bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of β
1
-Blockade on Oxidative Metabolism and the Metabolic Cost of Ventricular Work in Patients With Left Ventricular Dysfunction
Authors: Beanlands R. S. B. , Nahmias C. , Gordon E. , Coates G. , deKemp R. , Firnau G. , Fallen E.
Published: June 2012

Background
—The mechanism for the beneficial effect of β-blocker therapy in patients with left ventricular (LV) dysfunction is unclear, but it may relate to an energy-sparing effect that results in improved cardiac efficiency. C-11 acetate kinetics, measured using positron-emission tomography (PET), are a proven noninvasive marker of oxidative metabolism and myocardial oxygen consumption (MV̇
o
2
). This approach can be used to measure the work-metabolic index, which is a noninvasive estimate of cardiac efficiency.

Methods and Results
—The aim of this study was to determine the effect of metoprolol on oxidative metabolism and the work-metabolic index in patients with LV dysfunction. Forty patients (29 with ischemic and 11 with nonischemic heart disease; LV ejection fraction <40%) were randomized to receive metoprolol or placebo in a treatment protocol of titration plus 3 months of stable therapy. Seven patients were not included in analysis because of withdrawal from the study, incomplete follow-up, or nonanalyzable PET data. The rate of oxidative metabolism (k) was measured using C-11-acetate PET, and stoke volume index (SVI) was measured using echocardiography. The work-metabolic index was calculated as follows: (systolic blood pressure×SVI×heart rate)/k. No significant change in oxidative metabolism occurred with placebo (k=0.061±0.022 to 0.054±0.012 per minute). Metoprolol reduced oxidative metabolism (k=0.062±0.024 to 0.045±0.015 per minute;
P
=0.002). The work-metabolic index did not change with placebo (from 5.29±2.46×10
6
to 5.14±2.06×10
6
mm Hg · mL/m
2
), but it increased with metoprolol (from 5.31±2.15×10
6
to 7.08±2.36×10
6
mm Hg · mL/m
2
;
P
<0.001).

Conclusions
—Selective β-blocker therapy with metoprolol leads to a reduction in oxidative metabolism and an improvement in cardiac efficiency in patients with LV dysfunction. It is likely that this energy-sparing effect contributes to the clinical benefits observed with β-blocker therapy in this patient population.
Sympathetic Neural Burst Amplitude Distribution
Authors: Sverrisdóttir Yrsa Bergmann , Rundqvist Bengt , Johannsson Gudmundur , Elam Mikael
Published: June 2012

Background
—Human muscle sympathetic nerve activity (MSNA) is usually measured as the number of pulse-synchronous bursts in multiunit mean voltage recordings. We recently suggested burst amplitude distribution as a more sensitive indicator of altered MSNA in congestive heart failure (CHF). Here, we test whether this distribution can discriminate between different conditions with increased MSNA burst frequency and whether it reflects single vasoconstrictor fiber firing intensity.

Methods and Results
—We analyzed resting multiunit MSNA in 36 CHF patients (24 with mild to moderate CHF, 12 with severe CHF investigated before and after heart transplantation), 14 patients with pituitary deficiency, 25 matched healthy control subjects, and an additional 56 healthy men with a wider age range (21 to 71 years). Pituitary deficiency was associated with increased MSNA burst frequency (60 versus 37 bursts/min in control subjects), equivalent to that in mild to moderate CHF (61 bursts/min). However, burst amplitude distribution in hypopituitary patients (median burst amplitude, 37%) did not deviate from matched control subjects (36%), whereas amplitudes increased with disease severity in CHF (43% in mild to moderate, 52% in severe) and normalized after transplantation (36%). In the larger healthy group, MSNA burst frequency increased with age, and burst amplitude distribution remained unaffected. In 8 CHF patients, single-unit firing frequency showed a close positive relationship to multiunit burst amplitude distribution (
r
=0.82,
P
<0.01) but none to burst frequency (
r
=0.39,
P
=0.3).

Conclusions
—Muscle vasoconstrictor fiber activity is better reflected by multiunit MSNA burst amplitude distribution than by burst frequency, at least in CHF. This distribution can discriminate between conditions with increased burst frequency.
Clinical Outcome of Fenestrated Fontan Patients After Closure
Authors: Goff Donna A. , Blume Elizabeth D. , Gauvreau Kimberlee , Mayer John E. , Lock James E. , Jenkins Kathy J.
Published: June 2012

Background
—The late clinical status of Fontan patients after fenestration closure is unknown. Data are now available on all patients who underwent closure from 1989 to 1999.

