bluuebunny/crossref_metadata_2025 huggingface dataset:
Serial Follow-up After Optimized Ultrasound-Guided Deployment of Palmaz-Schatz Stents
Authors: Mudra Harald , Regar Evelyn , Klauss Volker , Werner Frank , Henneke Karl-Heinz , Sbarouni Efthia , Theisen Karl
Published: June 2012

Background
The effects of ultrasound-guided high-pressure stenting on late stent and reference segment dimensions are unknown. In this study, we report about angiographic and ultrasound measurements to assess the amount and distribution of neointimal ingrowth within the stent and the changes of plaque burden and dimensions within the reference segments.

Methods and Results
Sixty-eight consecutive patients with 72 lesions received single or multiple Palmaz-Schatz coronary stents with a standardized protocol for stent optimization under ultrasound guidance. The residual angiographic diameter stenosis was 3±12% (reference diameter, 3.16±0.61 mm). At follow-up 4.8±2.5 months later, angiography revealed a diameter stenosis of 27±21% with a restenosis rate of 15.3% (confidence interval: 7.8% to 25.6%). Lumen renarrowing within the stent was exclusively due to neointimal ingrowth; no stent compression was observed. The neointima covered 20±20% of the stent area and was more pronounced in the midportion of the stent. Volumetric assessment performed in 26 patients resulted in 13±14% or 65±28% of the stent volume occupied by neointimal ingrowth in patients without or with restenosis, respectively. Vessel remodeling had an impact on lumen dimensions only at reference sites but not within the stent. Plaque burden of 46±11% and 48±11% at the proximal and distal reference sites, respectively, did not show a relevant progression during the follow-up.

Conclusions
Serial ultrasound analyses did not show any evidence of stent compression or relevant vessel remodeling. Restenosis was solely due to neointimal ingrowth. Despite a considerable plaque burden within the reference segments, there was no relevant progression of the disease adjacent to the stent.
Stent Endothelialization
Authors: Van Belle Eric , Tio Fermin O. , Couffinhal Thierry , Maillard Luc , Passeri Jonathan , Isner Jeffrey M.
Published: June 2012

Background
Because prior studies have established the critical role of the endothelium in preventing vascular thrombosis and intimal thickening, we designed a series of experiments to determine the feasibility of percutaneous local catheter delivery of recombinant protein to accelerate development of an intact endothelial monolayer after stent implantation.

Methods and Results
Balloon injury followed by percutaneous delivery of a 15-mm-long, balloon-expandable metallic stent was performed in 64 rabbit external iliac arteries (baseline diameter, 2.67±0.07 mm). Planimetric time-course analysis disclosed <20% stent endothelialization at 4 days, <40% at 7 days, and near-complete endothelialization at 28 days. The reporter protein horseradish peroxidase and the endothelial cell–specific recombinant protein vascular endothelial growth factor (VEGF) were each effectively delivered from a local delivery catheter (channel balloon catheter, ChB) after stent implantation. Although local catheter delivery (of vehicle control) itself mildly retarded the extent of stent endothelialization (10.6±2.9%) versus no local delivery (25.5±6.6%,
P
=.045), local ChB delivery of 100 μg VEGF overcame this catheter effect: By day 7, stent endothelialization was nearly complete (91.8±3.8%) (
P
<.0001 versus no local delivery). Consequently, stent thrombus was reduced in the VEGF-treated group (mural thrombus, 5.3±3.7%) versus no local delivery (29.3±6.8%,
P
=.006). Occlusive thrombus was seen only in the absence of local VEGF administration.

Conclusions
(1) Local delivery of recombinant protein to the arterial wall is feasible after stent implantation, and (2) local delivery of the endothelial cell mitogen VEGF accelerates stent endothelialization, reducing stent thrombosis. These results thus establish a novel means by which the safety and/or bioactivity of endovascular stents may be further enhanced.
Upregulation of Vascular Angiotensin II Receptor Gene Expression by Low-Density Lipoprotein in Vascular Smooth Muscle Cells
Authors: Nickenig G. , Sachinidis A. , Michaelsen F. , Bo¨hm M. , Seewald S. , Vetter H.
Published: June 2012

Background
Because LDL and the angiotensin II type 1 (AT1) receptor are thought to be involved in the pathogenesis of chronic vascular disease, we studied possible interactions between these two biological systems in cultured rat vascular smooth muscle cells.

Methods and Results
Incubation of vascular smooth muscle cells with 100 μg/mL LDL profoundly increased AT1 receptor mRNA to ≈250% of control levels as assessed by Northern hybridization analysis. This effect is maximal 12 hours after addition of LDL to the culture medium and is sustained for up to 24 hours. The LDL-induced upregulation is dose dependent, with a maximal effect obtained with 100 μg/mL LDL. There is a correlative increase of cell surface–associated AT1 receptors as assessed by saturation radioligand binding assays. The half-life of AT1 receptor mRNA is increased substantially by LDL compared with that of cells treated only with 5,6-dichlorobenzimidazole to block transcription. Angiotensin II–induced elevation of cytosolic calcium concentration is significantly increased in vascular smooth muscle cells pretreated with LDL to 368±41 nmol/L compared with control cells pretreated with vehicle (248±33 nmol/L). Moreover, angiotensin II–induced DNA synthesis is markedly enhanced when cells are coincubated with 100 μg/mL LDL.

