bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol
Authors: Chorro Francisco J. , Cánoves Joaquín , Guerrero Juan , Mainar Luis , Sanchis Juan , Such Luis , López-Merino Vicente
Published: June 2012

Background
—The purpose of this study was to determine whether the myocardial electrophysiological properties are useful for predicting changes in the ventricular fibrillatory pattern.

Methods and Results
—Thirty-two Langendorff-perfused rabbit hearts were used to record ventricular fibrillatory activity with an epicardial multiple electrode. Under control conditions and after flecainide, verapamil, or
d,l
-sotalol, the dominant frequency (FrD), type of activation maps, conduction velocity, functional refractory period, and wavelength (WL) of excitation were determined during ventricular fibrillation (VF). Flecainide (1.9±0.3 versus 2.4±0.6 cm,
P
<0.05) and sotalol (2.1±0.3 versus 2.5±0.5 cm,
P
<0.05) prolonged WL and diminished FrD during VF, whereas verapamil (2.0±0.2 versus 1.7±0.2 cm,
P
<0.001) shortened WL and increased FrD. Simple linear regression revealed an inverse relation between FrD and the functional refractory period (
r
=0.66,
P
<0.0001), a direct relation with respect to conduction velocity (
r
=0.33,
P
<0.01), and an inverse relation with respect to WL estimated during VF (
r
=0.49,
P
<0.0001). By stepwise multiple regression, the functional refractory periods were the only predictors of FrD. Flecainide and sotalol increased the circuit size of the reentrant activations, whereas verapamil decreased it. The 3 drugs significantly reduced the percentages of more complex activation maps during VF.

Conclusions
—The activation frequency is inversely related to WL during VF, although a closer relation is observed with the functional refractory period. Despite the diverging effects of verapamil versus flecainide and sotalol on the activation frequency, WL, and size of the reentrant circuits, all 3 drugs reduce activation pattern complexity during VF.
Elevated HDL Cholesterol Is a Risk Factor for Ischemic Heart Disease in White Women When Caused by a Common Mutation in the Cholesteryl Ester Transfer Protein Gene
Authors: Agerholm-Larsen Birgit , Nordestgaard Børge G. , Steffensen Rolf , Jensen Gorm , Tybjærg-Hansen Anne
Published: June 2012

Background
—The level of HDL cholesterol is inversely related to the risk of ischemic heart disease.

Methods and Results
—In 9168 women and men from a general population and 946 women and men with ischemic heart disease (all white), we tested the hypothesis that the Ile405Val mutation in the cholesteryl ester transfer protein gene (
CETP
) affects HDL cholesterol levels and the risk of ischemic heart disease. The relative frequencies of Ile/Ile, Ile/Val, and Val/Val carriers were 0.46, 0.43, and 0.11 for both women and men. Women with these 3 genotypes had mean HDL cholesterol levels of 1.68, 1.75, and 1.82 mmol/L, respectively (
P
<0.001, ANOVA), as well as a significant decrease in the ratio of total to HDL cholesterol (
P
=0.002, ANOVA). On multiple logistic regression analysis, women not treated with hormone replacement therapy who were heterozygous or homozygous for Val405 had a 1.4-fold (95% CI 1.0 to 1.9) to 2.1-fold (95% CI 1.3 to 3.4) increase in the risk of ischemic heart disease. No significant associations were found in men.

Conclusions
—Increased HDL cholesterol levels caused by mutations in
CETP
are associated with an increased risk of ischemic heart disease in white women.
Inhibition of Rho-Associated Kinase Results in Suppression of Neointimal Formation of Balloon-Injured Arteries
Authors: Sawada Naoki , Itoh Hiroshi , Ueyama Koji , Yamashita Jun , Doi Kentaro , Chun Tae-Hwa , Inoue Mayumi , Masatsugu Ken , Saito Takatoshi , Fukunaga Yasutomo , Sakaguchi Satsuki , Arai Hiroshi , Ohno Nobuhisa , Komeda Masashi , Nakao Kazuwa
Published: June 2012

Background
—Rho-associated kinase (ROCK), an effector of small GTPase Rho, regulates vascular tone via a calcium sensitization mechanism and plays a key role in the pathogenesis of hypertension. However, its role in vascular growth remains unclear.

Methods and Results
—Y-27632, a specific ROCK inhibitor, and the overexpression of dominant-negative ROCK suppressed the mitogen-induced DNA synthesis of cultured vascular smooth muscle cells (VSMCs), which indicates the essential role of ROCK in the control of VSMC proliferation in vitro. Y-27632 also suppressed the chemotaxis of VSMCs. Male Wistar rats were systemically given Y-27632 (35 to 70 mg · kg
−1
· day
−1
) through an intraperitoneal infusion. The neointimal formation of balloon-injured carotid arteries was significantly suppressed in Y-27632–treated rats (intima/media ratio, 0.22±0.02) compared with vehicle-treated rats (intima/media ratio, 0.92±0.21) or hydralazine-treated rats with a similar blood pressure decrease (intima/media ratio, 1.03±0.15). The phosphorylation of myosin phosphatase and myosin light chain was elevated in injured arteries in a Y-27632–sensitive manner, indicating the augmentation of ROCK activity in neointimal formation. The downregulation of the cyclin-dependent kinase inhibitor p27
kip1
in injured vessels was reversed by Y-27632 treatment, reflecting the antiproliferative effect of ROCK inhibition in vivo.

