bluuebunny/crossref_metadata_2025 huggingface dataset:
31
P NMR Spectroscopy Detects Metabolic Abnormalities in Asymptomatic Patients With Hypertrophic Cardiomyopathy
Authors: Jung Wulf-Ingo , Sieverding Ludger , Breuer Johannes , Hoess Thomas , Widmaier Stefan , Schmidt Oliver , Bunse Michael , van Erckelens Franz , Apitz Jürgen , Lutz Otto , Dietze Guenther J.
Published: June 2012

Background
—Hypertrophic cardiomyopathy (HCM) often causes sudden, unexpected death in adolescents and young adults. Alterations in myocardial metabolism are considered to be causes for contractile dysfunction. We examined the question of whether metabolic abnormalities antedate the manifestation of symptoms in patients with HCM.

Methods and Results
—Proton-decoupled
31
P NMR spectroscopy of the anterior left ventricular wall of the heart of 14 young, asymptomatic patients with HCM was performed with a 1.5-T whole-body imager. Spectra of the phosphate metabolites were compared with those of normal control subjects. The patients exhibited a significantly reduced (
P
<0.02) ratio of phosphocreatine (PCr) to ATP of 1.98±0.37 (mean±SD), compared with 2.46±0.53 obtained in 11 normal control subjects. In addition, the group of patients with severe hypertrophy of the interventricular septum (n=8) showed a significantly increased (
P
<0.05) P
i
-to-PCr ratio, with a P
i
×100/PCr of 20.0±8.3 versus 9.7±7.2 in control subjects. Both abnormalities are similar to those found in ischemic myocardium. This view is also supported by a significantly increased (
P
<0.01) phosphomonoester (PME)-to-PCr ratio, with a PME×100/PCr of 20.7±11.2 compared with 8.4±6.7 in control subjects, indicating altered glucose metabolism.

Conclusions
—
31
P NMR spectroscopy detects alterations of myocardial metabolism in asymptomatic patients with HCM. These alterations may contribute to the understanding of the pathophysiology and natural history of the disease.
Selective ET
A
Receptor Antagonism Reduces Neointimal Hyperplasia in a Porcine Coronary Stent Model
Authors: McKenna Charles J. , Burke Sandra E. , Opgenorth Terry J. , Padley Robert J. , Camrud LaDonna J. , Camrud Allan R. , Johnson Jodi , Carlson Paula J. , Lerman Amir , Holmes David R. , Schwartz Robert S.
Published: June 2012

Background
—As endothelin binds to ET
A
receptors, it stimulates vascular smooth muscle cell proliferation and may thus be pivotally involved in the pathogenesis of restenosis. This study assessed the ability of a potent and selective ET
A
antagonist to reduce neointimal hyperplasia in a porcine coronary artery stented injury model.

Methods and Results
—Fifty-five pigs were randomized to receive placebo or the oral ET
A
-selective antagonist ABT147627 twice daily for 28 days in one of three doses: 0.75 mg/kg (low), 3.75 mg/kg (mid), and 10.0 mg/kg (high). Each underwent oversized stent deployment in two randomly assigned major epicardial coronary arteries. Three animals (5.5%) died as a consequence of stent thrombosis within 24 hours of the procedure. The remaining 52 animals (13 pigs per group) survived without complication until predetermined euthanasia at 28 days. In the placebo group, mean injury score was 1.73±0.80, with a mean neointimal response of 0.45±0.24 mm. By comparison, the low-dose group had a similar mean injury score of 1.79±0.75 with reduced neointimal response, 0.36±0.22 mm (
P
<0.01). Mean injury score in the mid-dose animals was significantly greater than in the placebo group (1.94±0.92;
P
<0.05). The neointimal hyperplasia associated with this injury was less than with placebo, although the difference did not reach statistical significance (0.40±0.25 mm;
P
=0.05). In the high-dose pigs, mean injury score was also significantly greater than in the placebo arm (1.93±0.73;
P
<0.05). Despite this, neointimal response was also significantly less (0.37±0.37 mm;
P
<0.01).

Conclusions
—Oral, selective ET
A
receptor antagonism significantly reduced neointimal hyperplasia forming over porcine coronary stented injuries in the first 28 days. This strategy may have clinical potential for the limitation and treatment of coronary restenosis after percutaneous revascularization.
Six-Month Angiographic Outcome After Successful Repeat Percutaneous Intervention for In-Stent Restenosis
Authors: Bauters Christophe , Banos Jean-Luc , Van Belle Eric , Mc Fadden Eugène P. , Lablanche Jean-Marc , Bertrand Michel E.
Published: June 2012

Background
—In-stent restenosis is an increasing clinical problem. Discordant results have been published regarding the risk of recurrent restenosis after repeat angioplasty for the treatment of in-stent restenosis.

Methods and Results
—One hundred three consecutive patients (107 vessels) underwent repeat percutaneous intervention for the treatment of in-stent restenosis and were entered in a prospective angiographic follow-up program. Repeat balloon angioplasty was performed at 93 lesions (87%) and additional stenting at 14 lesions (13%). The primary success rate was 98%. Six-month angiographic follow-up was performed in 85% of eligible patients. Restenosis was determined by quantitative angiography. Restenosis defined as a >50% diameter stenosis at follow-up was observed at 22% of lesions. The rate of target-lesion revascularization at 6 months was 17%. Repeat intervention for diffuse in-stent restenosis and severe stenosis before repeat intervention were associated with significantly higher rates of recurrent restenosis.