Conclusions
These data reveal a significant upregulation of AT1 receptor gene expression by LDL in vascular smooth muscle cells through mechanisms that involve posttranscriptional mRNA stabilization. Ultimately, this AT1 receptor upregulation leads to an elevated functional response of vascular smooth muscle cells on angiotensin II stimulation.
A Focal Source of Atrial Fibrillation Treated by Discrete Radiofrequency Ablation
Authors: Jai¨s Pierre , Hai¨ssaguerre Michel , Shah Dipen C. , Chouairi Salah , Gencel Laurent , Hocini Me´le`ze , Cle´menty Jacques
Published: June 2012

Background
Atrial fibrillation is usually thought to be due to multiple circulating reentrant wavelets. From previous studies, a focal mechanism is considered to be very unlikely. In this report, focal atrial fibrillation is defined on an ECG pattern of atrial fibrillation and later demonstrated to be due to a focal source.

Methods and Results
Nine patients (five men and four women; age, 38±7 years) with paroxysmal focal atrial fibrillation are reported here. All were free of structural heart disease and had frequent episodes of atrial fibrillation despite the use of a mean of 4±2 antiarrhythmic drugs. Atrial fibrillation was associated with runs of irregular atrial tachycardia or monomorphic extrasystoles. The electrophysiological study demonstrated that all the atrial arrhythmias were due to the same focus firing irregularly and exhibiting a consistent and centrifugal pattern of activation. Three foci were found to be located in the right atrium, two near the sinus node and one in the ostium of the coronary sinus. Six others were located in the left atrium at the ostium of the right pulmonary veins (n=5) and at the ostium of the left superior pulmonary vein (n=1). All atrial arrhythmias were successfully treated by use of a mean of 4±4 radiofrequency pulses.

Conclusions
In some patients, the surface ECG pattern of atrial fibrillation is due to a focal rapidly firing source of activity that can be eliminated by discrete radiofrequency energy applications.
Tissue Factor Modulates the Thrombogenicity of Human Atherosclerotic Plaques
Authors: Toschi Vincenzo , Gallo Richard , Lettino Maddalena , Fallon John T. , Gertz S. David , Ferna´ndez-Ortiz Antonio , Chesebro James H. , Badimon Lina , Nemerson Yale , Fuster Valentin , Badimon Juan J.
Published: June 2012

Background
The thrombogenicity of a disrupted atherosclerotic lesion is dependent on the nature and extent of the plaque components exposed to flowing blood together with local rheology and a variety of systemic factors. We previously reported on the different thrombogenicity of the various types of human atherosclerotic lesions when exposed to flowing blood in a well-characterized perfusion system. This study examines the role of tissue factor in the thrombogenicity of different types of atherosclerotic plaques and their components.

Methods and Results
Fifty human arterial segments (5 foam cell–rich, 9 collagen-rich, and 10 lipid-rich atherosclerotic lesions and 26 normal, nonatherosclerotic segments) were exposed to heparinized blood at high shear rate conditions in the Badimon perfusion chamber. The thrombogenicity of the arterial specimens was assessed by
111
In-labeled platelets. After perfusion, specimens were stained for tissue factor by use of an in situ binding assay for factor VIIa. Tissue factor in specimens was semiquantitatively assessed on a scale of 0 to 3. Platelet deposition on the lipid-rich atheromatous core was significantly higher than on all other substrates (
P
=.0002). The lipid-rich core also exhibited the most intense tissue factor staining (3±0.1 arbitrary units) compared with other arterial components. Comparison of all specimens showed a positive correlation between quantitative platelet deposition and tissue factor staining score (
r
=.35,
P
<.01).

Conclusions
Our results show that tissue factor is present in lipid-rich human atherosclerotic plaques and suggest that it is an important determinant of the thrombogenicity of human atherosclerotic lesions after spontaneous or mechanical plaque disruption.
Assessment of Mitral Regurgitation Severity by Doppler Color Flow Mapping of the Vena Contracta
Authors: Hall Shelley A. , Brickner M. Elizabeth , Willett DuWayne L. , Irani Waleed N. , Afridi Imran , Grayburn Paul A.
Published: June 2012

Background
Although Doppler color flow mapping is widely used to assess the severity of mitral regurgitation (MR), a simple, accurate, and quantitative marker of MR by color flow mapping remains elusive. We hypothesized that vena contracta width by color flow mapping would accurately predict the severity of MR.

Methods and Results
We studied 80 patients with MR. Vena contracta width was measured in multiple views with zoom mode and nonstandard angulation to optimize its visualization. Flow volumes across the left ventricular outflow tract and mitral annulus were calculated by pulsed-Doppler technique to determine regurgitant volume. Effective regurgitant orifice area was calculated by dividing the regurgitant volume by the continuous-wave Doppler velocity-time integral of the MR jet. The cause of MR was ischemia in 24, dilated cardiomyopathy in 34, mitral valve prolapse in 12, endocarditis in 2, rheumatic disease in 2, mitral annular calcification in 1, and uncertain in 5. Regurgitant volumes ranged from 2 to 191 mL. Regurgitant orifice area ranged from 0.01 to 1.47 cm
2
. Single-plane vena contracta width from the parasternal long-axis view correlated well with regurgitant volume (
r
=.85, SEE=20 mL) and regurgitant orifice area (
r
=.86, SEE=0.15 cm
2
). Biplane vena contracta width from apical views correlated well with regurgitant volume (
r
=.85, SEE=19 mL) and regurgitant orifice area (
r
=.88, SEE=0.14 cm
2
). A biplane vena contracta width ≥0.5 cm was always associated with a regurgitant volume >60 mL and a regurgitant orifice area >0.4 cm
2
. A biplane vena contracta width ≤0.3 cm predicted a regurgitant volume <60 mL and a regurgitant orifice area <0.4 cm
2
in 24 of 29 patients. No other parameter, including jet area, left atrial size, pulmonary flow reversal, or semiquantitative MR grade, correlated significantly with regurgitant volume or regurgitant orifice area in a multivariate analysis.