Methods and Results
—All patients who underwent catheter closure of a Fontan fenestration were enrolled in either the Clamshell (1989 to 1994) or CardioSEAL (1996 to 1999) regulatory trials. Physiological values obtained at catheterization helped assess the hemodynamic effects of fenestration occlusion. In addition to survival, outcomes assessed included O
2
saturations, medication use, significant clinical findings (eg, heart failure, protein-losing enteropathy, or new arrhythmias), and somatic growth. Of 181 patients who underwent closure, 27 had additional significant leaks. The remaining 154 patients constituted the study group. Median time from closure to latest follow-up was 3.4 years (range 0.4 to 10.3 years). Fenestration closure increased O
2
saturation 9.4% on average (
P
<0.001). The numbers of patients receiving digoxin or diuretics decreased at the most recent follow-up compared with baseline (
P
<0.001), but use of antiarrhythmic agents increased marginally (
P
=0.05). Height and weight percentiles rose (medians of 2 and 4, respectively;
P
<0.001). Clinical decompensation during follow-up of 154 patients was rare (4.5%), with 2 deaths, 3 Fontan revisions, and 1 patient each with protein-losing enteropathy and ascites. No other patient developed chronic congestive symptoms; 21 patients developed new arrhythmias, and 2 had a stroke or transient ischemic attack.

Conclusions
—Fenestration closure in Fontan patients was followed by improved oxygenation, reduced need for anticongestive medication, and improved somatic growth at latest follow-up. Death (1.3%) or chronic decompensation (3.2%) was rare.
Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21
Waf1
and p27
Kip1
Authors: Marra Diego E. , Simoncini Tommaso , Liao James K.
Published: June 2012

Background
—Salicylates may have direct vascular effects by mechanisms that are independent of platelet inhibition.

Methods and Results
—We investigated the effect of salicylates on vascular smooth muscle cell (SMC) proliferation in response to platelet-derived growth factor (PDGF) in vitro. Salicylate concentrations of 5 and 10 mmol/L inhibited serum- or PDGF-induced SMC cell count and [
3
H]thymidine incorporation by 62% and 81%, respectively. There was no evidence of cellular toxicity or apoptosis as determined by trypan blue exclusion and FACS analyses. Because cell cycle progression is regulated by hyperphosphorylation of the retinoblastoma (Rb) protein, we examined the effects of salicylate on Rb hyperphosphorylation. Treatment with salicylate, but not indomethacin, inhibited nuclear factor-κB activation and completely abolished Rb hyperphosphorylation in PDGF-treated SMCs. This effect was associated with a decrease in cyclin-dependent kinase (Cdk)-2 and, to a lesser extent, Cdk-6, but not Cdk-4 activity, without changes in Cdk-2, -4, and -6 and cyclin D and E protein levels. Because Cdk-2 activity is regulated by the Cdk inhibitors p21
Waf1
and p27
Kip1
, we studied the effects of salicylate on p21
Waf1
and p27
Kip1
expression. Treatment with salicylate prevented PDGF-induced downregulation of p21
Waf1
and p27
Kip1
but not of the Cdk-4/-6 inhibitor p16
Ink4
.

Conclusions
—These findings indicate that high doses of salicylates inhibit SMC proliferation by cell cycle arrest at the G
1
-S phase and suggest a beneficial role for high-dose salicylates in the treatment of vascular proliferative disorders.
Effect of Second-Phase Duration on the Strength-Duration Relation for Human Transvenous Defibrillation
Authors: Shorofsky Stephen R. , Gold Michael R.
Published: June 2012

Background
—The mechanism by which biphasic waveforms improve defibrillation efficacy is unclear. In addition, the optimal shape of the biphasic waveforms remains controversial. Animal experiments suggest that prolonging the duration of the second phase longer than the first worsens defibrillation thresholds (DFT). The purpose of this study was to determine the strength-duration relation for the second phase of a biphasic defibrillation waveform in humans.

Methods and Results
—This was a prospective, randomized study of biphasic DFT in 36 patients; a uniform dual-coil transvenous lead system was used. In each patient, 3 DFTs were determined with the pulse duration for the second phase of the defibrillation waveform varying between 1 and 18 ms. The duration of the first phase was fixed at 6 ms and the capacitance was 150 μF. There was a significant increase in the leading edge voltage at DFT only when the second-phase pulse duration was decreased to 1 ms. There was no increase in DFT voltage even when the second-phase pulse duration was increased from 2 to 18 ms. Similar relations were observed for stored energy, leading edge current, or phase 2 energy. The normalized average current delivered during phase 2 decreased monotonically with increasing phase 2 duration.

Conclusions
—In humans, the biphasic DFT voltage or energy is increased only when the second phase of the waveform is <2 ms. The DFT voltage is insensitive to increasing the second phase of the defibrillator waveform to as long as 18 ms, or 3 times the duration of the first phase of the waveform.
Role of Monocyte Chemoattractant Protein-1 in Cardiovascular Remodeling Induced by Chronic Blockade of Nitric Oxide Synthesis
Authors: Koyanagi Masamichi , Egashira Kensuke , Kitamoto Shiro , Ni Weihua , Shimokawa Hiroaki , Takeya Motohiro , Yoshimura Teizo , Takeshita Akira
Published: June 2012

Background
—Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) to rats induces early vascular inflammatory changes (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 [MCP-1] expression) as well as subsequent arteriosclerosis (medial thickening and perivascular fibrosis) and cardiac fibrosis. However, the role of MCP-1 in this process is not known.