Conclusions
—The overall restenosis rate after repeat intervention for in-stent restenosis is low. The subgroup of patients with diffuse and/or severe in-stent restenosis, however, is at higher risk of recurrent restenosis and may benefit from alternative therapeutic strategies.
Body Surface Mapping During Pacing at Multiple Sites in the Human Atrium
Authors: SippensGroenewegen Arne , Peeters Heidi A. P. , Jessurun Emile R. , Linnenbank Andre C. , Robles de Medina Etienne O. , Lesh Michael D. , van Hemel Norbert M.
Published: June 2012

Background
—The morphology and polarity of the P wave on 12-lead ECG are of limited clinical value in localizing ectopic atrial rhythms. It was the aim of this study to assess the spatial resolution of body surface P-wave integral mapping in identifying the site of origin of ectopic right atrial (RA) impulse formation in patients without structural atrial disease.

Methods and Results
—Sixty-two–lead ECG recordings were obtained during RA pacing at 86 distinct endocardial sites in nine patients with normal biatrial anatomy. After P-wave integral maps were generated for each paced activation sequence, 17 groups with nearly identical map features were visually selected, and a mean P-wave integral map was computed for each group. Supportive statistical analysis to corroborate qualitative group selection was performed by assessment of (1) intragroup pattern uniformity by use of jackknife correlation coefficient analysis of the integral maps contained in each group and (2) intergroup pattern variability by use of the calculation of cross correlations between the 17 mean integral maps. The spatial resolution of paced P-wave body surface mapping in the right atrium was obtained by estimating the area size of endocardial segments with nearly identical P-wave integral maps by use of a biplane fluoroscopic method to compute the three-dimensional position of each pacing site. The latter approach yielded a mean endocardial segment size of 3.5±2.9 cm
2
(range, 0.79 to 10.75 cm
2
).

Conclusions
—Use of the P-wave morphology on the 62-lead surface ECG in patients with normal biatrial anatomy allows separation of the origin of ectopic RA impulse formation into one of 17 different endocardial segments with an approximated area size of 3.5 cm
2
. This database of paced P-wave integral maps provides a versatile clinical tool to perform detailed noninvasive localization of right-sided atrial tachycardia before radiofrequency catheter ablation.
[
18
F]Fluorodeoxyglucose Single Photon Emission Computed Tomography
Authors: Srinivasan Gopal , Kitsiou Anastasia N. , Bacharach Stephen L. , Bartlett Marissa L. , Miller-Davis Claiborne , Dilsizian Vasken
Published: June 2012

Background
—New high-energy collimators for single photon emission computed tomography (SPECT) cameras have made imaging of positron-emitting tracers, such as [
18
F]fluorodeoxyglucose (
18
FDG), possible. We examined differences between SPECT and PET technologies and between
18
FDG and thallium tracers to determine whether
18
FDG SPECT could be adopted for assessment of myocardial viability.

Methods and Results
—Twenty-eight patients with chronic coronary artery disease (mean left ventricular ejection fraction [LVEF]=33±15% at rest) underwent
18
FDG SPECT,
18
FDG PET, and thallium SPECT studies. Receiver operating characteristic curves showed overall good concordance between SPECT and PET technologies and thallium and
18
FDG tracers for assessing viability regardless of the level of
18
FDG PET cutoff used (40% to 60%). However, in the subgroup of patients with LVEF≤25%, at 60%
18
FDG PET threshold value, thallium tended to underestimate myocardial viability. In a subgroup of regions with severe asynergy, there were considerably more thallium/
18
FDG discordances in the inferior wall than elsewhere (73% versus 27%,
P
<.001), supporting attenuation of thallium as a potential explanation for the discordant observations. When uptake of
18
FDG by SPECT and PET was compared in 137 segments exhibiting severely irreversible thallium defects (scarred by thallium), 59 (43%) were viable by
18
FDG PET, of which 52 (88%) were also viable by
18
FDG SPECT. However, of the 78 segments confirmed to be nonviable by
18
FDG PET, 57 (73%) were nonviable by
18
FDG SPECT (
P
<.001).

Conclusions
—Although
18
FDG SPECT significantly increases the sensitivity for detection of viable myocardium in tissue declared nonviable by thallium (to 88% of the sensitivity achievable by PET), it will occasionally (27% of the time) result in falsely identifying as viable tissue that has been identified as nonviable by both PET and thallium.
Selective Defect in Nitric Oxide Synthesis May Explain the Impaired Endothelium-Dependent Vasodilation in Patients With Essential Hypertension
Authors: Cardillo Carmine , Kilcoyne Crescence M. , Quyyumi Arshed A. , Cannon Richard O. , Panza Julio A.
Published: June 2012

Background
—Patients with essential hypertension have impaired endothelial NO activity, but the mechanism underlying this abnormality is unknown.

Methods and Results
—To investigate whether the endothelial dysfunction of hypertensive patients is related to a selective defect in NO synthesis, we studied the forearm blood flow responses to intra-arterial infusion of acetylcholine (7.5 to 30 μg/min), an endothelial agonist linked to NO synthase through the Ca
2+
signaling pathway, and isoproterenol (50 to 200 ng/min), a β-adrenoceptor agonist that stimulates NO production by increasing intracellular cAMP, in 12 normotensive subjects and 12 hypertensive patients. The infusion of isoproterenol was repeated during the concurrent blockade of NO synthesis by
N
G
-monomethyl-
l
-arginine (L-NMMA; 4 μmol/min). The vasodilator response to acetylcholine was significantly reduced in hypertensives compared with normotensives (maximum blood flow: 10.4±4.6 versus 14.4±3.7 mL · min
−1
· dL
−1
;
P
=.008). However, the vasodilator effect of isoproterenol was similar in normotensives and hypertensives (maximum blood flow: 14.4±5.4 versus 13.5±5 mL · min
−1
· dL
−1
;
P
=.56) and was significantly (both
P
<.01) and equally blunted by L-NMMA in both groups (maximum blood flow: 11±3 mL · min
−1
· dL
−1
in normotensives versus 10.8±3.9 mL · min
−1
· dL
−1
in hypertensives;
P
=.77). The vasodilator response to sodium nitroprusside (0.8 to 3.2 μg/min), an exogenous NO donor, was similar in both groups and was not modified by L-NMMA.