Conclusions
Our results demonstrate that careful color flow mapping of the vena contracta of the MR jet provides a simple quantitative assessment of MR that correlates well with quantitative Doppler techniques.
Intracoronary Application of C1 Esterase Inhibitor Improves Cardiac Function and Reduces Myocardial Necrosis in an Experimental Model of Ischemia and Reperfusion
Authors: Horstick Georg , Heimann Axel , Go¨tze Otto , Hafner Gerd , Berg Oliver , Bo¨ehmer Peter , Becker Phillip , Darius Harald , Rupprecht Hans-Ju¨rgen , Loos Michael , Bhakdi Sucharit , Meyer Ju¨rgen , Kempski Oliver
Published: June 2012

Background
Myocardial injury from ischemia can be aggravated by reperfusion of the jeopardized area. The precise underlying mechanisms have not been clearly defined, but proinflammatory events, including complement activation, leukocyte adhesion, and infiltration and release of diverse mediators, probably play important roles. The present study addresses the possibility of reducing reperfusion damage by the application of C1 esterase inhibitor (C1-INH).

Methods and Results
Cardioprotection by C1-INH 20 IU/kg IC was examined in a pig model with 60 minutes of coronary occlusion, followed by 120 minutes of reperfusion. C1-INH was administered during the first 5 minutes of coronary reperfusion. Compared with the NaCl controls, C1-INH reduced myocardial injury (48.8±7.8% versus 73.4±4.0% necrosis of area at risk,
P
≤.018). C1-INH treatment significantly reduced circulating C3a and slightly attenuated C5a plasma concentrations. Myocardial protection was accompanied by reduced plasma concentration of creatine kinase and troponin-T. C1-INH had no effect on global hemodynamic parameters, but local myocardial contractility was markedly improved in the ischemic zone. In the short-axis view, 137° of the anteroseptal region showed significantly improved wall motion at early and 29° at late reperfusion with C1-INH treatment.

Conclusions
C1-INH significantly protects ischemic tissue from reperfusion damage, reduces myocardial necrosis, and improves local cardiac function.
Long-term Estradiol Replacement Decreases Contractility of Guinea Pig Coronary Arteries to the Thromboxane Mimetic U46619
Authors: Thompson Loren P. , Weiner Carl P.
Published: June 2012

Background
Estradiol replacement therapy reduces the incidence of coronary artery disease. Current evidence suggests that estradiol may stimulate the production of endothelium-derived NO and thereby reduce the contractile response of vascular smooth muscle. We investigated the effect of long-term replacement of estradiol on NO release and its effect on coronary artery contractility.

Methods and Results
Female guinea pigs were ovariectomized and allowed to recover for 100 days. Pellets containing 17β-estradiol (0.25, 0.5, 1.5, and 7.5 mg released over 21 days) were placed subcutaneously for 19 to 20 days. Animals were then anesthetized, and the coronary arteries were excised and cut into ring segments. Rings were placed in small-vessel myographs for measurement of isometric force. Contractile responses of coronary arteries to cumulative addition of U46619 (10
−10
to 10
−5
mol/L), a thromboxane mimetic, were measured in the presence and absence of nitro-
l
-arginine (LNA), a selective NO synthase inhibitor, and methylene blue, a guanylate cyclase inhibitor. Low (0.25-mg) but not high (0.5-, 1.5-, or 7.5-mg) doses of estradiol inhibited the maximal contractile responses to U46619 compared with arteries from untreated castrated animals. In addition, both LNA and methylene blue potentiated contractile responses to U46619 of arteries from animals receiving 0.25 and 0.5 mg but not 1.5 and 7.5 mg estradiol. Negative log EC
50
values were significantly inhibited at 0.25 and 7.5 mg but unaffected at 0.5 and 1.5 mg estradiol compared with castrated animals.

Conclusions
Estradiol at low doses may protect against vasospasm by stimulating endothelium-derived NO release and inhibiting coronary artery contractility.
Relaxation–Systolic Pressure Relation
Authors: Gillebert Thierry C. , Leite-Moreira Adelino F. , De Hert Stefan G.
Published: June 2012

Abstract
This contribution reviews the regulation of left ventricular pressure (LVP) fall by load and relates this regulation to left ventricular contractility. Load regulation of LVP fall has to be distinguished from neurohumoral regulation, from effects induced by arterial reflected waves and from long-term load effects on contractility. The response of LVP fall to a moderate elevation of systolic LVP is highly variable. It depends on the ratio between the actual systolic pressure and peak isovolumetric pressure, defined as “relative load”. Up to a relative load of 81% to 84%, LVP fall accelerates. Above this relative load, LVP fall decelerates. Depending on the level of relative load there is a wide variety of effects ranging from moderate acceleration of LVP fall to marked deceleration of LVP fall. Acceleration of LVP fall in response to a load elevation is associated with normal cardiac function, while slowing of LVP fall is associated with impaired cardiac function. Similar but opposite effects are observed with reductions of systolic LVP. Effects of changes in systolic LVP on time constant τ reveal a fair correlation with systolic elastance (Ees), peak dP/dt
max
and regional fractional shortening (or ejection fraction). There is an excellent correlation with measured isovolumetric LVP, indicating that contraction-relaxation coupling is close when contractility is expressed in terms of peak isovolumetric pressure. Assessment of contractility with systolic LVP-relaxation relation is precise and load independent and can be performed with the sole use of a high-fidelity pressure gauge positioned in the left ventricular cavity.
Use of Synchrotron Radiation Microangiography to Assess Development of Small Collateral Arteries in a Rat Model of Hindlimb Ischemia
Authors: Takeshita Satoshi , Isshiki Takaaki , Mori Hidezo , Tanaka Etsuro , Eto Koji , Miyazawa Yoshimichi , Tanaka Akira , Shinozaki Yoshiro , Hyodo Kazuyuki , Ando Masami , Kubota Misao , Tanioka Kenkichi , Umetani Keiji , Ochiai Masahiko , Sato Tomohide , Miyashita Hideo
Published: June 2012