Conclusions
—We conclude that ROCK plays a key role in the process of neointimal formation after balloon injury. Thus, the inhibition of ROCK may be a potential therapeutic strategy for treating vascular proliferative disorders and hypertension.
Racial Differences in Hemodynamic Responses to Environmental Thermal Stress Among Adolescents
Authors: Kelsey Robert M. , Alpert Bruce S. , Patterson Stephen M. , Barnard Marie
Published: June 2012

Background
—Previous studies by our laboratory and others have shown that blood pressure (BP) responses to many short-term laboratory stressors are greater in black than in white children. We sought to determine the cardiac and vascular contributions to these differences in BP reactivity and whether racial differences in vascular reactivity involve excessive vasoconstriction or deficient vasodilation.

Methods and Results
—We evaluated BP, heart rate, and impedance cardiographic measures of preejection period (PEP) and total peripheral resistance (TPR) in healthy black (n=76) and white (n=60) adolescents (mean age, 14.8 years) during passive exposure to a vasoconstrictive cold chamber (8°C to 10°C) and a vasodilatory heat chamber (40°C to 42°C). Results indicated greater decreases in PEP and increases in TPR in blacks than whites during cold exposure (
P
<0.05) but no group differences during heat exposure. Covariance analyses indicated that the racial differences during cold exposure probably reflected greater β-adrenergic cardiac reactivity and α-adrenergic vasoconstrictive reactivity in blacks than whites.

Conclusions
—Blacks and whites exhibited comparable myocardial and vasodilatory responses to heat stress, but blacks exhibited heightened myocardial and vasoconstrictive reactivity to cold stress. These results suggest that the locus of racial differences in vascular reactivity involves vasoconstrictive rather than vasodilatory function. The pattern of racial differences during cold stress raises the possibility that both myocardial and vasoconstrictive mechanisms may contribute to the increased risk of hypertension in blacks.
Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice
Authors: Dong Zhao Ming , Brown Allison A. , Wagner Denisa D.
Published: June 2012

Background
—Adhesive interactions between leukocytes and endothelial cells are characteristic of the development of atherosclerotic lesions, but the receptors involved remain to be defined. P-selectin is an adhesion receptor expressed on activated endothelial cells or platelets and was shown to be involved in fatty streak formation in LDL receptor–deficient mice on an atherogenic diet. The main purpose of this study is to examine the role of P-selectin in the spontaneous development of advanced atherosclerosis in apoE-deficient mice.

Methods and Results
—We intercrossed P-selectin–deficient mice with mice lacking apoE and compared lesion development in apoE-deficient mice with P-selectin (apoE
−/−
P
+/+
) and without P-selectin (apoE
−/−
P
−/−
) that were fed normal mouse chow. At 4 months of age, apoE
−/−
P
−/−
mice had 3.5-fold smaller aortic sinus lesions than apoE
−/−
P
+/+
mice. These were limited to fatty streaks in the apoE
−/−
P
−/−
mice, whereas 70% of apoE
−/−
P
+/+
lesions contained smooth muscle cells. Significantly more of the aortic sinus circumference was covered by lesions in the apoE
−/−
P
+/+
animals. The P-selectin genotype affected macrophage recruitment, because twice as many mononuclear cells were present in the P-selectin–positive lesions. At 15 months, the lesions progressed to the fibrous plaque stage in both genotypes and spread throughout the aorta, but this process was delayed in apoE
−/−
P
−/−
mice. In the aortic sinus, the lesions of the apoE
−/−
P
−/−
mice were 2.6-fold smaller and less calcified.

Conclusions
—P-selectin appears to be a key adhesion receptor mediating leukocyte recruitment into lesions and promoting advanced atherosclerosis in apoE-deficient mice.
Carvedilol Inhibits Reactive Oxygen Species Generation by Leukocytes and Oxidative Damage to Amino Acids
Authors: Dandona Paresh , Karne Rajaram , Ghanim Husam , Hamouda Wael , Aljada Ahmad , Magsino Cesar H.
Published: June 2012

Background
—The purpose of this study was to test whether carvedilol has an antioxidant effect in humans in vivo.

Methods and Results
—We administered 3.125 mg of carvedilol twice daily to normal subjects for 1 week. ROS generation by polymorphonuclear leukocytes and mononuclear cells fell from 314±183.43 and 303±116 mV to 185±157 and 189±63 mV (
P
<0.025), respectively.
m
-Tyrosine fell from 4.24±0.99 to 4.03±0.97 ng/mL (
P
=0.01), and
o
-tyrosine fell from 4.59±1.10 to 4.24±0.99 ng/mL (
P
=0.004) in the absence of a change in phenylalanine concentrations.

Conclusions
—We conclude that carvedilol significantly inhibits ROS generation by leukocytes and oxidative conversion of phenylalanine to
m
- and
o
-tyrosine.
Influence of a Nonionic, Iso-Osmolar Contrast Medium (Iodixanol) Versus an Ionic, Low-Osmolar Contrast Medium (Ioxaglate) on Major Adverse Cardiac Events in Patients Undergoing Percutaneous Transluminal Coronary Angioplasty
Authors: Bertrand Michel E. , Esplugas Enrique , Piessens Jan , Rasch Wenche
Published: June 2012

Background
—The potential merits and disadvantages of the use of ionic or nonionic contrast media in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have been the subjects of controversy. The present study was designed to evaluate the possible influence of both types of contrast media on major adverse cardiac events (MACE) in patients undergoing PTCA.

Methods and Results
—In a randomized, parallel-group, double-blind study, 1411 patients received either iodixanol (a nonionic, iso-osmolar contrast medium) or ioxaglate (an ionic, low-osmolar contrast medium) during PTCA. A standardized anticoagulation regimen was followed. Patients were monitored in the hospital for 2 days and followed-up at 1 month. The primary end point, a composite of MACE (death, stroke, myocardial infarction, coronary artery bypass grafting, and re-PTCA) after 2 days, occurred in 4.3% of the total population, with no statistically significant difference between groups (iodixanol, 4.7%; ioxaglate, 3.9%;
P
=0.45). Further, between 2-day and 1-month follow-ups, no significant difference (
P
=0.27) existed between the groups in the rates of MACE. Hypersensitivity reactions (
P
=0.007) and adverse drug reactions (
P
=0.002) were significantly less frequent in the iodixanol group. The only significant predicting factors for the occurrence of MACE were dissection/abrupt closure and country.

