bluuebunny/crossref_metadata_2025 huggingface dataset:
Widening of the Excitable Gap During Pharmacological Cardioversion of Atrial Fibrillation in the Goat
Authors: Wijffels Maurits C. E. F. , Dorland Rick , Mast Frans , Allessie Maurits A.
Published: June 2012

Background
—Previous studies suggest that the antifibrillatory action of class I and III drugs is due to prolongation of the atrial wavelength. The aim of the present study was to directly evaluate the electrophysiological action of antifibrillatory drugs in a goat model of chronic atrial fibrillation (AF).

Methods and Results
—Six goats were instrumented with multiple atrial electrodes, and sustained AF was induced by electrical remodeling. During sustained AF, the effects of intravenous infusion of cibenzoline, hydroquinidine, flecainide, and
d
-sotalol on AF cycle length (AFCL), refractory period (RP
AF
), conduction velocity (CV
AF
), pathlength (PL
AF
), wavelength (WL
AF
), temporal (AFCL−RP
AF
), and spatial (PL
AF
−WL
AF
) excitable gap were studied. The RP
AF
was measured by determining the earliest moment at which single stimuli could capture the fibrillating atria. CV
AF
was measured during regional entrainment of AF. Contrary to our expectation, cardioversion of AF could not be attributed to prolongation of WL
AF
. Hydroquinidine and
d
-sotalol did not affect WL
AF
significantly, whereas cibenzoline and flecainide even shortened WL
AF
by 18% and 36%, respectively. PL
AF
was increased by hydroquinidine and
d
-sotalol by 30%, whereas cibenzoline and flecainide did not prolong PL
AF
. The only parameter that correlated consistently with cardioversion of AF was a widening of the temporal excitable gap (cibenzoline 176%, hydroquinidine 105%, flecainide 86%,
d
-sotalol 88%).

Conclusions
—Pharmacological cardioversion of AF cannot be explained by prolongation of WL
AF
. An alternative explanation for the antifibrillatory effect of class I and III drugs may be a widening of the temporal excitable gap.
A Randomized Trial Comparing Stenting With Balloon Angioplasty in Small Vessels in Patients With Symptomatic Coronary Artery Disease
Authors: Kastrati Adnan , Schömig Albert , Dirschinger Josef , Mehilli Julinda , Dotzer Franz , von Welser Nicola , Neumann Franz-Josef
Published: June 2012

Background
—More than 30% of the lesions currently treated with interventional approaches are situated in vessels smaller in size than those representing an established indication for stenting. The objective of this randomized trial was to assess whether compared with PTCA, stenting of small coronary vessels is associated with a reduction of restenosis.

Methods and Results
—Patients with symptomatic coronary artery disease with lesions situated in native coronary vessels between 2 and 2.8 mm in size were randomly assigned to be treated with either stenting (n=204) or PTCA (n=200). Adjunct therapy consisted of abciximab, ticlopidine, and aspirin. Repeat angiography at 6-month follow-up was performed in 83% of the patients. The primary end point of the study was the incidence of angiographic restenosis (≥50% diameter stenosis) at follow-up; adverse clinical events, such as death, myocardial infarction, stroke, or target vessel revascularization, were assessed as secondary end points. After 7 months, there were no significant differences in the infarct-free survival rates between the 2 study groups: 96.6% for stent patients, and 97.0% for PTCA patients (
P
=0.80). Target vessel revascularization was needed in 20.1% of the stent patients and 16.5% of the PTCA patients (
P
=0.35). The primary end point of angiographic restenosis was found in 35.7% of the stent patients and 37.4% of the PTCA patients (
P
=0.74). The net lumen gain observed at follow-up was identical (0.76±0.78 in the stent group versus 0.76±0.63 mm in the PTCA group,
P
=0.93).

Conclusions
—Stenting and PTCA are associated with equally favorable results when used for treating lesions in small coronary vessels.
Rapid and Efficient Vascular Transport of Arginine Polymers Inhibits Myointimal Hyperplasia
Authors: Uemura Shiro , Fathman C. Garrison , Rothbard Jonathan B. , Cooke John P.
Published: June 2012

Background
—We recently discovered that short polymers of arginine efficiently translocate across the cytoplasmic membrane independent of the basic amino acid transporter. We evaluated the kinetics and biological effects of heptamers of
l
-arginine and
d
-arginine (L-R7 and D-R7, respectively) in vascular cells. We assessed the effects of these peptides on the NO synthesis pathway and vascular cell proliferation.

Methods and Results
—Human umbilical vein endothelial cell and rabbit vascular segments were incubated in medium containing biotin-labeled L-R7 or D-R7. Both polymers rapidly translocated through the vessel wall and into the vascular cells in a dose- and time-dependent fashion. At a dose of 10 μmol/L for 30 minutes, 100% of the endothelial cells showed evidence of cytoplasmic and nuclear localization of the peptides. To evaluate the biological effects of the polymer translocation on myointimal formation, rabbit jugular vein segments were incubated with polymers (10 μmol/L, 30 minutes) or vehicle before arterial interposition grafting. Planimetric measurement 28 days after surgery revealed that L-R7 and D-R7 substantially reduced myointimal formation compared with the control condition (intima/media ratio: control 1.50.5, L-R7 0.40.2, and D-R7 0.80.2;
P
<0.05). Furthermore, basal nitrate and nitrite production from L-R7–treated grafts was significantly higher than that from both control and D-R7–treated veins. Studies in vitro of cultured vascular smooth muscle cells revealed that both polymers also exhibit an NO-independent inhibition of vascular smooth muscle cell proliferation.