Background
Current methods of angiography cannot provide images of arteries measuring <200 μm in diameter. We have recently developed a new angiography system that uses monochromatic synchrotron radiation and a high-definition video system with a spatial resolution of 30 μm. In the present study, we applied this microangiography system to visualize small arteries in normal and ischemic rat limbs and investigated the development of collateral arteries.

Methods and Results
Microangiography was performed in the normal and the ischemic limb 4 weeks after the excision of the femoral artery. In the normal limb, up to the fourth branches of the iliac and/or femoral arteries (diameter <100 μm) were readily identified. Some of these branches were found to perfuse the distal thigh area. In the ischemic limb, an extensive structural remodeling of the vascular network was observed. Numerous small arteries had developed from the branches of the iliac artery to constitute a fine arterial network, the so-called “midzone,” which was composed of linear, normal-appearing arteries and those with an undulating, unbranched appearance.

Conclusions
The small collateral artery network was angiographically visualized with a resolution limit <100 μm. The linear collaterals appeared to result from an opening of preexisting vessels. The undulating, unbranched vessels were not observed in the normal limbs and seemed to be vessels that were newly formed after limb ischemia. Synchrotron radiation microangiography appears to be a powerful means of assessing the development of small collateral arteries, which may help to provide a basis for understanding of the collateral circulation.
Acute Profound Thrombocytopenia After c7E3 Fab (Abciximab) Therapy
Authors: Berkowitz Scott D. , Harrington Robert A. , Rund Michele M. , Tcheng James E.
Published: June 2012

Background
Platelets play a crucial role in the ischemic complications of percutaneous coronary procedures. The recent availability of c7E3 Fab (abciximab; ReoPro), a chimeric monoclonal antibody Fab fragment directed against the platelet glycoprotein IIb/IIIa receptor, has reduced abrupt closure and other adverse clinical events and lessened the need for revascularization procedures. As experience accrues, rare cases of acute profound thrombocytopenia have been revealed.

Methods and Results
From November 1991 to July 1996, patients at Duke University Medical Center who underwent percutaneous coronary revascularization and received their first exposure to c7E3 Fab were evaluated for the development of acute profound thrombocytopenia, defined as a platelet count <20×10
9
/L occurring within 24 hours of initial treatment. Four patients (0.5%) developed acute profound thrombocytopenia within 11 to 21 hours of receiving the c7E3 Fab bolus. Nadir platelet counts ranged from 1 to 16×10
9
/L and occurred within 11 to 26 hours. No patient developed a significant hemorrhagic complication, and each patient's platelet count responded to platelet transfusion. Platelet counts remained depressed for at least 3 days but returned to baseline within 2 weeks.

Conclusions
Acute profound thrombocytopenia can occur after c7E3 Fab administration. Its development was not predictable, and it requires consideration in every patient treated. A platelet count 2 to 4 hours after the bolus would likely have detected these four cases. When indicated, platelet transfusion will raise the platelet count to safer levels without adverse effects. The differential diagnosis (including heparin-induced thrombocytopenia), a plan for management, and postulates as to the mechanism are discussed.
Role of Compensatory Enlargement and Shrinkage in Transplant Coronary Artery Disease
Authors: Lim Tai Tian , Liang David H. , Botas Javier , Schroeder John S. , Oesterle Stephen N. , Yeung Alan C.
Published: June 2012

Background
Compensatory enlargement of the vessel wall has been described in the early stages of native atherosclerosis. Whether compensatory enlargement plays a role in transplant coronary artery disease is not known. The objective of this study was to determine, by use of serial intravascular ultrasound (IVUS), whether compensatory dilation occurs in transplant coronary artery disease over time.

Methods and Results
Seventy-five heart transplant recipients with 151 matched coronary segments were selected for the presence of intimal disease progression as detected by serial IVUS examinations 1 to 3 years apart. Intimal disease progression was defined as a >10% increase in intimal area (IA). IVUS catheter location in follow-up studies was verified angiographically in relation to branch vessels. Luminal area (LA) and total vessel area (TA) were measured at each site. Intimal area (IA=TA−LA) was calculated. Changes in IA (ΔIA) and TA (ΔTA) between baseline and follow-up IVUS were compared: ΔIA, 2.9±0.2 mm
2
; ΔTA, 2.7±0.4 mm
2
. A remodeling index (RI) was defined as RI=ΔTA/ΔIA. Three subgroups could be distinguished: overcompensation (RI >1), partial compensation (RI 0 to 1), and no compensation or shrinkage (RI ≤0). Seventy-four segments (49%) showed overcompensation, 44 (29%) showed partial compensation, and 33 (22%) showed no compensation or shrinkage.