Methods and Results
—We investigated the effect of a specific monoclonal anti–MCP-1 neutralizing antibody in rats treated with L-NAME to determine the role of monocytes in the regulation of cardiovascular remodeling. We found increased expression of MCP-1 mRNA in vascular endothelial cells and monocytes in inflammatory lesions. Cotreatment with an anti–MCP-1 antibody, but not with control IgG, prevented the L-NAME–induced early inflammation and reduced late coronary vascular medial thickening. In contrast, the anti–MCP-1 antibody did not decrease the development of perivascular fibrosis, the expression of transforming growth factor (TGF)-β
1
mRNA, or systolic pressure overload induced by L-NAME administration.

Conclusions
—These results suggest that MCP-1 is necessary for the development of medial thickening as well as monocyte recruitment. In contrast, the pathogenesis of fibrosis may involve other factors, such as TGF-β
1
.
Diastolic Fractional Flow Reserve to Assess the Functional Severity of Moderate Coronary Artery Stenoses
Authors: Abe Masayuki , Tomiyama Hirofumi , Yoshida Hideo , Doba Nobutaka
Published: June 2012

Background
—Coronary blood flow occurs mainly during the diastolic phase of each cardiac cycle and is mainly dependent on diastolic driving pressure, especially in the left anterior descending coronary artery (LAD). We hypothesized that calculation of the ratio of the diastolic driving pressure of a stenotic LAD to its normal value, namely diastolic FFR (d-FFR), might provide precise insight into the mechanism of FFR for assessment of the functional severity of the stenosis. We compared d-FFR with FFR, coronary flow reserve (CFR), and exercise myocardial thallium scintigraphy in an lesion of intermediate severity.

Methods and Results
—The study population consisted of 46 consecutive patients with a moderate stenosis in the LAD in whom simultaneous measurements of aortic pressure, left ventricular pressure, and coronary pressure distal to the stenosis were obtained. Coronary flow velocity was successfully measured with a Doppler guidewire in 37 of the 46 patients. Values for FFR, d-FFR, and CFR in the noninvasive test–positive group were significantly lower than those in the negative group. With cutoff values of 0.75, 0.76, and 2.0 for FFR, d-FFR, and CFR, sensitivities were 83.3%, 95.8%, and 88.2% and specificities were 100%, 100%, and 95.0%, respectively.

Conclusions
—The close similarity of the sensitivity and specificity of FFR and d-FFR, around almost identical cutoff values (0.75 versus 0.76), confirms the physiological validity of FFR as a clinical standard. In clinical practice, FFR remains the index of choice for assessment of the functional severity of moderate coronary artery stenoses.
Coronary Pressure Measurement to Assess the Hemodynamic Significance of Serial Stenoses Within One Coronary Artery
Authors: Pijls Nico H.J. , De Bruyne Bernard , Bech G. Jan Willem , Liistro Francesco , Heyndrickx Guy R. , Bonnier Hans J.R.M. , Koolen Jacques J.
Published: June 2012

Background
—When several stenoses are present within 1 coronary artery, the hemodynamic significance of each stenosis is influenced by the presence of the other(s), and the calculation of coronary and fractional flow reserve (CFR and FFR) for each individual stenosis is confounded. Recently, we developed and experimentally validated a method to determine the true FFR of each stenosis as it would be after the removal of the other stenosis; the true FFR can be reliably predicted by coronary pressures measured before treatment at specific locations within the coronary artery using equations accounting for stenosis interaction. The aim of the present study was to test the validity of these equations in humans.

Methods and Results
—In this study of 32 patients with 2 serial stenoses in 1 coronary artery, relevant pressures were measured before the intervention, after the treatment of 1 stenosis, and after the treatment of both stenoses. The true FFR of each stenosis (FFR
true
) was directly measured after the elimination of the other stenosis and compared with the value predicted (FFR
pred
) from the initial pressure measurements before treatment. Although the hyperemic gradient across 1 stenosis increased significantly (from 10±7 to 19±11 mm Hg after treatment of the other stenosis), FFR
pred
was close to FFR
true
in all patients (0.78±0.12 versus 0.78±0.11 mm Hg;
r
=0.92; Δ%=4±0%). Without accounting for stenosis interaction, the value of FFR for each stenosis would have been significantly overestimated (0.85±0.08;
P
<0.01).

Conclusions
—Coronary pressure measurements made by a pressure wire at maximum hyperemia provide a simple, practical method for assessing the individual hemodynamic significance of multiple stenoses within the same artery.
Impact of Atrioventricular Compliance on Pulmonary Artery Pressure in Mitral Stenosis
Authors: Schwammenthal Ehud , Vered Zvi , Agranat Oren , Kaplinsky Elieser , Rabinowitz Babeth , Feinberg Micha S.
Published: June 2012

Background
—The decay of the pressure gradient across a stenotic mitral valve is determined by the size of the orifice and net AV compliance (C
n
). We have observed a group of symptomatic patients, usually in sinus rhythm, characterized by pulmonary hypertension (particularly during exercise) despite a relatively large mitral valve area by pressure half-time. We speculated that this discrepancy was due to low atrial compliance causing both pulmonary hypertension and a steep decay of the transmitral pressure gradient despite significant stenosis. We therefore tested the hypothesis that C
n
is an important physiological determinant of pulmonary artery pressure at rest and during exercise in mitral stenosis.