Conclusions
—No significant differences were observed between the iodixanol and ioxaglate groups with regard to MACE, although hypersensitivity and adverse drug reactions were significantly less frequent in patients who received iodixanol.
Abnormal Aortic Valve Development in Mice Lacking Endothelial Nitric Oxide Synthase
Authors: Lee Tony C. , Zhao Yidan D. , Courtman David W. , Stewart Duncan J.
Published: June 2012

Background
—Endothelium-derived nitric oxide (NO) is produced by an oxidative reaction catalyzed by endothelial NO synthase (eNOS). NO plays a crucial role in controlling cell growth and apoptosis, as well as having well-characterized vasodilator and antithrombotic actions. More recently, endothelium-derived NO was shown to be involved in postdevelopmental vascular remodeling and angiogenesis, as well as in the formation of limb vasculature during embryogenesis. Therefore, we investigated the role of endothelium-derived NO during cardiovascular development using mice deficient in eNOS.

Methods and Results
—We examined the hearts of 12 mature eNOS-deficient and 26 mature wild-type mice. Five of the mature eNOS-deficient mice had a bicuspid aortic valve; none of the 26 wild-type animals exhibited identifiable valvular or cardiac abnormalities. Immunohistochemical analysis revealed prominent eNOS expression localized to the endothelium lining the valve cusps of the aorta in mature wild-type mice; expression was localized to the myocardium and endothelial cell monolayer lining the valve leaflets in the developing embryo.

Conclusions
—These results show a strong association between eNOS deficiency and the presence of a bicuspid aortic valve; they provide the first molecular insight into one of the most common types of congenital cardiac abnormality.
Selective Pharmacological Agents Implicate Mitochondrial but Not Sarcolemmal K
ATP
Channels in Ischemic Cardioprotection
Authors: Sato Toshiaki , Sasaki Norihito , Seharaseyon Jegatheesan , O’Rourke Brian , Marbán Eduardo
Published: June 2012

Background
—Pharmacological evidence has implicated ATP-sensitive K
+
(K
ATP
) channels as the effectors of cardioprotection, but the relative roles of mitochondrial (mitoK
ATP
) and sarcolemmal (surfaceK
ATP
) channels remain controversial.

Methods and Results
—We examined the effects of the K
ATP
channel blocker HMR1098 and the K
ATP
channel opener P-1075 on surfaceK
ATP
and mitoK
ATP
channels in rabbit ventricular myocytes. HMR1098 (30 μmol/L) inhibited the surfaceK
ATP
current activated by metabolic inhibition, whereas the drug did not blunt diazoxide (100 μmol/L)-induced flavoprotein oxidation, an index of mitoK
ATP
channel activity. P-1075 (30 μmol/L) did not increase flavoprotein oxidation but did elicit a robust surfaceK
ATP
current that was completely inhibited by HMR1098. These results indicate that HMR1098 selectively inhibits surfaceK
ATP
channels, whereas P-1075 selectively activates surface K
ATP
channels. In a cellular model of simulated ischemia, the mitoK
ATP
channel opener diazoxide (100 μmol/L), but not P-1075, blunted cellular injury. The cardioprotection afforded by diazoxide or by preconditioning was prevented by the mitoK
ATP
channel blocker 5-hydroxydecanoate (500 μmol/L) but not by the surfaceK
ATP
channel blocker HMR1098 (30 μmol/L).

Conclusions
—The cellular effects of mitochondria- or surface-selective agents provide further support for the emerging consensus that mitoK
ATP
channels rather than surfaceK
ATP
channels are the likely effectors of cardioprotection.
Relation Between Endothelial Cell Apoptosis and Blood Flow Direction in Human Atherosclerotic Plaques
Authors: Tricot Olivier , Mallat Ziad , Heymes Christophe , Belmin Joël , Lesèche Guy , Tedgui Alain
Published: June 2012

Background
—Blood flow characteristics influence endothelial cell apoptosis. However, little is known about the occurrence of endothelial cell apoptosis in human atherosclerosis and its relation to blood flow.

Methods and Results
—A total of 42 human carotid atherosclerotic plaques were retrieved by endarterectomy; they were examined in the longitudinal axial direction. Plaques were included in this study when upstream and downstream parts were clearly visible, occlusion was absent, and immunostaining for luminal endothelium was present all along the plaque. Using these criteria, 13 plaques were processed for further immunohistochemical studies (using anti-CD31, anti-Ki-67, and anti-splicing factor antibodies) and in situ detection of apoptosis (terminal dUTP nick end-labeling and ligase assay). Eight plaques showed ≥1 apoptotic endothelial cell at the luminal surface. Quantitative analysis of endothelial cell apoptosis in these plaques showed a systematic preferential occurrence of apoptosis in the downstream parts of plaques, where low flow and low shear stress prevail, in comparison with the upstream parts (18.8±3.3% versus 2.7±1.2%, respectively,
P
<0.001). Endothelial cell apoptosis was barely detectable in plaque microvessels.

Conclusions
—Our results suggest that in vivo local shear stress influences luminal endothelial cell apoptosis and may be a major determinant of plaque erosion and thrombosis.
Edge Restenosis After Implantation of High Activity
32
P Radioactive β-Emitting Stents
Authors: Albiero Remo , Nishida Takahiro , Adamian Milena , Amato Antonio , Vaghetti Marco , Corvaja Nicola , Di Mario Carlo , Colombo Antonio
Published: June 2012

Background
—A high restenosis rate has been reported at the edges (“edge restenosis”) of
32
P radioactive stents with an initial activity level of 3 to 12 μCi. This edge effect might be due to balloon injury and to a low dose of radiation at the stent margins. The aim of this study was to evaluate whether the implantation of
32
P radioactive stents with a higher activity level (12 to 21 μCi) combined with a nonaggressive stent implantation strategy could solve the problem of edge restenosis.