Conclusions
In this study, serial IVUS shows that early after cardiac transplantation, a large proportion of the coronary segments with progression of intimal thickening have compensatory dilation of the vessel wall. However, a substantial number of coronary segments (22%) show no compensatory dilation or shrinkage. The progressive luminal narrowing in transplant patients may be due in part to vessel shrinkage or the lack of compensatory dilation over time.
Evidence for the Rapid Onset of Apoptosis in Medial Smooth Muscle Cells After Balloon Injury
Authors: Perlman Harris , Maillard Luc , Krasinski Kevin , Walsh Kenneth
Published: June 2012

Background
Vascular myocyte apoptotic cell death has been reported in human atherectomy and endarterectomy specimens and for neointimal smooth muscle cells (SMCs) in balloon-injured rat carotid arteries between 7 and 30 days after injury. However, the immediate effect of balloon injury on medial SMC viability has not been examined.

Methods and Results
Rat carotid arteries were harvested at the time of balloon injury (T=0) and at 0.5, 1, 2, and 4 hours after injury. Uninjured vessels or vessels harvested at the time of injury (T=0) did not display evidence of apoptosis. However, as early as 30 minutes after injury, 70% of medial SMCs appeared apoptotic by TdT-mediated dUTP nick end labeling (TUNEL) analysis and by the appearance of condensed chromatin. High frequencies of TUNEL-positive cells were also observed at 1 and 2 hours after injury but not at 4 hours. Transmission electron microscopy revealed many cells with morphological characteristics of apoptosis in the injured sections. A marked decrease in bcl-X expression was detected in the most luminal layers of the media. To corroborate these findings in a second animal model, rabbit external iliac arteries were analyzed after balloon angioplasty. Apoptotic cell death was evident in rabbit arteries at 30 minutes and at 4 hours after injury.

Conclusions
As early as 30 minutes after balloon injury, myocytes appear to undergo apoptotic cell death at a high frequency as shown by TUNEL staining, chromatin condensation, and the appearance of morphological features in electron micrographs. The induction of apoptosis coincides with a marked downregulation of bcl-X expression.
Pathophysiology of Transient Myocardial Ischemia in Acute Coronary Syndromes
Authors: Patel Deven J. , Knight Charles J. , Holdright Diana R. , Mulcahy David , Clarke Debbie , Wright Christine , Purcell Henry , Fox Kim M.
Published: June 2012

Background
Transient ischemia in stable coronary disease peaks in the morning, reflecting increased myocardial oxygen demand and coronary vasomotor tone after waking. In acute coronary syndromes, however, ischemia may result from transient thrombus formation or coronary spasm at the site of a ruptured plaque. We report on the pathophysiological mechanisms underlying transient ischemia in acute coronary syndromes despite optimal therapy, on the basis of analysis of heart rate changes preceding ischemia and its circadian variation.

Methods and Results
Two hundred fifty-six patients with unstable angina or non–Q-wave myocardial infarction underwent continuous ST-segment monitoring for 48 hours while receiving maximal medical therapy. All ischemic episodes were characterized by their timing, duration, association with pain, and heart rate changes before the onset of ischemia. During 10 629 hours of monitoring, 44 patients (17.2%) had 176 episodes of transient ischemia. The mean heart rate at onset of ischemia was 68±12.8 bpm, and >55% of ischemic episodes were not preceded by a significant increase in heart rate. Ischemic activity had a single nocturnal peak, with 64% of all episodes occurring between 10
pm
and 8
am
, this nocturnal preponderance being evident for episodes with or without a preceding increase in heart rate. The characteristics and timing of transient ischemia were similar in unstable angina and non–Q-wave myocardial infarction, but transient ischemia was more frequent (27.3% versus 15.1%;
P
<.05) and prolonged (median, 20 versus 13.5 minutes;
P
<.01) in non–Q-wave myocardial infarction.

Conclusions
In acute coronary syndromes, transient ischemia has a low threshold, occurs predominantly without an increase in myocardial oxygen demand, and is present mainly at night rather than in the morning. These findings in patients receiving maximal medical therapy suggest significant pathophysiological differences underlying transient ischemia compared with stable coronary disease.
Collagen Content Is Significantly Lower in Restenotic Versus Nonrestenotic Vessels After Balloon Angioplasty in the Atherosclerotic Rabbit Model
Authors: Coats William D. , Whittaker Peter , Cheung David T. , Currier Jesse W. , Han Bo , Faxon David P.
Published: June 2012

Background
It is recognized that restenosis is primarily due to alterations in geometric remodeling of the extracellular matrix rather than intimal hyperplasia. Prior studies have shown that angioplasty stimulates an increase in both synthesis and degradation of collagen in the atherosclerotic vessel. However, differences in collagen content and metabolism between restenotic and nonrestenotic vessels have not been examined.

Methods and Results
Four weeks after angioplasty in an atherosclerotic rabbit model, collagen content in restenotic and nonrestenotic vessels was measured both biochemically by hydroxyproline quantitation and histologically by a digital subtraction method with the use of circularly polarized images of picrosirius red–stained sections. Collagenase and gelatinase activity also were measured in the same restenotic and nonrestenotic vessels by use of a radiosubstrate assay. Collagen content was found to be significantly lower in restenotic vessels than in nonrestenotic vessels both biochemically (127.0±32.6 versus 212.6±84.3 μg/mg tissue; n=11 vessels;
P
<.05) and histologically (67.3±7.9% versus 76.3±11.8% area fraction; n=20 sections from 6 vessels;
P
=.05). There was a significant inverse correlation between biochemically determined collagen content and gelatinase activity (
P
=.02) and a significant correlation between histologically determined lumen area and percent collagen content (
P
=.0071).

