examination at 1 week after infusion identified labeled cells either in the infarcted or border zone but not in remote viable myocardium or sham-MI hearts. Labeled cells were also identified in the lung, liver, spleen, and bone marrow.

Conclusions—

Systemic intravenous delivery of BM-MSCs to rats after MI, although feasible, is limited by entrapment of the donor cells in the lungs. Direct left ventricular cavity infusion enhances migration and colonization of the cells preferentially to the ischemic myocardium.
Randomized Study to Assess the Effectiveness of Slow- and Moderate-Release Polymer-Based Paclitaxel-Eluting Stents for Coronary Artery Lesions
Authors: Colombo Antonio , Drzewiecki Janusz , Banning Adrian , Grube Eberhard , Hauptmann Karl , Silber Sigmund , Dudek Dariusz , Fort Stephen , Schiele Francois , Zmudka Krysztof , Guagliumi Giulio , Russell Mary E.
Published: August 2003

Background—

Early clinical studies demonstrated the feasibility of local paclitaxel delivery in reducing restenosis after treatment of de novo coronary lesions in small patient populations.

Methods and Results—

We conducted a randomized, double-blind trial of 536 patients at 38 medical centers evaluating slow-release (SR) and moderate-release (MR) formulations of a polymer-based paclitaxel-eluting stent (TAXUS) for revascularization of single, primary lesions in native coronary arteries. Cohort I compared TAXUS-SR with control stents, and Cohort II compared TAXUS-MR with a second control group. The primary end point was 6-month percent in-stent net volume obstruction measured by intravascular ultrasound. Secondary end points were 6-month angiographic restenosis and 6- and 12-month incidence of major adverse cardiac events, a composite of cardiac death, myocardial infarction, and repeat revascularization. At 6 months, percent net volume obstruction within the stent was significantly lower for TAXUS stents (7.9% SR and 7.8% MR) than for respective controls (23.2% and 20.5%;
P
<0.0001 for both). This corresponded with a reduction in angiographic restenosis from 17.9% to 2.3% in the SR cohort (
P
<0.0001) and from 20.2% to 4.7% in the MR cohort (
P
=0.0002). The incidence of major adverse cardiac events at 12 months was significantly lower (
P
=0.0192) in the TAXUS-SR (10.9%) and TAXUS-MR (9.9%) groups than in controls (22.0% and 21.4%, respectively), predominantly because of a significant reduction in repeat revascularization of the target lesion in TAXUS-treated patients.

Conclusions—

Compared with a bare metal stent, paclitaxel-eluting stents reduced in-stent neointimal formation and restenosis and improved 12-month clinical outcome of patients with single de novo coronary lesions.
Intra-Atrial Pressure Increases Rate and Organization of Waves Emanating From the Superior Pulmonary Veins During Atrial Fibrillation
Authors: Kalifa Jérôme , Jalife José , Zaitsev Alexey V. , Bagwe Suveer , Warren Mark , Moreno Javier , Berenfeld Omer , Nattel Stanley
Published: August 2003

Background—

Atrial fibrillation (AF) commonly associates with atrial dilatation by poorly understood mechanisms. We hypothesized that elevation of intra-atrial pressure elicits high-frequency and spatio-temporally organized left atrial (LA) sources emanating from the superior pulmonary veins.

Methods and Results—

We used a stretch-related AF model in the sheep heart to induce stable episodes of AF (>40 minutes) in 9 animals. Video movies of the LA free wall (LAFW) and LA superior pulmonary vein junction (JPV) were obtained by using di-4-ANEPPS. Electrograms from the right atrium were recorded. At intra-atrial pressures >10 cm H
2
O, the maximum dominant frequency (DF
Max
) was significantly higher in the JPV than in the LAFW (12.0±0.2 and 10.5±0.2 Hz, respectively [mean±SEM];
P
<0.001). Below 10 cm H
2
O, DF
Max
was similar in the JPV and LAFW (10.8±0.3 versus 10.2±0.3 Hz;
P
=0.6); DF
Max
in both JPV and LAFW was significantly higher than in the right atrium (7.8±0.3 Hz;
P
<0.001). Analysis of excitation direction in JPV showed positive correlation between intra-atrial pressure and the number of waves emanating from the left superior pulmonary vein (
r
=0.79,
P
=0.02) but not from the LAFW (
r
=0.54,
P
=0.09). The number of spatio-temporally periodic waves in the JPV correlated with pressure (
r
=0.92,
P
=0.002). In 3 cases, JPV rotors were identified with a cycle length equal to 1/DF
Max
.