Methods and Results
—We compared the results of lesions treated with single radioactive BX stents with an activity of 12 to 21 μCi (group 2, n=54 lesions) with the results of lesions treated by single radioactive BX stents with an initial activity level of 3 to 12 μCi (group 1, n=42 lesions). There were no procedural events. At the 6-month follow-up, no myocardial infarctions, deaths, or stent thromboses had occurred. Intrastent binary restenosis was 0% in group 1 versus 4% in group 2 (n=2, both at the ostium of the right coronary artery,
P
=NS). Intrastent neointimal hyperplasia was significantly lower in group 2 than in group 1. The intralesion (intrastent plus peri-stent) restenosis rate was 38% in group 1 versus 30% in group 2 (
P
=NS).

Conclusions
—Single
32
P radioactive stents with an initial activity level of 12 to 21 μCi reduced intrastent neointimal hyperplasia compared with stents of 3 to 12 μCi, but they did not solve the problem of edge restenosis, even if a nonaggressive stent implantation strategy was used.
Geographic Miss
Authors: Sabaté Manel , Costa Marco A. , Kozuma Ken , Kay I. Patrick , van der Giessen Willem J. , Coen Veronique L. M. A. , Ligthart Jurgen M. R. , Serrano Pedro , Levendag Peter C. , Serruys Patrick W.
Published: June 2012

Background
—A recognized limitation of endovascular β-radiation therapy is the development of new stenosis at the edges of the irradiated area. The combination of injury and low-dose radiation may be the precursor of this phenomenon. We translated the radio-oncological concept of “geographic miss” to define cases in which the radiation source did not fully cover the injured area. The aims of the study were to determine the incidence and causes of geographic miss and evaluate the impact of this inadequate treatment on the outcome of patients treated with intracoronary β-radiation.

Methods and Results
—We analyzed 50 consecutive patients treated with β-radiation after percutaneous coronary intervention. The prescribed dose ranged between 12 and 20 Gy at 2 mm from the source axis. By means of quantitative coronary angiography, the irradiated segment (IRS) and both edges were studied before and after intervention and at 6-month follow-up. Edges that were injured during the procedure constituted the geographic miss edges. Twenty-two edges were injured during the intervention, mainly because of procedural complications that extended the treatment beyond the margins of the IRS. Late loss was significantly higher in geographic miss edges than in IRSs and uninjured edges (0.84±0.6 versus 0.15±0.4 and 0.09±0.4 mm, respectively;
P
<0.0001). Similarly, restenosis rate was significantly higher in the injured edges (10% within IRS, 40.9% in geographic miss edges, and 1.9% in uninjured edges;
P
<0.001).

Conclusions
—These data support the hypothesis that the combination of injury and low-dose β-radiation induces deleterious outcome.
Long-Term Clinical Outcome in the Bypass Angioplasty Revascularization Investigation Registry
Authors: Feit Frederick , Brooks Maria Mori , Sopko George , Keller Norma M. , Rosen Allan , Krone Ronald , Berger Peter B. , Shemin Richard , Attubato Michael J. , Williams David O. , Frye Robert , Detre Katherine M.
Published: June 2012

Background
—The Bypass Angioplasty Revascularization Investigation (BARI) included 4039 patients with multivessel coronary artery disease; 1829 consented to randomization, and 2010 did not but were followed up in a registry. Thus, we can evaluate the outcome of physician-guided versus random assignment of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG).

Methods and Results
—We compared the baseline features and outcomes for PTCA and CABG in the overall registry and its predesignated subgroups. We assessed the impact of treatment by choice versus random assignment by comparing the results in the registry with those of the randomized trial. Statistical adjustments for differences in baseline characteristics were made. Within the registry, nearly twice as many patients were selected for PTCA (1189) as CABG (625); mortality at 7 years was similar for PTCA (13.9%) and CABG (14.2%) (
P
=0.66) before and after adjustment for baseline differences between patients selected for PTCA versus CABG (adjusted RR, 1.02;
P
=0.86). In contrast to the randomized trial, the 7-year mortality rate of treated diabetics in the registry was equally high (26%) with PTCA or CABG. Seven-year mortality was higher for patients undergoing PTCA in the randomized trial than in the registry (19.1% versus 13.9%,
P
<0.01) but not for those undergoing CABG (15.6% versus 14.2%,
P
=0.57). The adjusted relative mortality risk for PTCA in the randomized versus registry population was 1.17 (
P
=0.16).

Conclusions
—BARI physicians were able to select PTCA rather than CABG for 65% of registry patients who underwent revascularization without compromising long-term survival either in the overall population or in treated diabetics.
Controlled Comparison of
l
-5-Methyltetrahydrofolate Versus Folic Acid for the Treatment of Hyperhomocysteinemia in Hemodialysis Patients
Authors: Bostom Andrew G. , Shemin Douglas , Bagley Pamela , Massy Ziad A. , Zanabli Abdul , Christopher Kenneth , Spiegel Paul , Jacques Paul F. , Dworkin Lance , Selhub Jacob
Published: June 2012

Background
—The hyperhomocysteinemia regularly found in hemodialysis patients is largely refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high-dose
l
-5-methyltetrahydrofolate–based regimen provided improved total homocysteine (tHcy)–lowering efficacy in chronic hemodialysis patients.