Methods and Results
—Twenty patients with mitral stenosis were examined by Doppler echocardiography. C
n
, calculated from the ratio of effective mitral valve area (continuity equation) and the E-wave downslope, ranged from 1.7 to 8.1 mL/mm Hg. Systolic pulmonary artery pressure (PAP) increased from 43±12 mm Hg at rest to 71±23 mm Hg (range, 40 to 110 mm Hg) during exercise. There was a particularly close correlation between C
n
and exercise PAP (
r
=−0.85). Patients with a low compliance were more symptomatic (
P
<0.025). Catheter- and Doppler-derived values for C
n
, determined in 10 cases, correlated well (
r
=0.79).

Conclusions
—C
n
, which can be noninvasively assessed, is an important physiological determinant of PAP in mitral stenosis. Patients with low C
n
represent an important clinical entity, with symptoms corresponding to severe increases in PAP during stress echocardiography.
Endothelins and Endothelin Receptor Antagonists
Authors: Lüscher Thomas F. , Barton Matthias
Published: June 2012

Abstract
—The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G
i
-protein–coupled receptors. ET
A
receptors mediate vasoconstriction and cell proliferation, whereas ET
B
receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1.

ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
Selective Targeting of Gene Transfer to Vascular Endothelial Cells by Use of Peptides Isolated by Phage Display
Authors: Nicklin Stuart A. , White Steve J. , Watkins Sarah J. , Hawkins Robert E. , Baker Andrew H.
Published: June 2012

Background
—Gene transfer to vascular cells is a highly inefficient and nonselective process, defined by the lack of specific cell-surface receptors for both nonviral and viral gene delivery vectors.

Methods and Results
—We used filamentous phage display to isolate a panel of peptides that have the ability to bind selectively and efficiently to quiescent human umbilical vein endothelial cells (HUVECs) with reduced or negligible binding to nonendothelial cells, including vascular smooth muscle cells and hepatocytes. By direct biopanning on HUVECs and a second approach involving preclearing steps before panning on HUVECs, we isolated and sequenced 140 individual phages and identified 59 peptides. We selected 7 candidates for further investigation by secondary screening of homogeneous phages on a panel of cell types. Using adenovirus-mediated gene transfer as a model gene delivery system, we cloned the peptide SIGYPLP and the positive control peptide KKKKKKK upstream of the S11e single-chain Fv (“adenobody”) directed against the knob domain of the adenovirus to create fusion proteins. Adenovirus-mediated gene transfer via fiber-dependent infection was blocked with S11e, whereas inclusion of the KKKKKKK peptide retargeted gene transfer. The peptide SIGYPLP, however, retargeted gene delivery specifically to endothelial cells with a significantly enhanced efficiency over nontargeted adenovirus and without transduction of nontarget cells.

Conclusions
—Our study demonstrates the feasibility of using small, novel peptides isolated via phage display to target gene delivery specifically and efficiently to HUVECs and highlights their use for retargeting both viral and nonviral gene transfer to vascular endothelial cells for future clinical applications.
Electrophysiological Breakthroughs From the Left Atrium to the Pulmonary Veins
Authors: Haïssaguerre Michel , Shah Dipen C. , Jaïs Pierre , Hocini Mélèze , Yamane Teiichi , Deisenhofer Isabel , Chauvin Michel , Garrigue Stéphane , Clémenty Jacques
Published: June 2012

Background
—The extent of ostial ablation necessary to electrically disconnect the pulmonary vein (PV) myocardial extensions that initiate atrial fibrillation from the left atrium has not been determined.

Methods and Results
—Seventy patients underwent PV mapping with a circumferential 10-electrode catheter during sinus rhythm or left atrial pacing. After assessment of perimetric distribution and activation sequence of PV potentials, ostial ablation was performed at segments showing earliest activation, with the end point of PV disconnection. A total of 162 PVs (excluding right inferior PVs) were ablated. PV potentials were present at 60% to 88% of their perimeter, but PV muscle activation was always sequential from a segment with earliest activation (breakthrough). Radiofrequency (RF) application at this breakthrough eliminated all PV potentials in 34 PVs, whereas a secondary breakthrough required RF applications at separate segments in 77; in others, >2 segments were ablated. A median of 5, 6, and 4 bipoles from the circular catheter were targeted in the right superior, left superior, and inferior PVs, respectively, to achieve PV disconnection. Early recurrence of arrhythmia was observed in 31 patients as a result of new venous or atrial foci or recovery of previously targeted PVs, most related to a single recovered breakthrough that was reablated with local RF application.

Conclusions
—Although PV muscle covers a large extent of the PV perimeter, there are specific breakthroughs from the left atrium that allow ostial PV disconnection by use of partial perimetric ablation.
Improved Vascular Endothelial Function After Oral B Vitamins
Authors: Chambers John C. , Ueland Per M. , Obeid Omar A. , Wrigley Jane , Refsum Helga , Kooner Jaspal S.
Published: June 2012

Background
—Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD.