Conclusions
—Hypertensive patients have impaired endothelium-dependent vasodilation in response to acetylcholine but preserved NO activity in response to β-adrenergic stimulation. These findings suggest that the endothelial dysfunction in essential hypertension is due to a selective abnormality of NO synthesis, probably related to a defect in the phosphatidylinositol/Ca
2+
signaling pathway.
Abciximab Therapy and Unplanned Coronary Stent Deployment
Authors: Kereiakes Dean J. , Lincoff A. Michael , Miller Dave P. , Tcheng James E. , Cabot Catherine F. , Anderson Keaven M. , Weisman Harlan F. , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
—The clinical and angiographic demographics of patients requiring unplanned coronary stent deployment and the optimal adjunct pharmacotherapy in this population are not well described. This report details the EPILOG trial experience with unplanned coronary stent deployment and the effect of abciximab platelet glycoprotein IIb/IIIa blockade to improve clinical outcomes during 6 months of follow-up.

Methods and Results
—After randomization in the EPILOG double-blind, placebo-controlled trial of abciximab therapy during percutaneous coronary intervention, 326 (12%) of 2792 patients required unplanned coronary stent deployment. Although stented patients were not distinguished by clinical variables, they had greater coronary lesion complexity by American Heart Association/American College of Cardiology criteria (
P
=.003) and greater incidence of lesion length >10 mm (
P
=.002), lesion eccentricity (
P
=.027), irregular lesion contour (
P
=.001), and bifurcation involvement (
P
=.019) than nonstented patients. Unplanned stents were required less often in patients treated with abciximab and low-dose, weight-adjusted heparin than in patients receiving placebo and standard-dose heparin (9.0% versus 13.7%;
P
=.001). Although adverse clinical outcomes including target-vessel revascularization and bleeding events were more frequent in patients requiring unplanned coronary stent deployment, abciximab therapy reduced adverse outcomes in these patients at 30 days and 6 months to a greater extent than was observed in patients not requiring stent placement. Among stented patients, abciximab therapy did not increase bleeding events.

Conclusions
—Patients requiring unplanned coronary stent deployment have more complex coronary lesion morphology and a more complicated clinical course after coronary intervention. Abciximab therapy both reduces the need for unplanned stent deployment and confers clinical benefit to patients requiring an unplanned stent, without increasing bleeding complications.
Microbubbles Targeted to Intercellular Adhesion Molecule-1 Bind to Activated Coronary Artery Endothelial Cells
Authors: Villanueva Flordeliza S. , Jankowski Ron J. , Klibanov Sasha , Pina Maris L. , Alber Sean M. , Watkins Simon C. , Brandenburger Gary H. , Wagner William R.
Published: June 2012

Background
—Preclinical atherosclerosis is associated with increased endothelial cell (EC) expression of leukocyte adhesion molecules (LAMs), which mediate monocyte adhesion during atherogenesis. Identification of cell-surface LAMs may uniquely allow assessment of endothelial function, but there are no in vivo methods for detecting LAMs. We tested a new microbubble designed to bind to and allow specific ultrasound detection of intercellular adhesion molecule-1 (ICAM-1).

Methods and Results
—A perfluorobutane gas–filled lipid-derived microsphere with monoclonal antibody to ICAM-1 covalently bound to the bubble shell was synthesized. Bubbles with either nonspecific IgG or no protein on the shell were synthesized as controls. Coverslips of cultured human coronary artery ECs were placed in a parallel-plate perfusion chamber and exposed to 1 of the 3 microbubble species, followed by perfusion with culture medium. Experiments were performed with either normal or interleukin-1β–activated ECs overexpressing ICAM-1, and bubble adherence was quantified with epifluorescent videomicroscopy. There was limited adherence of control bubbles to normal or activated ECs, whereas a 40-fold increase in adhesion occurred when anti–ICAM-1–conjugated bubbles were exposed to activated ECs compared with normal ECs (8.1±3.5 versus 0.21±0.09 bubbles per cell, respectively,
P
<0.001). Although diminished, this difference persisted even after perfusion at higher wall shear rates.

Conclusions
—A gas-filled microbubble with anti–ICAM-1 antibody on its shell specifically binds to activated ECs overexpressing ICAM-1. Diagnostic ultrasound in conjunction with targeted contrast agents has the unique potential to characterize cell phenotype in vivo.
Preliminary Animal and Clinical Experiences Using an Electromechanical Endocardial Mapping Procedure to Distinguish Infarcted From Healthy Myocardium
Authors: Kornowski Ran , Hong Mun K. , Gepstein Lior , Goldstein Steven , Ellahham Samer , Ben-Haim Shlomo A. , Leon Martin B.
Published: June 2012

Background
—A catheter-based left ventricular (LV) endocardial mapping procedure using electromagnetic field energy for positioning of the catheter tip was designed to acquire simultaneous measurements of endocardial voltage potentials and myocardial contractility. We investigated such a mapping system to distinguish between infarcted and normal myocardium in an animal infarction model and in patients with coronary artery disease.