Conclusions
Collagen content is significantly decreased in restenotic versus nonrestenotic vessels after angioplasty in the atherosclerotic rabbit model. The increased collagen content in nonrestenotic vessels was associated with preserved lumen area and may play a role in geometric remodeling after angioplasty.
Sexually Dimorphic Response of the Balloon-Injured Rat Carotid Artery to Hormone Treatment
Authors: Oparil Suzanne , Levine Ronald L. , Chen Shi-Juan , Durand Joan , Chen Y.F.
Published: June 2012

Background
Estrogen blunts the neointimal response to vascular injury in gonadectomized rats of both sexes; addition of a progestin blocks the estrogen effect. This study tested, in intact rats of both sexes, whether (1) exogenous estrogen has a vasoprotective effect in injured carotid arteries, (2) progestin (medroxyprogesterone acetate, MPA) blocks the vasoprotective effect of estrogen, and (3) any observed sexual dimorphism in the responses to estrogen and/or MPA can be accounted for by differences in serum 17β-estradiol levels.

Methods and Results
Intact male and female Sprague-Dawley rats were randomly divided into four subgroups treated with either (1) 17β-estradiol, (2) MPA, (3) 17β-estradiol+MPA, or (4) vehicle and were subjected to balloon injury of the right common carotid artery. Two weeks later, rats were killed by an overdose of pentobarbital, and the carotid arteries were evaluated for myointimal thickening. Neither estradiol nor MPA altered the neointimal response in males. In females, estradiol reduced and MPA enhanced the response, whereas addition of MPA to estradiol blocked the vasoprotective effects of estrogen.

Conclusions
Intact male rats but not intact females are resistant to the vasoprotective effects of exogenous estrogen, despite attainment of physiological (for females) serum 17β-estradiol levels. MPA enhances the neointimal response in intact females, presumably by blocking the production and thus the vasoprotective effect of endogenous estrogen.
Analysis of Coronary Ultrasound Thrombolysis Endpoints in Acute Myocardial Infarction (ACUTE Trial)
Authors: Rosenschein Uri , Roth Arie , Rassin Tovy , Basan Samuel , Laniado Shlomo , Miller Hylton I.
Published: June 2012

Background
It has been demonstrated that therapeutic ultrasound effects ultrasound thrombolysis by selectively disrupting the fibrin matrix of the thrombus. This study was conducted to evaluate the clinical feasibility of percutaneous transluminal coronary ultrasound thrombolysis in acute myocardial infarction (AMI).

Methods and Results
Consecutive patients (n=15) with evidence of anterior AMI and Thrombolysis In Myocardial Infarction (TIMI) grade 0 or 1 flow in the left anterior descending artery underwent coronary ultrasound thrombolysis. Angiographic follow-up was performed after 10 minutes and 12 to 24 hours. Ultrasound induced successful reperfusion (TIMI grade 3 flow) in 87% of the patients. Adjunct percutaneous transluminal coronary angioplasty (PTCA) after ultrasound thrombolysis produced a final residual stenosis of 20±12% as determined by quantitative coronary angiographic analysis. There were no adverse angiographic signs or clinical effects during the procedure. There was no change in the degree of flow in any of the patients at the 12- to 24-hour angiograms. During hospitalization, 1 patient had recurrent ischemia on the fifth day after the procedure, and emergent catheterization revealed occlusion at the treatment site. The patient was successfully treated with PTCA.

Conclusions
These results suggest that ultrasound thrombolysis has the potential to be a safe and effective catheter-based therapeutic modality in reperfusion therapy for patients with AMI and other clinical conditions associated with intracoronary thrombosis.
Angiotensin-Converting Enzyme Inhibition Prevents Arterial Nuclear Factor-κB Activation, Monocyte Chemoattractant Protein-1 Expression, and Macrophage Infiltration in a Rabbit Model of Early Accelerated Atherosclerosis
Authors: Hernández-Presa M. , Bustos C. , Ortego M. , Tuñon J. , Renedo G. , Ruiz-Ortega M. , Egido J.
Published: June 2012

Background
The migration of monocytes into the vessel wall is a critical event leading to the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is the main chemotactic factor involved in this phenomenon, and nuclear factor-κB (NF-κB) is one of the nuclear factors controlling its expression. ACE inhibitors have been useful in some experimental models of atherosclerosis. In this work, we addressed the hypothesis that angiotensin II (Ang II) may be implicated in the recruitment of monocytes into the vessel wall through the activation of NF-κB and the induction of MCP-1 expression.

Methods and Results
Accelerated atherosclerosis was induced in the femoral arteries of rabbits by endothelial desiccation and atherogenic diet for 7 days. Atherosclerotic vessels exhibited an increase in NF-κB–like activity, and p50 and p65 NF-κB subunits were identified as components of this activity. MCP-1 (mRNA and protein) was also expressed in the injured vessels coincidently with the neointimal macrophage infiltration. ACE inhibition with quinapril reduced these three parameters. In cultured monocytic and vascular smooth muscle cells, Ang II elicited an increase in NF-κB activation and MCP-1 expression that was prevented by preincubation of cells with pyrrolidinedithiocarbamate, an inhibitor of NF-κB activation.