Methods and Results
—We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow–mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B
12
(1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B
12
were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5±3.2% to 4.0±3.7%,
P
=0.002) but not placebo (2.3±2.6% to 1.9±2.6%,
P
=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0±3.4 to 9.3±1.9 μmol/L,
P
<0.001), protein-bound homocysteine (from 8.7±2.8 to 6.2±1.4 μmol/L,
P
<0.001), and free homocysteine (from 4.3±1.2 to 3.0±0.6 μmol/L,
P
<0.001) and raised concentrations of serum folate (from 10.3±4.3 to 31.2±10.8 ng/mL,
P
<0.001) and vitamin B
12
(from 314±102 to 661±297 pg/mL,
P
<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (
r
=−0.26,
P
=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B
12
. Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo.

Conclusions
—Folic acid and vitamin B
12
supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.
Sex Differences in Management and Outcome After Acute Myocardial Infarction in the 1990s
Authors: Gottlieb Shmuel , Harpaz David , Shotan Avraham , Boyko Valentina , Leor Jonathan , Cohen Miriam , Mandelzweig Lori , Mazouz Benjamin , Stern Shlomo , Behar Solomon
Published: June 2012

Background
—Previous studies have suggested that women with acute myocardial infarction (AMI) are less aggressively managed than are men. The aim of this study was to assess sex differences in medical and invasive coronary procedures (angiography, PTCA, and CABG) in AMI patients admitted to cardiac care units (CCUs) in Israel in the mid 1990s and their association with early and 1-year prognosis.

Methods and Results
—We studied 2867 consecutive AMI patients (2125 men, 74%) hospitalized in all 25 CCUs in Israel from 3 prospective nationwide surveys conducted in 1992, 1994, and 1996. Women were, on average, older than men (69 versus 61 years,
P
<0.0001) and had a higher prevalence of hypertension, diabetes, Killip class ≥II on admission, and in-hospital complications. Women received aspirin and β-blockers less often than did men, but these differences were not significant after age adjustment. The unadjusted rates of thrombolysis, angiography, and PTCA/CABG use were lower in women than in men but not after covariate adjustment: 42% versus 48% (adjusted odds ratio [OR] 0.92, 95% CI 0.77 to 1.11), 23% versus 31% (OR 0.88, 95% CI 0.70 to 1.09), and 15% versus 19% (OR 0.93, 95% CI 0.72 to 1.19), respectively. The 30-day mortality was higher in women than in men (17.6% versus 9.6%, respectively; OR 1.39, 95% CI 1.06 to 1.82), but the 30-day to 1-year mortality rate was not (9.1% versus 5.6%, respectively; hazard ratio 1.18, 95% CI 0.84 to 1.66).

Conclusions
—This prospective nationwide observational community-based study of consecutive AMI patients hospitalized in the CCUs in the mid 1990s indicates that women fare significantly worse than do men at 30 days but not thereafter at 1-year. The difference in 30-day outcome was not influenced by the use of different therapeutic modalities, including thrombolysis and invasive coronary procedures, but was rather due to the older age and greater comorbidity of women; these findings seem also to explain the less frequent use of invasive procedures in women.
Ultrasound-Guided Strategy for Provisional Stenting With Focal Balloon Combination Catheter
Authors: Frey Axel W. , Hodgson John M. , Müller Christian , Bestehorn Hans-Peter , Roskamm Helmut
Published: June 2012

Background
—Intracoronary ultrasound (ICUS) has provided insights into vascular pathology and interventional therapy. The Strategy for ICUS-Guided PTCA and Stenting (SIPS) trial tested the hypothesis that routine ICUS guidance of coronary interventions improves outcome.

Methods and Results
—A single-center consecutive-patient randomized design (with 6-month angiographic and 2-year clinical follow-up) was used. Consecutive patients (no chronic total occlusions or emergency procedures) were randomized to ICUS-guided provisional stenting or standard angiographic guidance. Quantitative angiographic minimal lumen diameter (MLD), angiographic restenosis, clinically driven target lesion revascularization, and major adverse cardiac events (MACEs) were evaluated. A total of 291 procedures (356 lesions) were included. Procedure success was higher in the ICUS-guided group than the group randomized to standard guidance (94.7% versus 87.4%, respectively;
P
=0.033), whereas time (65.2±31.0 versus 60.5±34.0 minutes,
P
=0.18) and contrast use (209.3±94.1 versus 197.5±89.5 mL,
P
=0.23) were not significantly different. Stenting rates were similar (49.7% versus 49.5%,
P
=0.89). Acute gain was greater in the ICUS-guided group than in the standard guidance group (1.85±0.72 versus 1.67±0.76 mm, respectively;
P
=0.02). Angiographic 6-month analysis revealed no difference in MLD (1.71±0.94 versus 1.57±0.90,
P
=0.19) or binary restenosis rate (>50% diameter stenosis) (29% versus 35%,
P
=0.42). Clinical follow-up (602±307 days) showed a significant decrease in clinically driven target lesion revascularization in the ICUS group compared with the standard guidance group (17% versus 29%, respectively;
P
=0.02).