Methods and Results
—We block-randomized 50 chronic, stable hemodialysis patients on the basis of their screening predialysis tHcy levels, sex, and dialysis center into 2 groups of 25 subjects treated for 12 weeks with oral folic acid at 15 mg/d (FA group) or an equimolar amount (17 mg/d) of oral
l
-5-methyltetrahydrofolate (MTHF group). All 50 subjects also received 50 mg/d of oral vitamin B
6
and 1.0 mg/d of oral vitamin B
12
. The mean percent reductions (±95% CIs) in predialysis tHcy were not significantly different: MTHF, 17.0% (12.0% to 22.0%); FA, 14.8% (9.6% to 20.1%);
P
=0.444 by matched ANCOVA adjusted for pretreatment tHcy. Final on-treatment values (mean with 95% CI) were MTHF, 20.0 μmol/L (18.8 to 21.2 μmol/L); FA, 19.5 μmol/L (18.3 to 20.7 μmol/L). Moreover, neither treatment resulted in “normalization” of tHcy levels (ie, final on-treatment values <12 μmol/L) among a significantly different or clinically meaningful number of patients: MTHF, 2 of 25 (8%); FA, 0 of 25 (0%); Fisher’s exact test of between-groups difference,
P
=0.490.

Conclusions
—Relative to high-dose folic acid, high-dose oral
l
-5-methyltetrahydrofolate–based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (ie, >90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absorption or circulating plasma and tissue distribution.
Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators
Authors: Pasceri Vincenzo , Wu Henry D. , Willerson James T. , Yeh Edward T. H.
Published: June 2012

Background
—Peroxisome proliferator–activated receptor-γ (PPARγ) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPARγ activators on endothelial activation and inflammatory response within the plaque are currently unknown.

Methods and Results
—We tested the hypothesis that PPARγ activators inhibit vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1) expression in cultured endothelial cells (evaluated by flow cytometry) and homing of monocyte/macrophages to atherosclerotic plaques in vivo. In endothelial cells, the PPARγ agonists troglitazone at 100 μmol/L and 15-deoxy-
Δ12,14
-prostaglandin J
2
(15d-PGJ2) at 20 μmol/L markedly attenuated the tumor necrosis factor–induced expression of VCAM-1 and ICAM-1. A significant inhibition of VCAM-1 expression was also evident at 5 and 10 μmol/L 15d-PGJ2 and 20 μmol/L troglitazone. Expression of E-selectin and PECAM-1 was not altered. To confirm the biological relevance of these results, we assessed the effects of troglitazone on monocyte/macrophage homing to atherosclerotic plaques in apoE-deficient mice. A 7-day treatment with troglitazone (400 mg/kg) significantly reduced monocyte/macrophage homing to atherosclerotic plaques (236±77 versus 177±43 macrophages,
P
=0.03); an even more striking inhibition was found at 3200 mg/kg troglitazone (344±76 versus 172±83 macrophages,
P
=0.005).

Conclusions
—PPARγ activators inhibit expression of VCAM-1 and ICAM-1 in activated endothelial cells and significantly reduce monocyte/macrophage homing to atherosclerotic plaques. These findings suggest that PPARγ activators, currently used in treatment of type II diabetes, may have beneficial effects in modulating inflammatory response in atherosclerosis.
Abciximab Improves Both Epicardial Flow and Myocardial Reperfusion in ST-Elevation Myocardial Infarction
Authors: de Lemos James A. , Antman Elliott M. , Gibson C. Michael , McCabe Carolyn H. , Giugliano Robert P. , Murphy Sabina A. , Coulter Stephanie A. , Anderson Keaven , Scherer Joel , Frey Martin J. , Van der Wieken R. , Van de Werf Frans , Braunwald Eugene
Published: June 2012

Background
—In the presence of ST-elevation myocardial infarction, patients with successful epicardial reperfusion (TIMI 3 flow) but persistent ST elevation on a 12-lead ECG are at high risk for subsequent death and left ventricular dysfunction. In the TIMI 14 trial, a dose-ranging angiographic study, combined therapy with abciximab plus reduced-dose tPA enhanced the speed and efficacy of epicardial reperfusion. We determined whether the combination of abciximab plus reduced-dose tPA provided additional benefit in terms of myocardial reperfusion, as evidenced by greater resolution of ST elevation.

Methods and Results
—All 346 patients with interpretable baseline and 90-minute ECGs, treated with either tPA alone or abciximab plus reduced-dose tPA (combination therapy), were included. Patients receiving combination therapy (n=221) had a 59% rate of complete (≥70%) ST resolution at 90 minutes versus 37% in those treated with tPA alone (n=125) (
P
<0.0001). When the analysis was limited to patients with TIMI 3 flow, patients treated with combination therapy (n=151) remained significantly more likely to achieve complete ST resolution than those receiving tPA alone (n=80) (69% versus 44%;
P
=0.0002).

Conclusions
—Combination therapy with abciximab and reduced-dose tPA improves myocardial (microvascular) reperfusion, as reflected in greater ST-segment resolution, in addition to epicardial flow. This finding may translate into improved clinical outcomes by enhancing myocardial salvage.
Inhibition of Late Vein Graft Neointima Formation in Human and Porcine Models by Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-3
Authors: George Sarah J. , Lloyd Clinton T. , Angelini Gianni D. , Newby Andrew C. , Baker Andrew H.
Published: June 2012

Background
—Autologous saphenous vein coronary artery bypass graft surgery is complicated by late graft failure due to neointima formation and subsequent atherosclerosis. Growth factors and metalloproteinases (MMPs) act in concert to promote neointima formation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), an extracellular matrix–associated MMP inhibitor, uniquely promotes apoptosis of isolated vascular smooth muscle cells. Here, we overexpressed TIMP-3 at the luminal surface of human saphenous veins before organ culture and in pig saphenous veins before interposition grafting into carotid arteries in vivo to assess neointima formation.