Conclusions
The present data support a role for Ang II in neointimal monocyte infiltration through NF-κB activation and MCP-1 expression in a model of accelerated atherosclerosis in rabbits. Our results suggest that ACE inhibitors may have a beneficial effect in early atherosclerosis.
Assessment of Transmyocardial Perfusion in Alligator Hearts
Authors: Kohmoto Takushi , Argenziano Michael , Yamamoto Noriyoshi , Vliet Kent A. , Gu Anguo , DeRosa Carolyn M. , Fisher Peter E. , Spotnitz Henry M. , Burkhoff Daniel , Smith Craig R.
Published: June 2012

Background
Techniques for achieving myocardial perfusion directly from the left ventricular chamber are currently under investigation. Although originally based on the anatomy of reptilian hearts, which are rich in transmural channels and reported to have a poorly developed coronary vasculature, the blood flow capacity of a transmyocardial blood supply has not been studied in these hearts. With the ultimate goal of providing insight into the potential for achieving transmyocardial perfusion in human hearts, we studied the relative contribution of transmyocardial and coronary perfusion in alligator hearts.

Methods and Results
After explantation from six American alligators, the left ventricle was instrumented, and coronary arteries were perfused with oxygenated physiological solution. Using microspheres to estimate regional myocardial perfusion in the beating hearts, we show that although the epicardium was well perfused by the coronary arteries (0.20±0.08 versus 0.07±0.01 mL·min
−1
·g
−1
owing to flow from the ventricular chamber), a significant proportion of endocardial perfusion was from the ventricular chamber (0.21±0.07 mL·min
−1
·g
−1
from the left ventricle versus 0.13±0.04 mL·min
−1
·g
−1
from coronary arteries).

Conclusions
A significant amount of direct transmyocardial perfusion is present in alligator hearts. The conditions that apparently permit this situation in reptilian hearts are reviewed, and their implications for aiding in the optimization of techniques for achieving transmyocardial flow in humans are discussed.
Acute T-Cell Activation Is Detectable in Unstable Angina
Authors: Neri Serneri Gian Gastone , Prisco Domenico , Martini Francesca , Gori AnnaMaria , Brunelli Tamara , Poggesi Loredana , Rostagno Carlo , Gensini Gian Franco , Abbate Rosanna
Published: June 2012

Background
Recent studies suggest a role for inflammation in the pathophysiology of unstable angina. This study was designed to investigate whether circulating lymphocytes are involved in the inflammatory reaction associated with the episodes of unstable angina.

Methods and Results
Twenty-nine patients with proven unstable angina, 36 with stable angina, and 30 healthy subjects were studied. Both early and short-lived (interleukin-2 receptor [IL-2R], α-chain CD25, and transferrin receptor CD71) and late antigen (HLA-DR) expression were investigated by flow cytometric analysis. Soluble IL-2R (sIL-2R) was also measured in plasma by ELISA. Lymphocyte activation was studied at day 1 of hospital admission and after 7, 15, 30, 60, and 90 days. In patients with unstable angina, the number of HLA-DR+ CD3 lymphocytes and levels of sIL-2R were higher (
P
<.001) than in patients with stable angina and control subjects. Both CD4+ and CD8+ lymphocytes expressed HLA-DR antigens. No differences were found among the different groups of subjects in regard to the expression of CD25 and CD71. Lymphocyte activation was more marked in patients with urgent revascularization. No relationships were found between the number of HLA-DR+ lymphocytes and either the severity of coronary angiographic lesions or the number of ischemic episodes. Observations over time showed a gradual decrease in the number of HLA-DR+ lymphocytes and sIL-2R levels from weeks 3 through 8 to 12.

Conclusions
The present results indicate that (1) CD4+ and CD8+ circulating lymphocytes are activated in patients with unstable angina, and their activation state lasts 6 to 8 weeks; and (2) activation of lymphocytes is not a consequence of myocardial ischemia. These results support the immune system–mediated inflammatory nature of unstable angina.
Differential Effects of Kinins on Cardiomyocyte Hypertrophy and Interstitial Collagen Matrix in the Surviving Myocardium After Myocardial Infarction in the Rat
Authors: Wollert Kai C. , Studer Roland , Doerfer Kristin , Schieffer Elisabeth , Holubarsch Christian , Just Hanjörg , Drexler Helmut
Published: June 2012

Background
Left ventricular remodeling after myocardial infarction (MI) involves the hypertrophic growth of cardiomyocytes and the accumulation of fibrillar collagen in the interstitial space. We evaluated the role of kinins in postinfarction ventricular remodeling and their potential contribution to the antiremodeling effects of ACE inhibition and angiotensin II type 1 (AT1) receptor blockade.

Methods and Results
Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant. Additional groups of infarcted rats were treated with the ACE inhibitor lisinopril or the AT1 receptor antagonist ZD7155, each separately and in combination with icatibant. B2 kinin receptor blockade enhanced the interstitial deposition of collagen after MI, whereas morphological and molecular markers of cardiomyocyte hypertrophy (cardiac weight, myocyte cross-sectional area, prepro–atrial natriuretic factor mRNA expression) were not affected. Chronic ACE inhibition and AT1 receptor blockade reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition and AT1 receptor blockade on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy.