Methods and Results
—Measurements of LV endocardial unipolar (UP) and bipolar (BP) voltages and local endocardial shortening were derived from dogs at baseline (n=12), at 24 hours (n=6), and at 3 weeks (n=6) after occlusion of the left anterior descending coronary artery. Also, 12 patients with prior myocardial infarction (MI) and 12 control patients underwent the LV endocardial mapping study for assessment of electromechanical function in infarcted versus healthy myocardial regions. In the canine model, a significant decrease in voltage potentials was noted in the MI zone at 24 hours (UP, 42.8±9.6 to 29.1±12.2 mV,
P
=0.007; BP, 11.6±2.3 to 4.9±1.2 mV,
P
<0.0001) and at 3 weeks (UP, 41.0±8.9 to 13.9±3.9 mV,
P
<0.0001; BP, 11.2±2.8 to 2.4±0.4 mV,
P
<0.0001). No change in voltage was noted in zones remote from MI. In patients with prior MI, the average voltage was 7.2±2.7 mV (UP)/1.4±0.7 mV (BP) in MI regions, 17.8±4.6 mV (UP)/4.5±1.1 mV (BP) in healthy zones remote from MI, and 19.7±4.4 mV (UP)/5.8±1.0 mV (BP) in control patients without prior MI (
P
<0.001 for MI values versus remote zones or control patients). In the canine model and patients, local endocardial shortening was significantly impaired in MI zones compared with controls.

Conclusions
—These preliminary data suggest that infarcted myocardium could be accurately diagnosed and distinguished from healthy myocardium by a reduction in both electrical voltage and mechanical activity. Such a diagnostic electromechanical mapping study might be clinically useful for accurate assessment of myocardial function and viability.
Application of Color Doppler Flow Mapping to Calculate Orifice Area of St Jude Mitral Valve
Authors: Leung Dominic Y. , Wong James , Rodriguez Leonardo , Pu Min , Vandervoort Pieter M. , Thomas James D.
Published: June 2012

Background
—The effective orifice area (EOA) of a prosthetic valve is superior to transvalvular gradients as a measure of valve function, but measurement of mitral prosthesis EOA has not been reliable.

Methods and Results
—In vitro flow across St Jude valves was calculated by hemispheric proximal isovelocity surface area (PISA) and segment-of-spheroid (SOS) methods. For steady and pulsatile conditions, PISA and SOS flows correlated with true flow, but SOS and not PISA underestimated flow. These principles were then used intraoperatively to calculate cardiac output and EOA of newly implanted St Jude mitral valves in 36 patients. Cardiac output by PISA agreed closely with thermodilution (
r
=0.91, Δ=−0.05±0.55 L/min), but SOS underestimated it (
r
=0.82, Δ=−1.33±0.73 L/min). Doppler EOAs correlated with Gorlin equation estimates (
r
=0.75 for PISA and
r
=0.68 for SOS,
P
<0.001) but were smaller than corresponding in vitro EOA estimates.

Conclusions
—Proximal flow convergence methods can calculate forward flow and estimate EOA of St Jude mitral valves, which may improve noninvasive assessment of prosthetic mitral valve obstruction.
Role of Adenosine Receptors in the Paradoxic Bradycardia Response of Rats to Inferior Vena Cava Occlusion During an Infusion of Isoproterenol
Authors: Waxman Menashe B. , Asta John A.
Published: June 2012

Background
—In susceptible humans, vasodepressor reactions are induced by restriction of venous return (upright tilting) and administration of isoproterenol. Because paradoxic bradycardia is a major manifestation of vasodepressor reactions, and allowing for extrapolation between paradoxic bradycardia in rats and vasodepressor reactions, we examined whether adenosine receptors mediate the paradoxic bradycardia reaction.

Methods and Results
—Paradoxic bradycardia was induced in rats by inferior vena cava occlusion during an isoproterenol infusion. We studied whether dipyridamole, an adenosine transport inhibitor, and aminophylline (nonselective) or DPCPX (selective) A
1
antagonists augmented or inhibited paradoxic bradycardia, respectively, during inferior vena cava occlusion. The maximum changes in R-R during 60 seconds of inferior vena cava occlusion were that (1) in control, the rate accelerated (ΔR-R, −9.7±0.8 ms,
P
<0.001); (2) during isoproterenol (0.8 μg · min
−1
), paradoxic bradycardia occurred (ΔR-R, +92.0±32.0 ms,
P
<0.001); (3) during isoproterenol but after dipyridamole, paradoxic bradycardia occurred at a much lower dose of isoproterenol (0.2 μg · min
−1
), and the magnitude was increased at all doses (at 0.8 μg · min
−1
isoproterenol, ΔR-R, +195.6±27.6 ms,
P
<0.001 versus isoproterenol alone, ΔR-R, +92.0±32 ms); (4) during isoproterenol and dipyridamole, atropine did not block paradoxic bradycardia, but cervical vagotomy inhibited paradoxic bradycardia (ΔR-R, +5.6±1.8 ms,
P
<0.001 compared with isoproterenol and dipyridamole alone); and (5) during isoproterenol alone, aminophylline or DPCPX blocked paradoxic bradycardia (ΔR-R, −5.4±1.0 ms, and ΔR-R, −2.6±0.5 ms, respectively, each
P
<0.001 compared with isoproterenol alone).

Conclusions
—The adenosine A
1
receptor mediates the paradoxic bradycardia reflex during inferior vena cava occlusion in the face of isoproterenol via vagal afferents.
Spatiotemporal Periodicity During Atrial Fibrillation in the Isolated Sheep Heart
Authors: Skanes Allan C. , Mandapati Ravi , Berenfeld Omer , Davidenko Jorge M. , Jalife José
Published: June 2012

Background
—The activation patterns that underlie the irregular electrical activity during atrial fibrillation (AF) have traditionally been described as disorganized or random. Recent studies, based predominantly on statistical methods, have provided evidence that AF is spatially organized. The objective of this study was to demonstrate the presence of spatial and temporal periodicity during AF.