Conclusions
—Although angiographic MLD did not differ significantly after 6 months, ICUS-guided provisional stenting improved 2-year clinical results after intervention.
Expression of Platelet-Activating Factor Receptor in Human Carotid Atherosclerotic Plaques
Authors: Brochériou Isabelle , Stengel Dominique , Mattsson-Hultén Lillemor , Stankova Jana , Rola-Pleszczynski Marek , Koskas Fabien , Wiklund Olov , Le Charpentier Yves , Ninio Ewa
Published: June 2012

Background
—Human monocyte-derived macrophages synthesize numerous proinflammatory and prothrombotic substances, including lipid mediators, such as platelet-activating factor (PAF), which may play a major role in the onset and perpetuation of atherosclerotic lesions. In addition, both monocytes and macrophages express PAF receptors (PAF-R). The expression of PAF-R is transcriptionally downregulated by oxidized LDL in in vitro primary cultures of monocyte/macrophages. In this study, we evaluated the expression of PAF-R in human carotid plaque tissue, in foam cells isolated from human carotid plaques, and in primary cultures of umbilical smooth muscle cells (SMCs).

Methods and Results
—We show that PAF-R was expressed at low levels in foam cells compared with monocyte/macrophages in plaques, as assessed by immunohistochemical staining and in situ hybridization. In addition, low levels of mRNA were also detected by RT-PCR in isolated human carotid foam cells. A prominent finding of our study was the demonstration that contractile SMCs were positive for PAF-R, and its mRNA was extracted from primary cultures of umbilical SMCs.

Conclusions
—As macrophages loose their inflammatory phenotype on transformation into foam cells, they may equally loose their capacity of defense against aggression. We postulate that the diminished expression of PAF-R may be deleterious in the context of plaque formation and progression. The observation that arterial SMCs of contractile phenotype express PAF-R opens new avenues concerning the migration of these cells from media to intima and atherosclerotic plaque formation.
Noninvasive Coronary Vessel Wall and Plaque Imaging With Magnetic Resonance Imaging
Authors: Botnar René M. , Stuber Matthias , Kissinger Kraig V. , Kim Won Y. , Spuentrup Elmar , Manning Warren J.
Published: June 2012

Background
—Conventional x-ray angiography frequently underestimates the true burden of atherosclerosis. Although intravascular ultrasound allows for imaging of coronary plaque, this invasive technique is inappropriate for screening or serial examinations. We therefore sought to develop a noninvasive free-breathing MR technique for coronary vessel wall imaging. We hypothesized that such an approach would allow for in vivo imaging of coronary atherosclerosis.

Methods and Results
—Ten subjects, including 5 healthy adult volunteers (aged 35±17 years, range 19 to 56 years) and 5 patients (aged 60±4 years, range 56 to 66 years) with x-ray–confirmed coronary artery disease (CAD), were studied with a T2-weighted, dual-inversion, fast spin-echo MR sequence. Multiple adjacent 5-mm cross-sectional images of the proximal right coronary artery were obtained with an in-plane resolution of 0.5×1.0 mm. A right hemidiaphragmatic navigator was used to facilitate free-breathing MR acquisition. Coronary vessel wall images were readily acquired in all subjects. Both coronary vessel wall thickness (1.5±0.2 versus 1.0±0.2 mm) and wall area (21.2±3.1 versus 13.7±4.2 mm
2
) were greater in patients with CAD (both
P
<0.02 versus healthy adults).

Conclusions
—In vivo free-breathing coronary vessel wall and plaque imaging with MR has been successfully implemented in humans. Coronary wall thickness and wall area were significantly greater in patients with angiographic CAD. The presented technique may have potential applications in patients with known or suspected atherosclerotic CAD or for serial evaluation after pharmacological intervention.
Impairment of Endothelium-Dependent Vasodilation of Resistance Vessels in Patients With Obstructive Sleep Apnea
Authors: Kato Masahiko , Roberts-Thomson Philip , Phillips Bradley G. , Haynes William G. , Winnicki Mikolaj , Accurso Valentina , Somers Virend K.
Published: June 2012

Background
—Patients with obstructive sleep apnea (OSA) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges, each of which may impair endothelial function. We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation, even in the absence of overt cardiovascular disease.

Methods and Results
—We studied 8 patients with OSA (age 44±4 years) and 9 obese control subjects (age 48±3 years). Patients with OSA were newly diagnosed, never treated for OSA, on no medications, and free of any other known diseases. All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA. Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine (a vasodilator that stimulates endothelial release of nitric oxide), sodium nitroprusside (an exogenous nitric oxide donor), and verapamil (a calcium channel blocker). Conduit-vessel function was also evaluated by ultrasonography. Brachial artery diameter was measured under baseline conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). Patients with OSA had a blunted vasodilation in response to acetylcholine (
P
<0.007), but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects. No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects.