Conclusion—

We demonstrate for the first time that an increase in intra-atrial pressure increases the rate and organization of waves emanating from the superior pulmonary veins underlying stretch-related AF.
Is Pulmonary Vein Isolation Necessary for Curing Atrial Fibrillation?
Authors: Stabile Giuseppe , Turco Pietro , La Rocca Vincenzo , Nocerino Pasquale , Stabile Eugenio , De Simone Antonio
Published: August 2003

Background—

Pulmonary veins (PVs) play a pivotal role in initiating and perpetuating atrial fibrillation (AF). We investigated if PV electrical isolation from the left atrium is required for curing AF.

Methods and Result—

Fifty-one patients with paroxysmal or persistent AF underwent circumferential radiofrequency ablation of PV ostia performed with an anatomic approach. The end point of the ablation procedure was the recording of low peak-to-peak bipolar potentials (<0.1 mV) inside the lesions. Left atrium pacing was used to assess the conduction between the PVs and the left atrium. During a mean follow-up period of 16.6±3.9 months, 41 patients (80.4%) were free of atrial arrhythmias. When patients with and without AF recurrence were analyzed, no significant difference was observed in the mean number of PVs in which the ablation end point was reached (3.4±1.2 versus 3.7±0.87) and PVs isolated (1.5±1.4 versus 1.6±1). We noted that, although in 29 of 41 patients (71%) without AF recurrence, the ablation end point was reached in all PVs mapped, it was only possible to demonstrate the isolation of all PVs mapped in 2 patients. On the other hand, in 7 of 10 patients (70%) with AF recurrence, the ablation end point was reached in all PVs mapped, whereas one patient had all PVs isolated.

Conclusions—

Our findings show that with the use of a pure anatomic approach, it is possible to prevent AF in >80% of patients undergoing catheter ablation. Moreover, the isolation of PVs is not crucial for curing AF.
Overexpression of Apolipoprotein A-I Promotes Reverse Transport of Cholesterol From Macrophages to Feces In Vivo
Authors: Zhang YuZhen , Zanotti Ilaria , Reilly Muredach P. , Glick Jane M. , Rothblat George H. , Rader Daniel J.
Published: August 2003

Background—

Abundant data indicate that overexpression of apolipoprotein A-I (apoA-I) in mice inhibits atherosclerosis. One mechanism is believed to be promotion of reverse cholesterol transport, but no direct proof of this concept exists. We developed a novel approach to trace reverse transport of labeled cholesterol specifically from macrophages to the liver and feces in vivo and have applied this approach to investigate the ability of apoA-I overexpression to promote macrophage-specific reverse cholesterol transport.

Method and Results—

J774 macrophages were loaded with cholesterol by incubation with acetylated LDL, labeled with
3
H-cholesterol, and then injected intraperitoneally into mice. Plasma and feces were collected at 24 hours and 48 hours, when mice were exsanguinated, tissues were harvested, and all were analyzed for tracer counts.
3
H-cholesterol was found in the plasma, liver, and feces. For apoA-I overexpression, mice were injected intravenously with apoA-I adenovirus (10
11
particles per animal) 3 days before labeled macrophages were injected. ApoA-I overexpression led to significantly higher
3
H-cholesterol in plasma, liver, and feces. The amount of
3
H-tracer in the liver was 35% higher (
P
<0.05) and the
3
H-tracer excreted into feces over 48 hours was 63% higher (
P
<0.05) in apoA-I–expressing mice than in control mice.