Methods and Results
—We used a combination of high-resolution video imaging, ECG recordings, and spectral analysis to identify sequential wave fronts with temporal periodicity and similar spatial patterns of propagation during 20 episodes of AF in 6 Langendorff-perfused sheep hearts. Spectral analysis of AF demonstrated multiple narrow-band peaks with a single dominant peak in all cases (mean, 9.4±2.6 Hz; cycle length, 112±26 ms). Evidence of spatiotemporal periodicity was found in 12 of 20 optical recordings of the right atrium (RA) and in all (n=19) recordings of the left atrium (LA). The cycle length of spatiotemporal periodic waves correlated with the dominant frequency of their respective optical pseudo-ECGs (LA:
R
2
=0.99, slope=0.94 [95% CI, 0.88 to 0.99]; RA:
R
2
=0.97, slope=0.92 [95% CI, 0.80 to 1.03]). The dominant frequency of the LA pseudo-ECG alone correlated with the global bipolar atrial EG (
R
2
=0.76, slope=0.75 [95% CI, 0.52 to 0.99]). In specific examples, sources of periodic activity were seen as rotors in the epicardial sheet or as periodic breakthroughs that most likely represented transmural pectinate muscle reentry. However, in the majority of cases, periodic waves were seen to enter the mapping area from the edge of the field of view.

Conclusions
—Reentry in anatomically or functionally determined circuits forms the basis of spatiotemporal periodic activity during AF. The cycle length of sources in the LA determines the dominant peak in the frequency spectra in this experimental model of AF.
Endothelium-Dependent Relaxation of Collateral Microvessels After Intramuscular Gene Transfer of Vascular Endothelial Growth Factor in a Rat Model of Hindlimb Ischemia
Authors: Takeshita Satoshi , Isshiki Takaaki , Ochiai Masahiko , Eto Koji , Mori Hidezo , Tanaka Etsuro , Umetani Keiji , Sato Tomohide
Published: June 2012

Background
—Recent investigations have demonstrated the ability of vascular endothelial growth factor (VEGF) to augment the development of collateral arteries in vivo. In vitro studies have suggested that the use of VEGF also improves the endothelium-dependent relaxation of collaterals at the microvascular level. The purpose of this study was to determine in vivo the extent to which vasomotor responses of collateral microvessels are altered after VEGF treatment.

Methods and Results
—Ischemia was induced in the hindlimb of 35 rats by excision of the femoral artery. Immediately thereafter, 400 μg of a plasmid encoding VEGF or β-galactosidase (control) was transfected into limb muscles. Four weeks later, synchrotron radiation microangiography, with a spatial resolution of 30 μm, was performed to document the reactivity of collateral microvessels. Administration of the endothelium-dependent vasodilator acetylcholine failed to induce dilation of collateral microvessels in control animals. By contrast, profound dilation of collaterals was observed after acetylcholine in VEGF-treated animals. This response was evident in vessels with a linear appearance but not in those with an undulating appearance. The resulting blood flow in the ischemic limb after administration of acetylcholine in the control animals was only 64.6±17.0% of that of the contralateral normal limb, whereas blood flow was augmented to 106.1±8.4% in VEGF-treated animals (
P
<0.05).

Conclusions
—These results demonstrate in vivo that the use of VEGF restores impaired vasomotor responses in some types of collateral microvessels, which may help to provide a basis for understanding the microcirculation after therapeutic angiogenesis with VEGF.
Synergism Between Platelets and Neutrophils in Provoking Cardiac Dysfunction After Ischemia and Reperfusion
Authors: Lefer Allan M. , Campbell Barry , Scalia Rosario , Lefer David J.
Published: June 2012

Background
—Neutrophils (PMNs) are known to contribute to both cardiac dysfunction and myocardial necrosis after reperfusion of an ischemic heart. Moreover, platelets are also important blood cells that can aggravate myocardial ischemic injury. This study was designed to test the effects of PMNs and platelets separately and together in provoking cardiac dysfunction in isolated perfused rat hearts after ischemia and reperfusion.

Methods and Results
—Control rat hearts not subjected to ischemia were perfused without blood cells for 80 minutes. Additional control rat hearts were perfused with 75×10

6

PMNs, with 100×10

6

platelets, or with 75×10

6

PMNs+100×10

6

platelets over a 5-minute perfusion followed by a 75-minute observation period. No significant reduction in coronary flow, left ventricular developed pressure (LVDP), or the first derivative of LVDP (dP/dt
max
) was observed at the end of the observation period in any nonischemic group. Similarly, global ischemia (I) for 20 minutes followed by 45 minutes of reperfusion (R) produced no sustained effects on the final recovery of any of these parameters in any group of hearts perfused in the absence of blood cells. However, I/R hearts perfused with either PMNs or platelets alone exhibited decreases in these variables of 10% to 12% (
P
<0.05 from control). Furthermore, I/R hearts perfused with both PMNs and platelets exhibited decreases of 50% to 60% in all measurements of cardiac function (
P
<0.001). These dual-cell–perfused I/R hearts also exhibited marked increases in cardiac myeloperoxidase (MPO) activity, indicating a significant PMN infiltration, and enhanced P-selectin expression on the coronary microvascular endothelium. All cardiodynamic effects as well as MPO accumulation and PMN infiltration were markedly attenuated by a sialyl Lewis
X
-oligosaccharide or a recombinant soluble P-selectin ligand, which inhibits selectin-mediated cell adhesion.

Conclusions
—These results provide evidence that platelets and neutrophils act synergistically in provoking postreperfusion cardiac dysfunction and that this may be largely due to cell-to-cell interactions mediated by P-selectin. These findings may help explain the reperfusion injury phenomenon.
Effect of Platelet Activation on Coronary Collateral Blood Flow
Authors: Kinn James W. , Bache Robert J.
Published: June 2012

Background
—The platelet products thromboxane A
2
and serotonin have been shown to cause constriction of well-developed coronary collateral vessels. This study was performed to determine whether intravascular platelet activation produced with platelet activating factor (PAF) can cause a decrease in coronary collateral blood flow.