Conclusions
—Short polymers of arginine have the unique ability of vascular cell translocation, and they also have direct biological effects. These attributes are potentially useful in treating myointimal hyperplasia.
Anisotropic Reentry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium
Authors: Schalij Martin J. , Boersma Lucas , Huijberts Maya , Allessie Maurits A.
Published: June 2012

Background
—Anisotropy creates nonuniformity in electrical propagation and may contribute to the occurrence of unidirectional conduction block and reentry. We describe the characteristics of reentrant tachycardia in a 2D layer of anisotropic ventricular myocardium.

Methods and Results
—A Langendorff-perfused epicardial sheet (1.0±0.4 mm, n=35) was created by freezing the intramural layers of the rabbit left ventricle. Epicardial activation maps were constructed by use of different high-resolution mapping arrays connected to a mapping system. In 5 experiments, monophasic action potentials were recorded. In the intact left ventricle, no arrhythmias except VF could be induced. After freezing, programmed electrical stimulation or rapid pacing led to the induction of sustained VT (cycle length 130±11 ms). VT was caused by reentry around a functional line of block oriented parallel to the epicardial fiber direction. Action potential recordings demonstrated that the central line of block was kept refractory by electrotonic currents generated by the depolarization waves propagating at either side of the line of block. At the pivot points of the line of block, the pronounced curvature of the turning wave and abrupt loading changes created an excitable gap of 30 ms in the reentrant pathway.

Conclusions
—In uniform anisotropic myocardium, reentry around a functional Z-shaped line of block may occur. The core of the circuit is kept refractory by electrotonic currents. The pronounced wave-front curvature and abrupt loading changes at the pivot points cause local conduction delay and create a small excitable gap.
Fish Oil–Derived Fatty Acids, Docosahexaenoic Acid and Docosapentaenoic Acid, and the Risk of Acute Coronary Events
Authors: Rissanen Tiina , Voutilainen Sari , Nyyssönen Kristiina , Lakka Timo A. , Salonen Jukka T.
Published: June 2012

Background
—Previous findings concerning the serum levels of fish-derived (n-3) fatty acids and coronary heart disease are inconsistent. The purpose of this study was to investigate the association between the serum n-3 end-product fatty acids docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid and the risk of acute coronary events in middle-aged men.

Methods and Results
—We studied this association in the Kuopio Ischaemic Heart Disease Risk Factor Study, a prospective population study in Eastern Finland. Subjects were randomly selected and included 1871 men aged 42 to 60 years who had no clinical coronary heart disease at baseline examination. A total of 194 men had a fatal or nonfatal acute coronary event during follow-up. In a Cox proportional hazards’ model adjusting for other risk factors, men in the highest fifth of the proportion of serum DHA+DPA in all fatty acids had a 44% reduced risk (
P
=0.014) of acute coronary events compared with men in the lowest fifth. Men in the highest fifth of DHA+DPA who had a low hair content of mercury (≤2.0 μg/g) had a 67% reduced risk (
P
=0.016) of acute coronary events compared with men in the lowest fifth who had a high hair content of mercury (>2.0 μg/g). There was no association between proportion of eicosapentaenoic acid and the risk of acute coronary events.

Conclusions
—Our data provide further confirmation for the concept that fish oil–derived fatty acids reduce the risk of acute coronary events. However, a high mercury content in fish could attenuate this protective effect.
Impaired Endothelial Function and Increased Carotid Stiffness in 9-Year-Old Children With Low Birthweight
Authors: Martin Helena , Hu Jie , Gennser Gerhard , Norman Mikael
Published: June 2012

Background
—Low birthweight (LBW) has been associated with an increased incidence of adult cardiovascular disease. Endothelial dysfunction and loss of arterial elasticity are early markers of hypertension and atherosclerosis. We studied the prevalence of these markers in 44 healthy, prepubertal (age 9±1.3 years) children, 22 with LBW for age.

Methods and Results
—Endothelial function in skin was tested with the local application of acetylcholine (inducing endothelium-dependent vasodilation) and nitroglycerin (endothelium-independent vasodilation), and local perfusion changes were measured with the laser Doppler method. The elastic properties of the abdominal aorta and common carotid artery were measured with an ultrasonic vessel-wall tracking system. Endothelium-dependent vasodilation was lower in children with LBW (88±33 perfusion units [PU]) than in normal-birthweight controls (133±34 PU,
P
<0.001). There was no difference in aortic or carotid elasticity between the 2 groups, but a negative correlation was found between birthweight and stiffness of the carotid artery wall (
r
=−0.45,
P
<0.01). Endothelium-independent vasodilation and blood pressure were similar in the 2 groups.

Conclusions
—Schoolchildren with a history of LBW show impaired endothelial function and a trend toward increased carotid stiffness. These findings may be early expressions of vascular compromise, contributing to susceptibility to disease in adult life.
Physiological Induction of a β-Adrenergic Receptor Kinase Inhibitor Transgene Preserves β-Adrenergic Responsiveness in Pressure-Overload Cardiac Hypertrophy
Authors: Manning Brian S. , Shotwell Kyle , Mao Lan , Rockman Howard A. , Koch Walter J.
Published: June 2012

Background
—Transgenic mice with constitutive myocardium-targeted expression of a peptide inhibitor of the β-adrenergic receptor kinase (βARKct) have increased in vivo cardiac function and enhanced β-adrenergic receptor (βAR) responsiveness.