Methods and Results
—In both models, high TIMP-3 immunoreactivity occurred in the luminal and upper medial extracellular matrix after adenovirus delivery. MMP activity measured by in situ zymography was reduced throughout the veins, confirming a bystander effect. By use of 3 independent techniques, apoptosis levels in the neointima and medial layer were significantly elevated by TIMP-3 overexpression. Neointima formation was reduced by 84% in 14-day human organ cultures and by 58% in 28-day pig vein grafts (both
P
<0.05). In contrast, TIMP-2 overexpression had no effect on neointima formation in vivo.

Conclusions
—Our results highlight the potential therapeutic benefit for TIMP-3 overexpression to reduce neointima formation associated with late vein graft failure.
Laminar Shear Stress Upregulates the Complement-Inhibitory Protein Clusterin
Authors: Urbich Carmen , Fritzenwanger Michael , Zeiher Andreas M. , Dimmeler Stefanie
Published: June 2012

Background
—The complement system is implicated in the pathogenesis of atherosclerosis. Complement has been shown to activate endothelial cells (ECs) by inducing a proinflammatory response. Physiological levels of shear stress exert potent antiatherosclerotic effects. Therefore, we investigated whether shear stress antagonizes the effects of complement on ECs.

Methods and Results
—Incubation of ECs with nonlytic concentrations of complement serum (CS: 0.2 U/mL for 6 hours) resulted in an upregulation of interleukin-8 (IL-8) (165±12%) and monocyte chemoattractant protein-1 (MCP-1) mRNA expression (267±34%). Preexposure of ECs for 18 hours with laminar shear stress (15 dyne/cm
2
) abrogated CS-induced IL-8 release to 106±10% (
P
<0.001) and reduced CS-induced MCP-1 expression (170±31%;
P
<0.05). To examine the mechanism of the protective effect of shear stress, expression of the complement-inhibitory protein clusterin was analyzed under shear exposure. Shear stress increased clusterin mRNA (225±76%, 6 hours) and protein expression (164±22%, 18 hours). Specific inhibition of clusterin by transfection with antisense oligonucleotides reversed the protective effect of shear stress on CS-induced MCP-1 and IL-8 upregulation (
P
<0.05 versus sense-transfected cells). Moreover, clusterin overexpression inhibited CS-induced EC activation.

Conclusions
—Shear stress abrogates the complement-induced proinflammatory response of ECs by upregulation of the complement-inhibitory protein clusterin. Upregulation of clusterin may contribute to the potent antiatherosclerotic effects of shear stress by preventing endothelial activation through the complement cascade.
Three-Year Clinical and Angiographic Follow-Up After Intracoronary Radiation
Authors: Teirstein Paul S. , Massullo Vincent , Jani Shirish , Popma Jeffrey J. , Russo Robert J. , Schatz Richard A. , Guarneri Erminia M. , Steuterman Stephen , Sirkin Kathleen , Cloutier David A. , Leon Martin B. , Tripuraneni Prabhakar
Published: June 2012

Background
—Although several early trials indicate treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The objective of this report is to document angiographic and clinical outcome 3 years after treatment of restenotic stented coronary arteries with catheter-based
192
Ir.

Methods and Results
—A double-blind, randomized trial compared
192
Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Over a 9-month period, 55 patients were enrolled; 26 were randomized to
192
Ir and 29 to placebo. At 3-year follow-up, target-lesion revascularization was significantly lower in the
192
Ir group (15.4% versus 48.3%;
P
<0.01). The dichotomous restenosis rate at 3-year follow-up was also significantly lower in
192
Ir patients (33% versus 64%;
P
<0.05). In a subgroup of patients with 3-year angiographic follow-up not subjected to target-lesion revascularization by the 6-month angiogram, the mean minimal luminal diameter between 6 months and 3 years decreased from 2.49±0.81 to 2.12±0.73 mm in
192
Ir patients but was unchanged in placebo patients.

Conclusions
—The early clinical benefits observed after treatment of coronary restenosis with
192
Ir appear durable at late follow-up. Angiographic restenosis continues to be significantly reduced in
192
Ir-treated patients, but a small amount of late loss was observed between the 6-month and 3-year follow-up time points. No events occurred in the
192
Ir group to suggest major untoward effects of vascular radiotherapy. At 3-year follow-up, vascular radiotherapy continues to be a promising new treatment for restenosis.
Induction of a Myocardial Adrenomedullin Signaling System During Ischemic Heart Failure in Rats
Authors: Øie Erik , Vinge Leif Erik , Yndestad Arne , Sandberg Cecilie , Grøgaard Haakon K. , Attramadal Håvard
Published: June 2012

Background
—Increased plasma adrenomedullin (ADM) levels have been reported in congestive heart failure (HF). The present study was designed to investigate myocardial regulation of the different components of the ADM signaling system (ADM, ADM receptor, and receptor-activity–modifying protein-2, RAMP-2) during ischemic HF in rats and to identify the cells in the myocardium displaying ADM-like immunoreactivity (ADM-ir). Furthermore, the effects of endothelin (ET) receptor antagonism on expression of the myocardial ADM system during HF were investigated.

Methods and Results
—Northern blot analysis revealed increased ADM mRNA expression in the nonischemic left ventricle, with maximal levels 28 days after induction of myocardial infarction (1.5-fold,
P
<0.05) compared with the sham group. Parallel elevations of myocardial ADM receptor and RAMP-2 mRNA levels were also observed (2.3- and 1.5-fold increase, respectively;
P
<0.05). In addition, high levels of ADM mRNA were seen in the ischemic region. Immunohistochemical analysis revealed a substantial increase of ADM-ir in microvascular endothelium and perivascular interstitial cells of myocardial tissue contiguous to the ischemic region. In addition, radioligand binding studies demonstrated a 1.6-fold increase of specific ADM binding sites in the failing left ventricle (
P
<0.05). Intervention with the mixed ET
A
/ET
B
receptor antagonist bosentan (100 mg · kg
−1
· day
−1
PO) for 15 days prevented the increase of RAMP-2 mRNA.