Conclusion—

Injection of
3
H-cholesterol–labeled macrophage foam cells is a method of measuring reverse cholesterol transport specifically from macrophages to feces in vivo, and apoA-I overexpression promotes macrophage-specific reverse cholesterol transport.
Repeat Intracoronary Radiation for Recurrent In-Stent Restenosis in Patients Who Failed Intracoronary Radiation
Authors: Waksman Ron , Lew Robert , Ajani Andrew E. , Pichard Augusto D. , Satler Lowell F. , Kent Kenneth M. , Chan Rosanna , White R. Larry , Suddath William O. , Pinnow Ellen , Torguson Rebecca , Dilcher Christian , Wolfram Roswitha , Lindsay Joseph
Published: August 2003

Background—

Intracoronary radiation therapy (IRT) is the only proven treatment for in-stent restenosis (ISR). It is, however, associated with a significant failure rate. The present study evaluated the outcomes of patients who underwent repeat intracoronary radiation for recurrent ISR.

Methods and Results—

Fifty-one consecutive patients who failed a previous radiation treatment, presented with angina and angiographic evidence of ISR, and were treated with percutaneous coronary intervention (PCI) and repeat radiation to the same segment were studied. Twenty-five patients were treated with gamma radiation in a dose of 15 Gy, and 26 were treated with beta radiation doses of 18.3 to 23 Gy. The mean cumulative dose for this cohort was 39.5±11.9 Gy (range, 29 to 75.6 Gy). The outcomes of those patients were compared with outcomes of 299 patients who also failed initial radiation but were treated with repeat conventional PCI to a previously irradiated segment without repeat radiation. At 9 months after treatment, the repeat-IRT group had lower rates of target lesion revascularization (23.5% versus 54.6%;
P
<0.001) and major adverse cardiac events, including target vessel revascularization (29.4% versus 61.3%;
P
<0.001). At 9 months, patients with repeat IRT were free of angiographic and clinical events related to the radiation therapy.

Conclusions—

Repeat gamma or beta radiation to treat failed IRT for ISR after conventional PCI is safe and effective at 9 months and should be considered as a therapeutic option for this difficult patient subset.
Sympathoexcitation by PVN-Injected Bicuculline Requires Activation of Excitatory Amino Acid Receptors
Authors: Chen Qing Hui , Haywood Joseph R. , Toney Glenn M.
Published: August 2003

Acute blockade of γ-aminobutyric acid (GABA)-A receptors in the hypothalamic paraventricular nucleus (PVN) increases mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). However, the underlying neural mechanisms have not been fully determined. We tested the hypothesis that responses to GABA-A receptor blockade in the PVN require activation of local ionotropic excitatory amino acid (EAA) receptors. MAP, HR, and renal SNA responses to unilateral PVN microinjection of bicuculline methobromide (BIC, 0.1 nmol) were recorded before and after ipsilateral PVN injection of either vehicle (saline), the nonselective ionotropic EAA receptor antagonist kynurenate (KYN), the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5), or the non-NMDA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX). Responses to PVN-injected BIC were unaltered by vehicle injection. In contrast, injection of KYN (7.2 nmol; n=4) nearly abolished ABP and renal SNA responses to BIC (
P
<0.01) and significantly attenuated (
P
<0.05) HR responses as well. Similarly, graded doses of AP5 (0.6, 3, and 6 nmol) and NBQX (0.26, 1.3, and 2.6 nmol) reduced responses to PVN-injected BIC in a dose-related manner, with the 3 nmol (n=7) and 1.3 nmol (n=6) doses producing maximal effects (
P
<0.05). KYN, AP5, and NBQX did not affect baseline parameters. Effects of a cocktail containing AP5 (3 nmol) and NBQX (1.3 nmol) were greater (
P
<0.01) than either antagonist alone and were not statistically different from KYN. These data indicate that cardiovascular and renal sympathetic responses to acute GABA-A receptor blockade in the PVN require local actions of EAAs at both NMDA and non-NMDA receptors.
Perturbation of D
1
Dopamine and AT
1
Receptor Interaction in Spontaneously Hypertensive Rats
Authors: Zeng Chunyu , Luo Yingjin , Asico Laureano D. , Hopfer Ulrich , Eisner Gilbert M. , Felder Robin A. , Jose Pedro A.
Published: August 2003