Methods and Results
—In the present study, we created transgenic mice with myocardium-targeted βARKct transgene expression under control of the CARP (cardiac ankyrin repeat protein) promoter, which is active during cardiac development and inactive in the normal adult mouse heart. Consistent with this, adult CARP-βARKct transgenic mice have normal in vivo cardiac contractility and βAR responsiveness indistinguishable from their nontransgenic littermates (NLCs). However, because CARP is in a group of fetal genes activated in the adult ventricle during hypertrophy, we subjected animals to transverse aortic constriction (TAC) to induce pressure overload. Seven days after TAC, CARP-βARKct hearts had elevations in left ventricular mass similar to those in NLCs; however, TAC did induce demonstrable βARKct expression in the transgenic hearts. TAC in NLC mice resulted in an upregulation of myocardial βARK1 and a loss of βAR-mediated inotropic reserve. Importantly, although βARK1 was increased in the hypertrophic CARP-βARKct mice, the in vivo loss of βAR responsiveness was not seen after induced βARKct expression.

Conclusions
—These results demonstrate that acute βARK1 inhibition can restore lost myocardial βAR responsiveness and inotropic reserve in vivo. Furthermore, these mice demonstrate the novel utility of the CARP promoter as an inducible element responsive to pathophysiological conditions in the adult heart.
Evidence for Possible Involvement of 5-HT
2B
Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications
Authors: Rothman Richard B. , Baumann Michael H. , Savage Jason E. , Rauser Laura , McBride Ace , Hufeisen Sandra J. , Roth Bryan L.
Published: June 2012

Background
—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis.

Methods and Results
—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (−)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (−)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite
m
-chlorophenylpiperazine. (±)-, (+)-, and (−)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT
2B
receptor and were partial to full agonists at the 5-HT
2B
receptor.

Conclusions
—Our data imply that activation of 5-HT
2B
receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT
2B
receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT
2B
receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT
2B
receptors.
Effect of Intracoronary γ-Radiation Therapy on In-Stent Restenosis
Authors: Mintz Gary S. , Weissman Neil J. , Teirstein Paul S. , Ellis Steven G. , Waksman Ron , Russo Robert J. , Moussa Issam , Tripuraneni Prabhaker , Jani Shrish , Kobayashi Yoshio , Giorgianni Joseph A. , Pappas Chrysoula , Kuntz Richard A. , Moses Jeffrey , Leon Martin B.
Published: June 2012

Background
—The aim of this study was to use serial volumetric intravascular ultrasound to evaluate the effect of γ-radiation on recurrent in-stent restenosis.

Methods and Results
—After successful reintervention, patients were randomized to receive either
192
Ir or placebo. Intravascular ultrasound studies with motorized pullback (0.5 mm/s) were performed immediately after irradiation and at 8-month follow-up in 70 patients. Paired volumetric analysis of the stented segment and of 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque and media (external elastic membrane minus lumen), stent, and intimal hyperplasia (stent minus lumen). Baseline proximal reference, stent, and distal reference measurements were similar in both groups. The changes in proximal and distal reference measurements of the external elastic membrane, plaque and media, and lumen areas were similar in both groups. However, the decrease in stented segment lumen volume was less in the
192
Ir patients than the placebo patients (–25±34 mm
3
versus –48±42 mm
3
;
P
=0.0225), and the increase in the volume of intimal hyperplasia in the stented segment was less in the
192
Ir patients than in the placebo patients (28±37 mm
3
versus 50±40 mm
3
;
P
=0.0352). When averaged over the length of the stented segment (32±13 mm versus 33±14 mm;
P
=0.9), the increase in mean area of intimal hyperplasia was 0.8±1.0 mm
2
in the
192
Ir group and 1.6±1.2 mm
2
in the control group (
P
=0.0065). Late stent-vessel wall malapposition was noted in one placebo patient and no
192
Ir patients.

Conclusions
—γ-Radiation therapy can effectively prevent recurrent in-stent restenosis by inhibiting neointimal formation within the stent. At the stent edge, there were no significant differences between
192
Ir and placebo patients.
Transfer of CD4
+
T Cells Aggravates Atherosclerosis in Immunodeficient Apolipoprotein E Knockout Mice
Authors: Zhou Xinghua , Nicoletti Antonino , Elhage Rima , Hansson Göran K.
Published: June 2012

Background
—Atherosclerosis is associated with immune responses to oxidized lipoproteins and certain microorganisms, but the role of specific immunity has remained unclear.

Methods and Results
—To study the role of immunity in atherosclerosis, we crossed atherosclerosis-prone apoE
—/–
mice with immunodeficient
scid/scid
mice. The offspring showed a 73% reduction in aortic fatty streak lesions when compared with immunocompetent apoE
–/–
mice. Transfer of CD4
+
T cells from apoE
–/–
to immunodeficient apoE
–/–
/
scid/scid
mice increased lesions by 164%. This was associated with the infiltration of transferred T cells into lesions, increased circulating interferon-γ levels, and increased I-A expression in lesions.