Conclusions
—Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation. This may be implicated in the pathogenesis of hypertension and heart failure in this condition.
Tumor Necrosis Factor-α Promotes In Vitro Calcification of Vascular Cells via the cAMP Pathway
Authors: Tintut Yin , Patel Jignesh , Parhami Farhad , Demer Linda L.
Published: June 2012

Background
—Vascular calcification is an ectopic calcification that commonly occurs in atherosclerosis. Because tumor necrosis factor-α (TNF-α), a pleiotropic cytokine found in atherosclerotic lesions, is also a regulator of bone formation, we investigated the role of TNF-α in in vitro vascular calcification.

Methods and Results
—A cloned subpopulation of bovine aortic smooth muscle cells previously shown capable of osteoblastic differentiation was treated with TNF-α, and osteoblastic differentiation and mineralization were assessed. Treatment of vascular cells with TNF-α for 3 days induced an osteoblast-like morphology. It also enhanced both activity and mRNA expression of alkaline phosphatase, an early marker of osteoblastic differentiation. Continuous treatment with TNF-α for 10 days enhanced matrix mineralization as measured by radiolabeled calcium incorporation in the matrix. Pretreatment of cells with a protein kinase A–specific inhibitor, KT5720, attenuated cell morphology, the alkaline phosphatase activity, and mineralization induced by TNF-α. Consistent with this, the intracellular cAMP level was elevated after TNF-α treatment. Electrophoretic mobility shift assay demonstrated that TNF-α enhanced DNA binding of osteoblast specific factor (Osf2), AP1, and CREB, transcription factors that are important for osteoblastic differentiation.

Conclusions
—These results suggest that TNF-α enhances in vitro vascular calcification by promoting osteoblastic differentiation of vascular cells through the cAMP pathway.
Differential Effects of Oral and Transdermal Estrogen Replacement Therapy on Endothelial Function in Postmenopausal Women
Authors: Vehkavaara Satu , Hakala-Ala-Pietilä Tiina , Virkamäki Antti , Bergholm Robert , Ehnholm Christian , Hovatta Outi , Taskinen Marja-Riitta , Yki-Järvinen Hannele
Published: June 2012

Background
—We determined whether the vascular effects of estradiol depend on the route of administration by comparing the effects of oral estradiol and transdermal placebo, transdermal estradiol and oral placebo, and transdermal placebo and oral placebo on in vivo endothelial function in 27 postmenopausal women.

Methods and Results
—Endothelial function was assessed from blood flow responses to intrabrachial artery infusions of endothelium-dependent (7.5 and 15 μg/min acetylcholine) and endothelium-independent (3 and 10 μg/min of sodium nitroprusside) vasodilators at 0, 2, and 12 weeks. In the oral estradiol group, the increase in flow above basal during infusion of the low dose of acetylcholine at 0, 2, and 12 weeks averaged 6.0±0.8, 6.9±0.8, and 11.3±1.2 (
P
<0.01 versus 0 and 2 weeks) mL · dL
−1
· min
−1
at 0, 2, and 12 weeks. The percentage increases versus 0 weeks averaged 21±14% at 2 and 120±34% at 12 weeks. During the high-dose acetylcholine infusion, the increase in flow above basal averaged 8.6±1.3, 10.2±1.5, and 15.1±1.8 (
P
<0.05 versus 0 weeks) mL · dL
−1
· min
−1
, respectively. The percentage increases versus 0 weeks averaged 22±10% at 2 weeks and 119±46% at 12 weeks. In the oral estradiol group, endothelium-independent vasodilatation also improved significantly, but less markedly than endothelium-dependent responses. In the transdermal and placebo groups, all vascular responses remained unchanged. Oral but not transdermal estradiol also induced significant decreases in LDL cholesterol and Lp(a) concentrations and an increase in HDL cholesterol within 2 weeks.

Conclusions
—We conclude that oral but not transdermal estradiol induces potentially antiatherogenic changes in in vivo endothelium-dependent vasodilatation and lipid concentrations.
Endovascular Brachytherapy for Prophylaxis of Restenosis After Femoropopliteal Angioplasty
Authors: Minar Erich , Pokrajac Boris , Maca Thomas , Ahmadi Ramazanali , Fellner Claudia , Mittlböck Martina , Seitz Wolfgang , Wolfram Roswitha , Pötter Richard
Published: June 2012

Background
—Inasmuch as endovascular brachytherapy (BT) has gained recent interest because of its inhibitory effect on mechanisms leading to restenosis after percutaneous transluminal angioplasty (PTA), we performed this randomized study to determine its efficacy for prophylaxis of restenosis after femoropopliteal PTA.