Methods and Results
—Collateral vessel growth was induced by embolization of a hollow stainless steel plug into the left anterior descending coronary artery (LAD) of adult dogs. The animals were returned to the laboratory 3 to 6 weeks later for surgical instrumentation and measurement of collateral blood flow. Collateral flow was assessed by measuring retrograde blood flow from the cannulated collateral-dependent artery. PAF (10 nmol) was injected into the left main coronary artery to allow products of platelet activation to reach collateral vessels arising from the left coronary system. PAF caused a vasoconstrictor response, which became maximal 3 minutes after injection and resulted in a 40.3±7.4% decrease in retrograde blood flow (32.1±2.1 to 19.6±3.2 mL/min;
P
<0.05). By 15 minutes after the PAF injection, both retrograde blood flow and transcollateral resistance had returned to normal. After pretreatment with the thromboxane A
2
receptor antagonist SQ30,741, the vasoconstrictor response to PAF was abolished and, in contrast to the decrease in retrograde blood flow from PAF alone, a weak vasodilator effect was unmasked.

Conclusions
—PAF caused a decrease in coronary collateral blood flow. This vasoconstrictor response required the participation of thromboxane A
2
.
Transmembrane Potential Properties at the Core of Functional Reentrant Wave Fronts in Isolated Canine Right Atria
Authors: Athill Charles A. , Ikeda Takanori , Kim Young-Hoon , Wu Tsu-Juey , Fishbein Michael C. , Karagueuzian Hrayr S. , Chen Peng-Sheng
Published: June 2012

Background
—The characteristics of transmembrane potential (TMP) at the core of functional reentry in the atrium are not well understood.

Methods and Results
—In protocol 1 (11 dogs), isolated perfused canine right atria were mapped from the endocardial surface while simultaneous TMPs were recorded from the epicardial surface. Episodes of reentry (n=64) were induced in the presence of 1 to 5 μmol/L acetylcholine. Successful simultaneous TMP recordings and activation maps were made in 8 episodes. The TMP was “near the core” if it was within 3.2 mm of the core; otherwise, it was considered to be “in the periphery.” The mean cycle length of reentry was 110±35 ms. The TMP amplitude, duration (90% repolarization), and (dV/dt)
max
near the core (n=106) were 58±22 mV, 46±14 ms, and 33±20 V/s, respectively, significantly less than those in the periphery (n=241): 70±8 mV, 94±32 ms, and 55±10 V/s (
P
<0.001 for all). In 2 episodes of reentry, the cell at the core remained unexcited at its resting membrane potential. In protocol 2 (2 dogs), we performed simultaneous high-density mapping in 4 episodes of reentry and showed synchronous activation patterns on both surfaces with similar locations of the core.

Conclusions
—During meandering functional reentry in isolated canine right atria, (1) TMPs of cells near the core have a reduced amplitude, duration, and (dV/dt)
max
, and (2) cells at the core may remain unexcited at their resting membrane potential. These findings are compatible with the spiral wave concept of functional reentry in the atrium.
Development of Endothelium-Dependent Relaxation in Canine Coronary Collateral Arteries
Authors: Rapps Julie A. , Myers Paul R. , Zhong Qiao , Parker Janet L.
Published: June 2012

Background
—Little information exists regarding development of vasomotor control mechanisms during coronary collateral artery maturation. Therefore, we studied endothelium-dependent relaxation of canine collateral arteries isolated 2, 4, and 9 months after placement of an ameroid occluder around the proximal left circumflex coronary artery.

Results
—Collateral arteries isolated after 2 months exhibited markedly reduced endothelium-dependent relaxation in response to acetylcholine (ACh; 10
−10
to 10
−4
mol/L) and bradykinin (BK; 10
−11
to 10
−6
mol/L) compared with relaxation of noncollateral coronary arteries (
P
<0.01). In contrast, endothelium-independent relaxation of collateral arteries to nitroprusside was only slightly reduced compared with relaxation of noncollateral arteries (
P
<0.05). Endothelium-dependent relaxation of collateral arteries isolated after 4 and 9 months was increased significantly, to the extent that relaxation to ACh and BK was not significantly different between collateral and noncollateral arteries at these periods. Inhibition of nitric oxide synthesis with
N
Τ
-nitro-
l
-arginine methyl ester (L-NAME; 100 μmol/L) markedly inhibited ACh-induced relaxation in all noncollateral arteries and in collateral arteries isolated after 9 months. However, neither L-NAME nor indomethacin (5 μmol/L) alone inhibited ACh-mediated relaxation of collateral arteries isolated after 4 months. ACh-induced relaxation of these collateral arteries was only inhibited when arteries were preconstricted with 30 mmol/L K
+
and pretreated with L-NAME and indomethacin (ie, when synthesis/effects of nitric oxide, prostaglandins, and endothelium-derived hyperpolarizing factor were inhibited).

Conclusions
—Development of endothelium-dependent relaxation in canine coronary collateral arteries is not complete after 2 months. After 4 months, endothelium-dependent relaxation of collateral arteries is similar to relaxation of noncollateral arteries, but the relaxation exhibits decreased dependence on synthesis of nitric oxide and increased involvement of prostaglandins and endothelium-derived hyperpolarizing factor(s). After 9 months of development, collateral arteries exhibit normal nitric oxide–dependent relaxation, similar to noncollateral arteries.
Comparative Study of Fluoroscopy and Intracardiac Echocardiographic Guidance for the Creation of Linear Atrial Lesions
Authors: Epstein Laurence M. , Mitchell Mark A. , Smith Timothy W. , Haines David E.
Published: June 2012

Background
—Recently, attempts have been made to cure atrial fibrillation by creating multiple linear atrial lesions with radiofrequency energy. Intracardiac echocardiography (ICE) offers imaging of endocardial anatomy and the ablation electrode–tissue interface not available with standard fluoroscopy. This study sought to prospectively compare fluoroscopic with ICE guidance for the creation of linear atrial lesions in a canine model.