Conclusions
—CD4
+
T cells carry disease-promoting immunity in atherosclerosis.
Economic Assessment of Platelet Glycoprotein IIb/IIIa Receptor Blockade With Abciximab and Low-Dose Heparin During Percutaneous Coronary Revascularization
Authors: Lincoff A. Michael , Mark Daniel B. , Tcheng James E. , Califf Robert M. , Bala Mohan V. , Anderson Keaven M. , Davidson-Ray Linda , Knight J. David , Cabot Catherine F. , Topol Eric J.
Published: June 2012

Background
—In the EPILOG trial (Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade), abciximab administered with weight-adjusted heparin diminished the risk of ischemic complications within 30 days by 56% among patients undergoing percutaneous coronary revascularization, without increased bleeding complications.

Methods and Results
—A prospective economic assessment was performed in the 2792 patients enrolled in EPILOG. Patients were randomized to receive placebo with standard-dose weight-adjusted heparin, abciximab with low-dose weight-adjusted heparin, or abciximab with standard-dose weight-adjusted heparin during percutaneous coronary intervention. Hospital billing data for the baseline hospitalization were collected for 2581 patients (92.4% of total) and imputed for the remainder, with physician fees estimated from the Medicare Fee Schedule. For the baseline hospitalization, medical costs (hospitalization and physician fees) averaged $9632 for the placebo arm compared with $8758 (
P
=0.005) and $9092 (
P
=0.176) for the abciximab with low-dose and standard-dose heparin arms, respectively. Inclusive of average drug cost ($1454 to $1457), the net incremental baseline cost of these 2 abciximab strategies was $583 with low-dose weight-adjusted heparin and $914 with standard-dose weight-adjusted heparin. During 6-month follow-up, average hospital costs were not significantly different in the 3 treatment groups; cumulative net incremental costs were $1236 and $1268 in the abciximab with low-dose and standard-dose heparin groups, respectively.

Conclusions
—Treatment with abciximab and low-dose, weight-adjusted heparin during percutaneous coronary revascularization reduces ischemic events and associated costs, thereby offsetting some of the cost of the drug. The suppression of bleeding complications associated with this agent by heparin dose reduction optimizes the economic attractiveness of this treatment strategy.
Plasma Cytokine Parameters and Mortality in Patients With Chronic Heart Failure
Authors: Rauchhaus Mathias , Doehner Wolfram , Francis Darrel P. , Davos Constantinos , Kemp Michael , Liebenthal Christa , Niebauer Josef , Hooper James , Volk Hans-Dieter , Coats Andrew J. S. , Anker Stefan D.
Published: June 2012

Background
—Inflammatory immune activation is an important feature in chronic heart failure (CHF). Little is known about the prognostic importance of tumor necrosis factor-α (TNF-α), soluble TNF-receptor 1 and 2 (sTNF-R1/sTNF-R2), interleukin-6 (IL-6), and soluble CD14 receptors (sCD14) in CHF patients.

Methods and Results
—In 152 CHF patients (age 61±1 years, New York Heart Association [NYHA] class 2.6±0.1, peak V̇
o
2
17.3±0.6 mL · kg
−1
· min
−1
, mean±SEM) plasma concentrations of immune variables were prospectively assessed. During a mean follow-up of 34 months (>12 months in all patients), 62 patients (41%) died. Cumulative mortality was 28% at 24 months. In univariate analyses, increased total and trimeric TNF-α, sTNF-R1, and sTNF-R2 (all
P
≤0.0001), sCD14 (
P
=0.0007), and IL-6 (
P
=0.005) predicted 24-month mortality. With multivariate analysis and receiver operating characteristics, sTNF-R1 emerged among all cytokine parameters as the strongest and most accurate prognosticator in this CHF population, regardless of follow-up duration and independently of NYHA class, peak V̇
o
2
, V̇
e
/V̇
co
2
slope, left ventricular ejection fraction, and wasting (
P
<0.001). The receiver operating characteristic area under the curve for sTNF-R1 was greater than for sTNF-R2 at 6, 12, and 18 months (all
P
<0.05).

Conclusions
—sTNF-R1 was the strongest and most accurate prognosticator, independent of established markers of CHF severity. Assessment of sTNF-R1 may be useful in identifying patients who are at high risk of death and in monitoring patients undergoing anti–TNF-α treatment.
Initial and 6-Month Results of Biodegradable Poly-
l
-Lactic Acid Coronary Stents in Humans
Authors: Tamai Hideo , Igaki Keiji , Kyo Eisho , Kosuga Kunihiko , Kawashima Akiyoshi , Matsui Shigeo , Komori Hidenori , Tsuji Takafumi , Motohara Seiichiro , Uehata Hiromu
Published: June 2012

Background
—Although metallic stents are effective in preventing acute occlusion and reducing late restenosis after coronary angioplasty, many concerns still remain. Compared with metallic stents, poly-
l
-lactic acid (PLLA) stents are biodegradable and can deliver drugs locally. The aim of this study was to evaluate the feasibility, safety, and efficacy of the PLLA stent.

Methods and Results
—Fifteen patients electively underwent PLLA Igaki-Tamai stent implantation for coronary artery stenoses. The Igaki-Tamai stent is made of a PLLA monopolymer, has a thickness of 0.17 mm, and has a zigzag helical coil pattern. A balloon-expandable covered sheath system was used, and the stent expanded by itself to its original size with an adequate temperature. A total of 25 stents were successfully implanted in 19 lesions in 15 patients, and angiographic success was achieved in all procedures. No stent thrombosis and no major cardiac event occurred within 30 days. Coronary angiography and intravascular ultrasound were serially performed 1 day, 3 months, and 6 months after the procedure. Angiographically, both the restenosis rate and target lesion revascularization rate per lesion were 10.5%; the rates per patient were 6.7% at 6 months. Intravascular ultrasound findings revealed no significant stent recoil at 1 day, and they revealed stent expansion at follow-up. No major cardiac event, except for repeat angioplasty, developed within 6 months.