Conclusions
—The study demonstrates a concerted induction of several components of the myocardial ADM signaling system during postinfarction failure and that the vessels are the main source of myocardial ADM. Our observations indicate a role for ADM as an autocrine/paracrine factor during ventricular remodeling after myocardial infarction.
Characteristics of Coronary Smooth Muscle Cells and Adventitial Fibroblasts
Authors: Patel Sachin , Shi Yi , Niculescu Rodica , Chung Eugene H. , Martin Jack L. , Zalewski Andrew
Published: June 2012

Background
—Recent findings suggesting the involvement of adventitial cells in coronary repair have raised questions regarding the phenotypic “plasticity” of medial smooth muscle cells (SMCs). Accordingly, the aims of the present study were to examine the characteristics of coronary medial and adventitial cells and to compare the responses of coronary and noncoronary SMCs to stimulation.

Methods and Results
—Enzymatically isolated coronary SMCs (human and porcine) were distinct from noncoronary SMCs, showing poor adhesion and spreading, as well as lower proliferation, collagen synthesis, and LDL degradation. Several extracellular matrix components (Matrigel, collagen I and IV, laminin, vitronectin, fibronectin) or growth factors (epidermal growth factor, platelet-derived growth factor-BB, insulin growth factor-1, interleukin-1α) failed to augment the adhesion or proliferation of coronary SMCs to the levels observed in noncoronary SMCs. Unlike coronary SMCs, coronary fibroblasts demonstrated high adhesion, proliferation, collagen synthesis, and avid LDL metabolism. Limited responses of coronary SMCs were associated with sustained expression of differentiation markers (α-smooth muscle actin, h-caldesmon, and smooth muscle myosin heavy chain), whereas noncoronary SMCs showed marked phenotypic heterogeneity.

Conclusions
—Coronary SMCs appeared to maintain highly differentiated phenotype in response to stimulation, whereas coronary adventitial fibroblasts demonstrated several characteristics that are essential during vascular repair. Coronary SMCs, however, were distinct from noncoronary medial cells, which displayed greater phenotypic heterogeneity and versatility in culture. We postulate that the mechanism of vascular repair may differ among vascular beds, pointing to the importance of coronary artery–specific investigations in vascular biology.
A Randomized Comparison of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin After the Placement of Coronary-Artery Stents
Authors: Müller Christian , Büttner Heinz J. , Petersen Jens , Roskamm Helmut
Published: June 2012

Background
—The introduction of an effective antiplatelet therapy with aspirin and ticlopidine after the placement of coronary-artery stents has decreased the risk of thrombotic stent occlusions (TSO) and hemorrhagic complications. However, the use of ticlopidine is limited by hematological and gastrointestinal adverse effects. The safety and efficacy of clopidogrel after stenting remains to be established.

Methods and Results
—After successful coronary stenting during elective or emergency percutaneous transluminal coronary angioplasty, 700 patients with 899 lesions were randomly assigned to receive a 4-week course of either 500 mg ticlopidine (n=345) or 75 mg clopidogrel (n=355), in addition to 100 mg aspirin. All the following clinical events reflecting TSO were included in the prespecified primary cardiac endpoint: cardiac death, urgent target vessel revascularization, angiographically documented TSO, or nonfatal myocardial infarction within 30 days. The primary noncardiac endpoint was defined as noncardiac death, stroke, severe peripheral vascular or hemorrhagic events, or any adverse event resulting in discontinuation of study medication. Cardiac events occurred in 17 patients [11 (3.1%) with clopidogrel and 6 (1.7%) with ticlopidine (
P
=0.24)]. The primary noncardiac endpoint was observed in 16 patients (4.5%) assigned to receive clopidogrel versus 33 patients (9.6%) assigned to receive ticlopidine (
P
=0.01).

Conclusions
—After the placement of coronary-artery stents in unselected patients, antiplatelet therapy with aspirin and clopidogrel seems to be comparably safe and effective as aspirin and ticlopidine. Noncardiac events were significantly reduced with clopidogrel.
Diastolic Blood Pressure Changes During Exercise Positively Correlate With Serum Cholesterol and Insulin Resistance
Authors: Brett Sally E. , Ritter James M. , Chowienczyk Philip J.
Published: June 2012

Background
—Metabolic factors, including plasma concentrations of cholesterol and insulin resistance, may influence blood pressure through effects on vascular reactivity. Such effects might influence blood pressure during exercise more strongly than at rest.

Methods and Results
—We examined whether there is an association between serum cholesterol or insulin resistance and change in blood pressure during mild exercise. Blood pressure was measured at rest and during fixed low-workload bicycle ergometry (50, 75, and 100 W, each for 3 minutes) in 75 healthy active men (age, 18 to 66 years). Blood pressure at rest was not significantly correlated with serum cholesterol or insulin resistance (estimated from the fasting glucose–insulin product). The change from resting values in diastolic but not systolic blood pressure during exercise was correlated with serum cholesterol (
R
>0.47,
P
<0.0001 for each workload) and insulin resistance (
R
>0.38,
P
<0.01 for each workload). Serum cholesterol and insulin resistance were the only independent predictors of the change in diastolic blood pressure during exercise in a stepwise regression model incorporating age, body mass index, serum cholesterol, triglycerides, HDL cholesterol, insulin resistance, and heart rate during exercise. In a further study, the change in diastolic blood pressure during exercise was greater in men with uncomplicated type 2 diabetes (13.6 mm Hg [95% CI, 8.5 to 18.8]; n=10) than in nondiabetic control men (2.7 mm Hg [95% CI, −2.0 to 7.3]; n=10;
P
=0.002).