Methods and Results
—The creation of 3 linear atrial lesions was attempted in each of 10 dogs, half guided by fluoroscopy alone and half by ICE. Coil-tissue contact was prospectively graded. After ablation, animals were euthanized, and the location and continuity of lesions were evaluated. ICE guidance led to a higher percentage of successful applications (
P
=0.02) and mean achieved temperature (
P
=0.004). The contact scores of excellent, fair, and poor correlated well with successful energy delivery, mean temperature, and efficiency of heating (
P
<0.0001). In 25% of the blinded energy deliveries, the location, as determined by the ablation operator, differed from that of ICE. Pathological evaluation revealed improved lesion formation in the ICE-guided compared with the ICE-blinded group. Lesions were found outside the target areas in the ICE-blinded but not the ICE-guided group.

Conclusions
—Compared with fluoroscopy, ICE guidance improved targeting, energy delivery, and lesion formation in this canine model. This study suggests that ICE guidance improves lesion formation and prevents energy delivery to potentially dangerous sites.
Comparison Between Left Ventricular Electromechanical Mapping and Radionuclide Perfusion Imaging for Detection of Myocardial Viability
Authors: Kornowski Ran , Hong Mun K. , Leon Martin B.
Published: June 2012

Background
—A novel 3-dimensional left ventricular (LV) mapping system uses low-intensity magnetic field energy to determine the location of sensor-tipped electrode catheters within the LV. Using this system, we sought to distinguish between infarcted, ischemic, and normal myocardium by comparing LV electromechanical mapping data with myocardial perfusion imaging studies.

Methods and Results
—Unipolar voltage potentials and local endocardial shortening (LS) were measured in 18 patients (mean age, 58±12 years) with symptomatic chronic angina having reversible and/or fixed myocardial perfusion defects on single photon emission computed tomography imaging studies using
201
Tl at rest and
99m
Tc-sestamibi after adenosine stress. Overall, a significant difference in voltage potentials and LS values was found between groups (
P
<0.001 for each comparison by ANOVA). The average voltage potentials (14.0±2.0 mV) and LS values (12.5±2.8%) were highest when measured in myocardial segments (n=56) with normal perfusion and lowest (7.5±3.4 mV and 3.4±3.4%) when measured in myocardial segments with fixed perfusion defects (n=20) (
P
<0.0001). Myocardial segments with reversible perfusion defects (n=66) had intermediate voltage amplitudes (12.0±2.8 mV,
P
=0.048 versus normal and
P
=0.005 versus fixed segments) and LS values (10.3±3.7%,
P
=0.067 versus normal and
P
=0.001 versus fixed segments).

Conclusions
—In patients with myocardial ischemia, LV mapping, compared with myocardial perfusion imaging, shows (1) mild reduction of endocardial voltage potentials and LS in segments with reversible perfusion defects and (2) profound electromechanical impairment in segments with fixed perfusion defects. Thus, such an LV mapping procedure may allow the detection on-line of myocardial viability in the catheterization laboratory.
Vessel Size and Long-Term Outcome After Coronary Stent Placement
Authors: Elezi Shpend , Kastrati Adnan , Neumann Franz-Josef , Hadamitzky Martin , Dirschinger Josef , Schömig Albert
Published: June 2012

Background
—The role of coronary stenting in the treatment of patients with small vessels is not well defined. The purpose of this study was to investigate the influence of vessel size on long-term clinical and angiographic outcome after coronary stent placement.

Methods and Results
—The study comprised 2602 patients with successful stent implantation for symptomatic coronary artery disease. Patients were subdivided into 3 equally sized groups (tertiles) according to vessel size, with respective ranges of <2.8, 2.8 to 3.2, and >3.2 mm. Event-free survival at 1 year was 69.5% in the group with smaller vessels, 77.5% in the second group, and 81% in the group with larger vessels (
P
<0.001). Late lumen loss was similar between the 3 groups (1.12±0.73, 1.12±0.79, and 1.09±0.88 mm, respectively). Angiographic restenosis rate was significantly higher in the small-vessel group (38.6%, 28.4%, and 20.4% in groups 1, 2, and 3, respectively;
P
<0.001). The analysis identified subgroups with different risk for restenosis even among patients with small vessels. Within this group, the restenosis rate may be as low as 29.6% in patients without additional risk factors and as high as 53.5% in patients with diabetes and complex lesions.

Conclusions
—Patients with small vessels present a higher risk for an adverse outcome after coronary stent placement because of a higher incidence of restenosis. However, the unusually high risk for restenosis is confined to those patients with small vessels who have concomitant risk factors such as diabetes and complex lesions.
In Vivo Gene Transfer of Nitric Oxide Synthase Enhances Vasomotor Function in Carotid Arteries From Normal and Cholesterol-Fed Rabbits
Authors: Channon Keith M. , Qian HuSheng , Neplioueva Valentina , Blazing Michael A. , Olmez Ercument , Shetty Geetha A. , Youngblood Scot A. , Pawloski John , McMahon Timothy , Stamler Jonathan S. , George Samuel E.
Published: June 2012

Background
—The vascular endothelium is anatomically intact but functionally abnormal in preatherosclerotic states, and an early deficit in the bioavailability of nitric oxide (NO) or related molecules has been described in both humans and animal models. We hypothesized that the targeted gene transfer of NO synthase (NOS) isoforms might ameliorate or reverse the deficit.