Conclusions
—Our preliminary experience suggests that coronary PLLA biodegradable stents are feasible, safe, and effective in humans. Long-term follow-up with more patients will be required to validate the long-term efficacy of PLLA stents.
Hemodynamic Effects of Bosentan, an Endothelin Receptor Antagonist, in Patients With Pulmonary Hypertension
Authors: Williamson D. James , Wallman Lucinda L. , Jones Richard , Keogh Anne M. , Scroope Frances , BEd  , Penny Ronald , Weber Cornelia , Macdonald Peter S.
Published: June 2012

Background
—Few treatments are available for isolated pulmonary hypertension (PHT), which has a high morbidity and mortality. This trial was designed to assess the hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with PHT, in which local overproduction of endothelin-1 (ET-1) is thought to play a pathogenic role.

Methods and Results
—An open-label, dose-ranging study was performed in 7 female patients with primary PHT (n=5) or isolated PHT associated with limited scleroderma (n=2). Infusions of 50, 150, and 300 mg were administered at 2-hour intervals, and the hemodynamic responses were measured. Bosentan caused a dose-dependent fall in total pulmonary resistance (−20.0±11.0%,
P
=0.01) and mean pulmonary artery pressure (−10.6±11.0%,
P
>0.05). However, there was also a fall in the systemic vascular resistance (−26.2±12.8%,
P
<0.005) and mean arterial pressure (−19.8±14.4%,
P
<0.001). There was a slight increase in cardiac index (15±12%,
P
>0.05) and a dose-dependent rise in ET-1 but no significant change in other hemodynamic variables, gas exchange, or other vasoactive mediators.

Conclusions
—Intravenous bosentan is a potent but nonselective pulmonary vasodilator at the doses tested, even in patients resistant to inhaled nitric oxide. Transient increases in plasma ET-1 were observed, consistent with a blockade of endothelial ET
B
receptors. Systemic hypotension and other significant events during the study indicate that its intravenous use in patients with severe PHT may be limited. Implications for future trial design and studies of chronic oral treatment are discussed.
Oral Beraprost Sodium, a Prostaglandin I
2
Analogue, for Intermittent Claudication
Authors: Lièvre Michel , Morand Sophie , Besse Bruno , Fiessinger Jean-Noel , Boissel Jean-Pierre , (BERCI) Research Group ;
Published: June 2012

Background
—Beraprost sodium (BPS) is a new stable, orally active prostaglandin I
2
analogue with antiplatelet and vasodilating properties. We report the results of a phase III clinical trial of BPS in patients with intermittent claudication.

Methods and Results
—Patients (n=549) with a pain-free walking distance of between 50 and 300 m were entered into a 4-week single-blind placebo run-in phase. Patients whose pain-free walking distance had changed by <25% were then randomized to receive either BPS (40 μg TID, n=209) or placebo (n=213) in a double-blind manner for 6 months. Pain-free and maximum walking distances were measured on the occasion of treadmill exercise tests performed at baseline and 1.5, 3, 4.5, and 6 months after randomization. Success was defined as an improvement of >50% in pain-free walking distance at month 6 and in ≥1 earlier treadmill exercise test in the absence of critical cardiovascular events. Success was observed more frequently in the BPS group (43.5%) than in the placebo group (33.3%,
P
=0.036). Pain-free walking distances increased by 81.5% and 52.5%, respectively, in the BPS and placebo groups (
P
=0.001) and maximum walking distances by 60.1% and 35.0%, respectively (
P
=0.004). The incidence of critical cardiovascular events was 4.8% in the BPS group and 8.9% in the placebo group.

Conclusions
—These results show that BPS is an effective symptomatic treatment of patients with intermittent claudication. The beneficial effects of BPS on critical cardiovascular events should be confirmed in appropriate clinical trials.
Application of the New York State PTCA Mortality Model in Patients Undergoing Stent Implantation
Authors: Holmes David R. , Berger Peter B. , Garratt Kirk N. , Mathew Verghese , Bell Malcolm R. , Barsness Gregory W. , Higano Stuart T. , Grill Diane E. , Hammes LaVon N. , Rihal Charanjit S.
Published: June 2012

Background
—This study applied the New York State conventional coronary angioplasty (PTCA) model of clinical outcomes to evaluate whether it has relevance in the current era of stent implantation. The model was developed in 62 670 patients treated with conventional PTCA from 1991 to 1994 to risk adjust mortality and bypass surgery after PTCA. Since then, stents have become the dominant form of intervention. Whether that model remains relevant is uncertain.

Methods and Results
—All patients undergoing stenting at the Mayo Clinic from 1995 to 1998 were analyzed for in-hospital mortality, bypass surgery performed after attempted stenting, and longer-term mortality. No patients were excluded. The New York model was used to risk adjust and predict in-hospital and follow-up mortality. There were 3761 patients with 4063 procedural admissions for stenting; 6472 target vessel segments were attempted, and 96.1% of procedures were successful. With the New York multivariable risk factor equation, 79 in-hospital deaths were expected (1.95%); 66 deaths (1.62%) were observed. The New York model risk score in a logistic regression model was the most significant factor associated with in-hospital mortality (OR, 1.86;
P
<0.001). During a mean follow-up of 1.2±1.0 years, there were 154 deaths. Multivariable analysis documented 6 factors associated with subsequent mortality; New York risk score was the most significant (χ
2
=16.64,
P
=0.0001).