The dopaminergic and renin-angiotensin systems interact to regulate blood pressure. Because this interaction may be perturbed in genetic hypertension, we studied D
1
dopamine and AT
1
angiotensin receptors in immortalized renal proximal tubule (RPT) and A10 aortic vascular smooth muscle cells. In normotensive Wistar-Kyoto (WKY) rats, the D
1
-like agonist fenoldopam increased D
1
receptors but decreased AT
1
receptors. These effects were blocked by the D
1
-like antagonist SCH 23390 (10
−7
mol/L per 24 hours). In spontaneously hypertensive rat (SHR) RPT cells, fenoldopam also decreased AT
1
receptors but no longer stimulated D
1
receptor expression. Basal levels of AT
1
/D
1
receptor coimmunoprecipitation were greater in WKY RPT cells (29±2 density units, DU) than in SHR RPT cells (21±2 DU, n=7 per group,
P
<0.05). The coimmunoprecipitation of D
1
and AT
1
receptors was increased by fenoldopam (10
−7
mol/L per 24 hours) in WKY RPT cells but decreased in SHR RPT cells. The effects of fenoldopam in RPT cells from WKY rats were similar in aortic vascular smooth muscle cells from normotensive BD IX rats, that is, fenoldopam decreased AT
1
receptors and increased D
1
receptors. Our studies show differential regulation of the expression of D
1
and AT
1
receptors in RPT cells from WKY and SHR. This regulation and D
1
/AT
1
receptor interaction are different in RPT cells of WKY and SHR. An altered interaction of D
1
and AT
1
receptors may play a role in the impaired sodium excretion and enhanced vasoconstriction in hypertension.
β2 Adrenoceptor Functional Gene Variants, Obesity, and Blood Pressure Level Interactions in the General Population
Authors: Pereira Alexandre C. , Floriano Marcilene S. , Mota Glória F.A. , Cunha Roberto S. , Herkenhoff Fernando L. , Mill José G. , Krieger José E.
Published: August 2003

We investigated the association of β2 adrenoceptor functional gene variants (Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms), obesity phenotypes, and blood pressure levels in a large, ethnically mixed urban population. The individuals (n=1576) were randomly selected for a cross-sectional study of cardiovascular risk factors in Vitória, Brazil. Statistically significant associations among systolic blood pressure and the Arg16Gly and Thr164Ile variants were identified in univariate analysis. The Gly16/Gly16 genotype was still associated with systolic blood pressure (SBP) in multivariate analysis adjusting for age, gender, ethnicity, total cholesterol, diabetes, and body mass index (BMI) (
P
=0.01). The Arg16 allele was the only genotypic variable associated with BMI, and, in a dominant model, it remained associated with an increased BMI even after adjustment for age, gender, ethnicity, triglycerides, HDL cholesterol, LDL cholesterol, diabetes, and hypertension status (
P
=0.02). Although the different polymorphisms did not interact in the determination of SBP, a significant interaction with BMI (
P
=0.02), not through linkage disequilibrium, was identified between the Gln27Glu and the Thr164Ile variants. Furthermore, a significant interaction among the Arg16Gly polymorphism and BMI (
P
=0.036) and waist-hip ratio (
P
=0.003) in determining SBP was disclosed by ANOVA factorial modeling, with SBP used as the dependent variable. An interaction between the Thr164Ile polymorphism and waist-hip ratio was also identified (
P
=0.018). Finally, multiple logistic regression models showed a 1.48-fold increase in the risk of hypertension in individuals harboring the Gly16/Gly16 genotype and a 1.31-fold (
P
=0.01) and a 1.49-fold (
P
=0.003) increased risk of obesity in individuals harboring the Gln27/Gln27 genotype or the presence of the Arg16 allele, respectively. Taken together, these data provide evidence for a strong but complex relation between β-adrenoceptor gene variants, hypertension, and obesity.