Conclusions
—Changes in diastolic blood pressure during gentle exercise are strongly associated with serum concentrations of total cholesterol and insulin resistance. This may contribute to development of hypertensive complications in dyslipidemic and/or insulin-resistant patients.
Analysis by Early Angiography of Right Internal Thoracic Artery Grafting Via the Transverse Sinus
Authors: Ura Masashi , Sakata Ryuzo , Nakayama Yoshihiro , Arai Yoshio , Oshima Shuichi , Noda Katsuo
Published: June 2012

Background
—There has been debate regarding whether technically demanding right internal thoracic artery (RITA) grafting via the transverse sinus can be extensively applied to patients in high-risk groups, such as patients with a small body size, elderly patients, and woman with relatively smaller coronary artery and internal thoracic artery (ITA) diameters.

Methods and Results
—Of the 1456 patients who underwent isolated coronary artery bypass grafting between January 1989 and December 1998 at Kumamoto Central Hospital, 393 patients (mean age, 62.4±9.0 years) with the RITA anastomosed to the major branches of the circumflex artery were studied. Left ITA grafting was performed in 384 patients, and in 369, the in situ left ITA was anastomosed to the left anterior descending coronary artery using standard methods. Early postoperative angiography was performed in 381 patients. The RITA was occluded in 4 patients, and string-like artery and significant stenosis were present in 11 and 7 patients, respectively; RITA graft patency was thus 94.1%. Of the preoperative variables and angiographic data, simple and multiple logistic regression analyses identified decreased severity of native stenosis, diffuse sclerosis of native vessels, and residual side branches of the ITA as independent predictors of nonfunctional grafts. The method of ITA grafting did not influence the patency of the graft.

Conclusions
—The excellent patency rate demonstrated by this study, the largest angiographic study to date of RITA grafting via the transverse sinus, indicates that this technique can provide reliable revascularization of the left ventricle and that it has the potential to be applied to a wide variety of patients with diseased circumflex arteries.
Paraoxonase Polymorphism (Gln192Arg) as a Determinant of the Response of Human Coronary Arteries to Serotonin
Authors: Bauters Christophe , Amant Carole , Boulier Agnès , Cabrol Philippe , McFadden Eugène , Duriez Patrick , Bertrand Michel E. , Amouyel Philippe
Published: June 2012

Background
—Oxidation of LDL plays a role in endothelial dysfunction. Paraoxonase, an enzyme present on HDL, protects LDL against oxidation. Paraoxonase activity is genetically determined in part, and 3 genotypes have been described with variable enzymatic activity. We hypothesized that the paraoxonase polymorphism might influence endothelial function.

Methods and Results
—Twenty-seven patients with clinical manifestations of coronary artery disease underwent provocative testing by intracoronary administration of serotonin. None of the coronary arteries studied had significant (>50%) stenosis. Ten patients had the QQ genotype and 17 had the QR genotype. At proximal segments, the mean percentage reduction in lumen diameter in response to serotonin was greater in QQ patients than in QR patients (10
−5
mol/L:
P
<0.05; 10
−4
mol/L:
P
<0.006). Similarly, at distal segments, constriction in response to serotonin was greater in QQ patients than in QR patients (10
−6
mol/L:
P
<0.03; 10
−5
mol/L:
P
<0.07).

Conclusions
—These results suggest a higher synthesis or release of endothelium-derived relaxing factors to counteract the vasoconstrictor effect of serotonin in patients with the R allele. These findings provide evidence that the paraoxonase polymorphism may play a role in the regulation of coronary vasomotor tone.
Early Percutaneous Coronary Intervention, Platelet Inhibition With Eptifibatide, and Clinical Outcomes in Patients With Acute Coronary Syndromes
Authors: Kleiman Neal S. , Lincoff A. Michael , Flaker Greg C. , Pieper Karen S. , Wilcox R. G. , Berdan Lisa G. , Lorenz Todd J. , Cokkinos Dennis V. , Simoons Maarten L. , Boersma Eric , Topol Eric J. , Califf Robert M. , Harrington Robert A.
Published: June 2012

Background
—Platelet glycoprotein (GP) IIb/IIIa antagonists prevent the composite end point of death or myocardial infarction (MI) in patients with acute coronary syndromes. There is uncertainty about whether this effect is confined to patients who have percutaneous coronary interventions (PCIs) and whether PCIs further prevent death or MI in patients already treated with GP IIb/IIIa antagonists.

Methods and Results
—PURSUIT patients were treated with the GP IIb/IIIa antagonist eptifibatide or placebo; PCIs were performed according to physician practices. In 2253 of 9641 patients (23.4%), PCI was performed by 30 days. Early (<72 hours) PCI was performed in 1228 (12.7%). In 34 placebo patients (5.5%) and 10 treated with eptifibatide (1.7%) (
P
=0.001), MI preceded early PCI. In patients censored for PCI across the 30-day period, there was a significant reduction in the primary composite end point in eptifibatide patients (
P
=0.035). Eptifibatide reduced 30-day events in patients who had early PCI (11.6% versus 16.7%,
P
=0.01) and in patients who did not (14.6% versus 15.6%,
P
=0.23). After adjustment for PCI propensity, there was no evidence that eptifibatide treatment effect differed between patients with or without early PCI (
P
for interaction=0.634). PCI was not associated with a reduction of the primary composite end point but was associated with a reduced (nonspecified) composite of death or Q-wave MI. This association disappeared after adjustment for propensity for early PCI.

Conclusions
—Eptifibatide reduced the composite rates of death or MI in PCI patients and those managed conservatively.