Conclusions
—Although the New York mortality model was developed in an era of conventional angioplasty, it remains relevant in patients undergoing stenting. The risk score derived from that model is the variable most significantly associated with not only in-hospital but also longer-term outcome.
Final Results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) Study
Authors: Fitzgerald Peter J. , Oshima Akio , Hayase Motoya , Metz Jonas A. , Bailey Steven R. , Baim Donald S. , Cleman Michael W. , Deutsch Ezra , Diver Daniel J. , Leon Martin B. , Moses Jeffrey W. , Oesterle Stephen N. , Overlie Paul A. , Pepine Carl J. , Safian Robert D. , Shani Jacob , Simonton Charles A. , Smalling Richard W. , Teirstein Paul S. , Zidar James P. , Yeung Alan C. , Kuntz Richard E. , Yock Paul G. , Investigators for the CRUISE
Published: June 2012

Background
—Intravascular ultrasound (IVUS) can assess stent geometry more accurately than angiography. Several studies have demonstrated that the degree of stent expansion as measured by IVUS directly correlated to clinical outcome. However, it is unclear if routine ultrasound guidance of stent implantation improves clinical outcome as compared with angiographic guidance alone.

Methods and Results
—The CRUISE (Can Routine Ultrasound Influence Stent Expansion) study, a multicenter study IVUS substudy of the Stent Anti-thrombotic Regimen Study, was designed to assess the impact of IVUS on stent deployment in the high-pressure era. Nine centers were prospectively assigned to stent deployment with the use of ultrasound guidance and 7 centers to angiographic guidance alone with documentary (blinded) IVUS at the conclusion of the procedure. A total of 525 patients were enrolled with completed quantitative coronary angiography, quantitative coronary ultrasound, and clinical events adjudicated at 9 months for 499 patients. The IVUS-guided group had a larger minimal lumen diameter (2.9±0.4 versus 2.7±0.5 mm,
P
<0.001) by quantitative coronary angiography and a larger minimal stent area (7.78±1.72 versus 7.06±2.13 mm
2
,
P
<0.001) by quantitative coronary ultrasound. Target vessel revascularization, defined as clinically driven repeat interventional or surgical therapy of the index vessel at 9 month-follow-up, occurred significantly less frequently in the IVUS-guided group (8.5% versus 15.3%,
P
<0.05; relative reduction of 44%).

Conclusions
—These data suggest that ultrasound guidance of stent implantation may result in more effective stent expansion compared with angiographic guidance alone.
Noninvasive Imaging of Inflammation by Ultrasound Detection of Phagocytosed Microbubbles
Authors: Lindner Jonathan R. , Dayton Paul A. , Coggins Matthew P. , Ley Klaus , Song Ji , Ferrara Katherine , Kaul Sanjiv
Published: June 2012

Background
—We have previously shown that microbubbles adhere to leukocytes in regions of inflammation. We hypothesized that these microbubbles are phagocytosed by neutrophils and monocytes and remain acoustically active, permitting their detection in inflamed tissue.

Methods and Results
—In vitro studies were performed in which activated leukocytes were incubated with albumin or lipid microbubbles and observed under microscopy. Microbubbles attached to the surface of activated neutrophils and monocytes, were phagocytosed, and remained intact for up to 30 minutes. The rate of destruction of the phagocytosed microbubbles on exposure to ultrasound was less (
P
≤0.05) than that of free microbubbles at all acoustic pressures applied. Intravital microscopy and simultaneous ultrasound imaging of the cremaster muscle was performed in 6 mice to determine whether phagocytosed microbubbles could be detected in vivo. Fifteen minutes after intravenous injection of fluorescein-labeled microbubbles, when the blood-pool concentration was negligible, the number of phagocytosed/attached microbubbles within venules was 7-fold greater in tumor necrosis factor-α (TNF-α)–treated animals than in control animals (
P
<0.01). This increase in retained microbubbles resulted in a 5- to 6-fold-greater (
P
<0.01) degree of ultrasound contrast enhancement than in controls.

Conclusions
—After attaching to activated neutrophils and monocytes, microbubbles are phagocytosed intact. Despite viscoelastic damping, phagocytosed microbubbles remain responsive to ultrasound and can be detected by ultrasound in vivo after clearance of freely circulating microbubbles from the blood pool. Thus, contrast ultrasound has potential for imaging sites of inflammation.
Assessment of Severity of Aortic Regurgitation Using the Width of the Vena Contracta
Authors: Tribouilloy Christophe M. , Enriquez-Sarano Maurice , Bailey Kent R. , Seward James B. , Tajik A. Jamil
Published: June 2012

Background
—The width of the vena contracta (VC-W), the smallest area of regurgitant flow, reflects the degree of valvular regurgitation and is measurable by color Doppler imaging, but this method has not been validated in aortic regurgitation (AR).