Methods and Results
—One hundred thirteen patients (63 men, 50 women; mean age 71 years) with de novo or recurrent femoropopliteal lesions were included in this randomized trial comparing the restenosis rate after PTA plus BT (57 patients, PTA+BT group) versus PTA (56 patients, PTA group) without stent implantation. The mean treated length was 16.7 cm (PTA+BT group) versus 14.8 cm (PTA group). In patients randomized to PTA plus BT, a dose of 12 Gy was applied by an
192
Ir source 3 mm from the source axis. Follow-up examinations included measurement of the ankle-brachial index, color-flow duplex sonography, and angiography. The primary end point of the study was patency after 6 months. The overall recurrence rate after 6 months was 15 (28.3%) of 53 in the PTA+BT group versus 29 (53.7%) of 54 in the PTA group (χ
2
test,
P
<0.05). The cumulative patency rates at 12 months of follow-up were 63.6% in the PTA+BT group and 35.3% in the PTA group (log-rank test,
P
<0.005).

Conclusions
—This is the first randomized study to demonstrate the efficacy of endovascular BT for prophylaxis of restenosis after femoropopliteal PTA. The value of this approach should now be improved by modification of the BT procedure and by combination with stent implantation.
Limitation of Excessive Extracellular Matrix Turnover May Contribute to Survival Benefit of Spironolactone Therapy in Patients With Congestive Heart Failure
Authors: Zannad Faiez , Alla François , Dousset Brigitte , Perez Alfonso , Pitt Bertram
Published: June 2012

Background
—In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF.

Methods and Results
—A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP >3.85 μg/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively.

Conclusions
—In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.
Endotoxin-Induced Myocardial Tumor Necrosis Factor-α Synthesis Depresses Contractility of Isolated Rat Hearts
Authors: Grandel Ulrich , Fink Ludger , Blum Andreas , Heep Martina , Buerke Michael , Kraemer Hans-Joachim , Mayer Konstantin , Bohle Rainer M. , Seeger Werner , Grimminger Friedrich , Sibelius Ulf
Published: June 2012

Background
—Although endotoxin (lipopolysaccharides, LPS) is recognized as a mediator of septic cardiodepression, its cardiac effects are still not fully elucidated.

Methods and Results
—Perfusion of isolated rat hearts with LPS for 180 minutes resulted in a decline of left ventricular contractility after 90 minutes, whereas coronary perfusion pressure remained unaffected. This cardiodepression was paralleled by a release of tumor necrosis factor (TNF)-α into the perfusate and preceded by myocardial TNF-α mRNA upregulation as quantified by real-time polymerase chain reaction. The cardiodepression was abrogated when LPS was perfused with a TNF-α antiserum or the ceramidase inhibitor
N
-oleoylethanolamine. In contrast, the cardiac release of nitric oxide (NO) was not augmented by LPS. Immunohistochemical studies of LPS-perfused hearts revealed a positive staining for the constitutive (NOSIII) but not for the inducible NO synthase (NOSII). Accordingly, NOSII mRNA levels commenced to increase only at the very end of the LPS perfusion period. Progressive liberation of thromboxane (Tx) A
2
and prostacyclin was induced by LPS together with myocardial cyclooxygenase (Cox)-2 mRNA expression. Both nonselective inhibition of Cox by indomethacin and selective inhibition of the inducible Cox-2 by NS-398 abolished prostanoid release. Interestingly, the generation of TNF-α and the associated cardiodepression caused by LPS were reduced by indomethacin, NS-398 and the Tx-receptor antagonist daltroban.

Conclusions
—LPS depresses contractility of isolated rat hearts by inducing TNF-α synthesis and subsequently activating the sphingomyelinase pathway, whereas no evidence for a role of NOSII- or NOSIII-generated NO was found. Moreover, Cox-2–derived TxA
2
appears to facilitate TNF-α synthesis in response to LPS.
Risk Factors for Infective Endocarditis
Authors: Strom Brian L. , Abrutyn Elias , Berlin Jesse A. , Kinman Judith L. , Feldman Roy S. , Stolley Paul D. , Levison Matthew E. , Korzeniowski Oksana M. , Kaye Donald
Published: June 2012

Background
—The risks of infective endocarditis (IE) associated with various conditions and procedures are poorly defined.

Methods and Results
—This was a population-based case-control study conducted in 54 Philadelphia, Pa–area hospitals from 1988 to 1990. Community-acquired IE cases unassociated with intravenous drug use were compared with matched community residents. Subjects were interviewed for risk factors. Diagnoses were confirmed by expert review of medical record abstracts with risk factor data removed. Cases were more likely than controls to suffer from prior severe kidney disease (adjusted OR [95% CI]=16.9 [1.5 to 193],
P
=0.02) and diabetes mellitus (adjusted OR [95% CI]=2.7 [1.4 to 5.2],
P
=0.004). Cases infected with skin flora had received intravenous fluids more often (adjusted OR [95% CI]=6.7 [1.1 to 41],
P
=0.04) and had more often had a previous skin infection (adjusted OR [95% CI]=3.5 [0.7 to 17],
P
=0.11). No association was seen with pulmonary, gastrointestinal, cardiac, or genitourinary procedures or with surgery. Edentulous patients had a lower risk of IE from dental flora than patients who had teeth but did not floss. Daily flossing was associated with a borderline decreased IE risk.

Conclusions
—Within the limits of the available sample size, the data showed that IE patients differ from people without IE with regard to certain important risk factors but not regarding recent procedures.