Conclusions
(1) Kinins inhibit the interstitial accumulation of collagen but do not modulate cardiomyocyte hypertrophy after MI. (2) Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition and AT1 receptor blockade. (3) The effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy are related to a reduced generation/receptor blockade of angiotensin II.
Calcifying Subpopulation of Bovine Aortic Smooth Muscle Cells Is Responsive to 17β-Estradiol
Authors: Balica Mihaela , Boström Kristina , Shin Victoria , Tillisch Kirsten , Demer Linda L.
Published: June 2012

Background
Arterial calcification, common in atherosclerosis, is associated with an increased risk of clinical events such as myocardial infarction. We previously identified a subpopulation of bovine aortic medial cells, calcifying vascular cells (CVCs), that have osteoblastic characteristics and form bone mineral in vitro in the form of calcified nodules. To assess whether estrogen modulates arterial calcification as well as bone calcification, we tested CVCs for estrogen receptors and for the effect of 17β-estradiol on formation of calcified nodules, calcium content, alkaline phosphatase activity, and osteocalcin concentration in the culture medium.

Methods and Results
Estrogen receptor immunoreactivity was identified in the cytoplasm and the perinuclear region of CVCs by immunocytochemistry. CVCs were treated with 17β-estradiol at concentrations of 0, 5, and 10 nmol/L. Twenty-one days of 17β-estradiol treatment resulted in a significantly increased number of calcified nodules, visualized by von Kossa staining, as well as increased calcium content of the cultures. Increases in alkaline phosphatase activity, a marker for early osteoblastic differentiation, and secreted osteocalcin, a marker for late osteoblastic differentiation, were enhanced in cells treated with 17β-estradiol compared with control cells.

Conclusions
These results suggest that 17β-estradiol promotes osteoblastic differentiation and calcification in vascular cells and that estrogen may play a regulatory role in arterial calcification.
Activation of the Hemostatic Mechanism After Pharmacological Cardioversion of Acute Nonvalvular Atrial Fibrillation
Authors: Oltrona Luigi , Broccolino Marco , Merlini Piera A. , Spinola Alessandra , Pezzano Antonio , Mannucci Pier M.
Published: June 2012

Background
Given that the restoration of sinus rhythm after chronic atrial fibrillation is associated with embolic events, anticoagulation is prescribed before and after pharmacological and electrical cardioversion. However, the need for anticoagulation in patients with acute atrial fibrillation (lasting <48 hours) who undergo cardioversion is less clear. In addition, it is not known whether cardioversion to sinus rhythm determines a hypercoagulable state in these patients.

Methods and Results
In 21 patients with acute nonvalvular atrial fibrillation, plasma median concentrations of thrombin-antithrombin complex, a marker of thrombin generation, significantly increased from 2.8 ng/mL (interquartile range, 2.1 to 4.0 ng/mL) on hospital admission to 3.5 ng/mL (interquartile range, 2.9 to 6.0 ng/mL) after cardioversion to sinus rhythm obtained by means of infusion of antiarrhythmic drugs and decreased to 2.5 ng/mL (interquartile range, 2.0 to 3.5 ng/mL) at the 1-month follow-up visit (
P
=.04). Similarly, the levels of fibrinopeptide A, a marker of thrombin activity, increased from 1.1 nmol/L (interquartile range, 0.7 to 1.5 nmol/L) at baseline to 1.8 nmol/L (interquartile range, 1.1 to 3.0 nmol/L) after cardioversion and returned to 0.8 nmol/L (interquartile range, 0.6 to 1.1 nmol/L) at the 1-month follow-up visit (
P
=.02).

Conclusions
A significant increase in plasma levels of the markers of thrombin generation and activity was observed in patients with acute atrial fibrillation early after pharmacological cardioversion to sinus rhythm. This is the first biochemical evidence that cardioversion of recent-onset atrial fibrillation determines a hypercoagulable state.
Major Benefit From Antiplatelet Therapy for Patients at High Risk for Adverse Cardiac Events After Coronary Palmaz-Schatz Stent Placement
Authors: Schühlen Helmut , Hadamitzky Martin , Walter Hanna , Ulm Kurt , Schömig Albert
Published: June 2012

Background
The Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial is a randomized study in which antiplatelet therapy is compared with anticoagulant therapy after coronary stent placement, showing a significantly lower rate of noncardiac and cardiac events with antiplatelet therapy. The present study is a report of the analysis of a prospective risk stratification protocol in the ISAR Trial and the association with the incidence of adverse cardiac events and stent vessel occlusion.

Methods and Results
In all 517 patients randomized in the ISAR Trial, risk stratification was done with a list of 18 clinical, procedural, and angiographic variables: 165 patients with two or fewer criteria were classified as low risk, 148 patients with three criteria were classified as intermediate risk, and 204 patients with four or more criteria were classified as high risk. Within a 30-day follow-up, cardiac event rate (death, myocardial infarction, repeat intervention) was 6.4% for high-risk, 3.4% for intermediate-risk, and 0% for low-risk patients (
P
<.01). Stent vessel occlusion occurred in 5.9%, 2.7%, and 0%, respectively (
P
<.01). There was no significant difference between anticoagulant and antiplatelet therapy in the low- and intermediate-risk groups. In high-risk patients, however, the cardiac event rate was 12.6% with anticoagulant therapy and 2.0% with antiplatelet therapy (
P
=.007), and the rate of stent vessel occlusion was 11.5% and 0%, respectively (
P
<.001).

Conclusions
This risk stratification protocol can help to identify patients at risk for adverse cardiac events and stent vessel occlusion. Patients in the high-risk group had the most benefit from antiplatelet therapy. These data suggest that antiplatelet therapy is the therapy of choice after coronary stenting specifically for patients with acute ischemic syndromes, difficult procedures, or suboptimal final results.