Methods and Results
—We prospectively examined 79 patients with isolated AR and 80 patients without regurgitation. The VC-W was measured from the long-axis parasternal view and compared with 2 simultaneous reference methods (quantitative Doppler and 2D echocardiography). In patients without regurgitation, the agreement between methods was excellent. In patients with AR, good correlations (all
P
<0.0001) were obtained between VC-W and effective regurgitant orifice (ERO) area and regurgitant volume recorded by quantitative Doppler (
r
=0.89 and 0.90, respectively) and 2D echocardiographic (
r
=0.90 and 0.89, respectively) methods. These correlations were similar with eccentric or central jets (all
P
>0.60). The other methods used showed good correlations of VC-W with aortographic grading of AR (n=8,
r
=0.82,
P
=0.01), with the proximal flow convergence method (n=53,
r
=0.85,
P
<0.0001), and with left ventricular end-diastolic volume (
r
=0.81,
P
<0.0001). Sensitivity and specificity of VC-W ≥6 mm for diagnosing severe AR (ERO ≥30 mm
2
) were 95% and 90%, respectively.

Conclusions
—For assessment of the degree of AR, VC-W shows good correlations with simultaneous quantitative measures (regardless of jet direction), shows good correlations with other methods of assessment of AR, and provides a high diagnostic value for severe AR. VC-W is a simple, reliable method that can be used clinically as part of comprehensive Doppler echocardiographic assessment of AR.
Photoangioplasty
Authors: Rockson Stanley G. , Lorenz David P. , Cheong Wai-Fung , Woodburn Kathryn W.
Published: June 2012

Abstract
—Photodynamic therapy (PDT) has been studied and applied to various disease processes. The potential of PDT for selective destruction of target tissues is especially appealing in cardiovascular disease, in which other existing interventional tools are somewhat nonselective and carry substantial risk of damage to the normal arterial wall. Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic and, potentially, restenotic lesions) is fueled by more effective second-generation photosensitizers and technological advances in endovascular light delivery. This excitement revolves around at least 4 significant attributes of light-activated therapy: the putative selectivity and safety of photoangioplasty, the potential for atraumatic and effective debulking of atheromatous plaque through a biological mechanism, the postulated capability to reduce or inhibit restenosis, and the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions. The available nonclinical data, coupled with the observations of a new phase I trial in human peripheral atherosclerosis, suggest a promising future for photoangioplasty in the treatment of primary atherosclerosis and prevention of restenosis.
Effect of Plasma Homocysteine Concentration on Early and Late Events in Patients With Acute Coronary Syndromes
Authors: Stubbs Peter J. , Al-Obaidi Mohamed K. , Conroy Ronan M. , MusB  , Collinson Paul O. , MRCPath  , Graham Ian M. , FRCPI  , Noble Mark I. M.
Published: June 2012

Background
—Although a raised plasma homocysteine is a risk factor for vascular disease, it is not known whether it is associated with an adverse cardiac outcome in patients admitted with acute coronary syndromes. We evaluated the relationship between plasma homocysteine and short-term (28 days) and long-term (median 2.5 years) prognosis in acute coronary syndromes.

Methods and Results
—We evaluated the relationship of quintiles of homocysteine to fatal and nonfatal coronary disease early (28 days) and late (29 days to a median of 2.5 years) after admission to a single unit of patients with unstable angina (n=204) and myocardial infarction (n=236). The end points studied were cardiac death (n=67) and/or myocardial (re)infarction (n=30). Cox regression and logistic regression were used to estimate the relationship of homocysteine to coronary events. The event rate within the first 28 days (22 cardiac deaths and 5 nonfatal infarctions) was not related to the admission homocysteine level. In the 203 unstable angina and 214 myocardial infarction survivors, an apparent threshold effect was seen on long-term follow-up, with a significant step-up in the frequency of events between the lowest 3 quintiles (14 cardiac deaths and 11 nonfatal infarctions) and the upper 2 quintiles (31 fatal and 12 nonfatal events). Patients in the upper 2 quintiles (>12.2 μmol/L) had a 2.6-fold increase in the risk of a cardiac event (95% CI, 1.5 to 4.3,
P
<0.001).

Conclusions
—Elevated total homocysteine levels on admission strongly predict late cardiac events in acute coronary syndromes.
Inadequate Response to Treatment in Coronary Heart Disease
Authors: Denollet Johan , Vaes Johan , Brutsaert Dirk L.
Published: June 2012

Background
—Improvement in treatment of patients with coronary heart disease (CHD) has caused longer survival but also an increase in the number of patients at risk for subsequent cardiac events and impaired quality of life (QOL). We hypothesized that chronic emotional distress confers an increased risk of poor outcome despite appropriate treatment.

Methods and Results
—This prospective study examined the 5-year prognosis of 319 patients with CHD. Baseline assessment included symptoms of depression/anxiety and distressed personality type (type D—ie, high negative affectivity and social inhibition). The main end points were cardiac death or nonfatal myocardial infarction and impaired QOL. There were 22 cardiac events (16 nonfatal); they were related to left ventricular ejection fraction (LVEF) ≤50%, poor exercise tolerance, age ≤55 years, symptoms of depression, and type D personality. Multivariate analysis yielded LVEF ≤50% (OR, 3.9;
P
=0.009), type D personality (OR, 8.9;
P
=0.0001), and age ≤55 years (OR, 2.6;
P
=0.05) as independent predictors of cardiac events. Convergence of these risk factors predicted the absence of the expected therapeutic response that was observed in 10% of the patients. When 2 or 3 risk factors occurred together, the rate of poor outcome was 4-fold higher (
P
=0.0001). Estimates of medical costs increased progressively with an increasing number of risk factors. Smoking, symptoms of depression, and type D personality were independent predictors of impaired QOL.

Conclusions
—Decreased LVEF, type D personality, and younger age increase the risk of cardiac events; convergence of these factors predicts nonresponse to treatment. Emotionally stressed and younger patients with CHD represent high-risk groups deserving of special study.
Sudden Cardiac Death With Apparently Normal Heart
Authors: Chugh Sumeet S. , Kelly Karen L. , Titus Jack L.
Published: June 2012

Background
—Mechanisms of sudden cardiac death (SCD) in subjects with apparently normal hearts are poorly understood. In survivors, clinical investigations may not establish normal cardiac structure with certainty. Large autopsy series may provide a unique opportunity to confirm structural normalcy of the heart before reviewing a patient’s clinical history.

Methods and Results
—We identified and reexamined structurally normal hearts from a 13-year series of archived hearts of patients who had sudden cardiac death. Subsequently, for each patient with a structurally normal heart, a detailed review of the circumstances of death as well as clinical history was performed. Of 270 archived SCD hearts identified, 190 were male and 80 female (mean age 42 years); 256 (95%) had evidence of structural abnormalities and 14 (5%) were structurally normal. In the group with structurally normal hearts (mean age 35 years), SCD was the first manifestation of disease in 7 (50%) of the 14 cases. In 6 cases, substances were identified in serum at postmortem examination without evidence of drug overdose; 2 of these chemicals have known associations with SCD. On analysis of ECGs, preexcitation was found in 2 cases. Comorbid conditions identified were seizure disorder and obesity (2 cases each). In 6 cases, there were no identifiable conditions associated with SCD.

Conclusions
—In 50% of cases of SCD with structurally normal hearts, sudden death was the first manifestation of disease. An approach combining archived heart examinations with detailed review of the clinical history was effective in elucidating potential SCD mechanisms in 57% of cases.
Differentiation Between Restrictive Cardiomyopathy and Constrictive Pericarditis by Early Diastolic Doppler Myocardial Velocity Gradient at the Posterior Wall
Authors: Palka Przemysław , Lange Aleksandra , Donnelly J. Elisabeth , Nihoyannopoulos Petros
Published: June 2012

Background
—The differential diagnosis between restrictive cardiomyopathy (RCM) and constrictive pericarditis (CP) is challenging and, despite combined information from different diagnostic tests, surgical exploration is often necessary.

Methods and Results
—A group of 55 subjects (mean age, 63±11 years; 36 men and 19 women) were enrolled in the study; 15 had RCM, 10 had CP, and 30 were age-matched, normal controls. The diagnosis of RCM was supported by a biopsy; in the CP group, the diagnosis was confirmed either surgically or at autopsy. All patients underwent a transthoracic echocardiogram that included the assessment of Doppler myocardial velocity gradient (MVG), as measured from the left ventricular posterior wall during the predetermined phases of the cardiac cycle. MVG was lower (
P
<0.01) in RCM patients compared with both CP patients and normal controls during ventricular ejection (2.8±1.2 versus 4.4±1.0 and 4.7±0.8 s
−1
, respectively) and rapid ventricular filling (1.9±0.8 versus 8.7±1.7 and 3.7±1.4 s
−1
, respectively). Additionally, during isovolumic relaxation, MVG was positive in RCM patients and negative in both CP patients and normal controls (0.7±0.4 versus −1.0±0.6 and −0.4±0.3 s
−1
, respectively;
P
<0.01). During atrial contraction, MVG was similarly low (
P
<0.01) in both RCM and CP patients compared with normal controls (1.6±1.7 and 1.7±1.8 versus 3.8±0.9 s
−1
, respectively).

Conclusions
—Doppler myocardial imaging–derived MVG, as measured from the left ventricular posterior wall in early diastole during both isovolumic relaxation and rapid ventricular filling, allows for the discrimination of RCM from CP.
Remnant Lipoproteins Induce Proatherothrombogenic Molecules in Endothelial Cells Through a Redox-Sensitive Mechanism
Authors: Doi Hideki , Kugiyama Kiyotaka , Oka Hideki , Sugiyama Seigo , Ogata Nobuhiko , Koide Shun-ichi , Nakamura Shin-ichi , Yasue Hirofumi
Published: June 2012

Background
—Triglyceride-rich lipoproteins (TGLs) are atherogenic. However, their cellular mechanisms remain largely unexplained. This study examined the effects of isolated remnant-like lipoprotein particles (RLPs) on the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and tissue factor (TF), proatherothrombogenic molecules, in cultured human endothelial cells.

Methods and Results
—RLPs were isolated from plasma of hypertriglyceridemic patients by use of the immunoaffinity gel mixture of anti–apoA-1 and anti–apoB-100 monoclonal antibodies. The incubation of cells with RLPs significantly upregulated mRNA and protein expression of these molecules. Total TGLs (
d
<1.006) and LDL had fewer or minimal effects on expression of these molecules compared with RLPs. RLPs increased intracellular oxidant levels, as assessed with an oxidant-sensitive probe. Combined incubation with α-tocopherol or
N
-acetylcysteine, both antioxidants, suppressed RLP-induced increase in expression of these molecules. In patients with higher plasma levels of RLPs, plasma levels of soluble forms of ICAM-1 and VCAM-1 were significantly higher than in patients with lower RLP levels. Treatment with α-tocopherol for 1 month decreased levels of the soluble adhesion molecules concomitantly with an increase in resistance of RLPs to oxidative modification in patients with high RLP levels.

Conclusions
—RLPs upregulated endothelial expression of ICAM-1, VCAM-1, and TF, proatherothrombogenic molecules, partly through a redox-sensitive mechanism. RLPs may have an important role in atherothrombotic complications in hypertriglyceridemic patients.