Methods and Results
—We constructed a recombinant adenovirus, Ad.nNOS, that expresses the neuronal isoform of NOS (nNOS) and used it for in vivo endovascular gene transfer to carotid arteries (CA) from normal and cholesterol-fed rabbits. Vessels were harvested 3 days after gene transfer. In CA from normal rabbits, Ad.nNOS generated high levels of functional nNOS protein predominantly in endothelial cells and increased vascular NOS activity by 3.4-fold relative to sham-infected control CA. Ad.nNOS gene transfer also significantly enhanced endothelium-dependent vascular relaxation to acetylcholine; at 3 μmol/L acetylcholine, Ad.nNOS-treated arteries showed an 86±4% reduction in precontracted tension, whereas control CA showed a 47±6% reduction in tension. Contraction in response to phenylephrine and relaxation in response to nitroprusside were unaffected in both control and Ad.nNOS-treated CA. To determine the effect of Ad.nNOS in atherosclerotic arteries, 10 male New Zealand White rabbits maintained on a 1% cholesterol diet for 10 to 12 weeks underwent gene transfer according to the same protocol used in normal rabbits. Ad.nNOS-treated arteries showed a 2-fold increase in NADPH-diaphorase staining intensity relative to sham-infected and Ad.βGal-treated arteries. The CA from cholesterol-fed rabbits showed impaired acetylcholine-induced relaxation, but this abnormality was almost entirely corrected by Ad.nNOS gene transfer.

Conclusions
—In vivo adenovirus-mediated endovascular delivery of nNOS markedly enhances vascular NOS activity and can favorably influence endothelial physiology in the intact and atherosclerotic vessel wall.
Electromechanical Characterization of Chronic Myocardial Infarction in the Canine Coronary Occlusion Model
Authors: Gepstein Lior , Goldin Alexander , Lessick Jonathan , Hayam Gal , Shpun Shlomo , Schwartz Yitzhak , Hakim Guil , Shofty Rona , Turgeman Aharon , Kirshenbaum Dina , Ben-Haim Shlomo A.
Published: June 2012

Background
—Defining the presence, extent, and nature of the dysfunctional myocardial tissue remains a cornerstone in diagnostic cardiology. A nonfluoroscopic, catheter-based mapping technique that can spatially associate endocardial mechanical and electrical data was used to quantify electromechanical changes in the canine chronic infarction model.

Methods and Results
—We mapped the left ventricular (LV) electromechanical regional properties in 11 dogs with chronic infarction (4 weeks after LAD ligation) and 6 controls. By sampling the location of a special catheter throughout the cardiac cycle at multiple endocardial sites and simultaneously recording local electrograms from the catheter tip, the dynamic 3-dimensional electromechanical map of the LV was reconstructed. Average endocardial local shortening (LS, measured at end systole and normalized to end diastole) and intracardiac bipolar electrogram amplitude were quantified at 13 LV regions. Endocardial LS was significantly lower at the infarcted area (1.2±0.9% [mean±SEM],
P
<0.01) compared with the noninfarcted regions (7.2±1.1% to 13.5±1.5%) and with the same area in controls (15.5±1.2%,
P
<0.01). Average bipolar amplitude was also significantly lower at the infarcted zone (2.3±0.2 mV,
P
<0.01) compared with the same region in controls (10.3±1.3 mV) and with the noninfarcted regions (4.0±0.7 to 10.2±1.5 mV,
P
<0.01) in the infarcted group. In addition, the electrical maps could accurately delineate both the location and extent of the infarct, as demonstrated by the high correlation with pathology (Pearson’s correlation coefficient=0.90) and by the precise identification of the infarct border.

Conclusions
—Chronic myocardial infarcted tissue can be characterized and quantified by abnormal regional mechanical and electrical functions. The unique ability to assess the regional ventricular electromechanical properties in various myocardial disease states may become a powerful tool in both clinical and research cardiology.
Cardiac Endothelin-1 Plays a Critical Role in the Functional Deterioration of Left Ventricles During the Transition From Compensatory Hypertrophy to Congestive Heart Failure in Salt-Sensitive Hypertensive Rats
Authors: Iwanaga Yoshitaka , Kihara Yasuki , Hasegawa Koji , Inagaki Koichi , Yoneda Takeshi , Kaburagi Satoshi , Araki Makoto , Sasayama Shigetake
Published: June 2012

Background
—To investigate whether endogenous ET-1 participates in an adaptive process of left ventricular hypertrophy (LVH) or a maladaptive process from LVH to congestive heart failure (CHF), we used a Dahl salt-sensitive (DS) rat model, in which systemic hypertension caused compensated concentric LVH at the age of 11 weeks followed by marked LV dilatation and global hypokinesis at the age of 17 weeks.

Methods and Results
—By specific sandwich enzyme immunoassay, serum and myocardial ET-1 levels at the LVH stage were not elevated compared with age-matched Dahl salt-resistant (DR) rats, despite the marked increase of LV/body weight ratio (LV/BW). However, at the CHF stage, serum and LV ET-1 levels increased by 3.8-fold and 5.4-fold, respectively. LV ET-1 contents had close relationships with the fractional shortening (
r
=0.763) and the systolic wall stress (
r
=0.858) measured by in vivo transthoracic echocardiography. Immunohistochemistry demonstrated that the remarkably increased ET-1 in LV is located mainly in cardiomyocytes. By competitive reverse transcriptase–polymerase chain reaction, LV prepro-ET-1 mRNA levels increased by 4.1-fold in CHF rats. We randomized 11-week-old LVH rats to chronic treatment with the endothelin receptor antagonist bosentan (Bos, 100 mg · kg
−1
· d
−1
, n=14), the α
1
-receptor antagonist doxazosin (Dox, 1 mg · kg
−1
· d
−1
, n=12), or vehicle (Cont, n=14). Bos treatment did not alter the LV geometry and function at 15 weeks; however, it attenuated the decrease of LV fractional shortening by 51% (
P
<0.01) without reducing the LV/BW at 17 weeks. Conversely, Dox, which decreased the blood pressure to the same extent as Bos, did not affect the progression of LV dysfunction. Bos (93%;
P
<0.0001 versus Cont) but not Dox (42%;
P
=0.8465 versus Cont) ameliorated the survival rate at 17 weeks (Cont; 36%).

Conclusions
—The accelerated myocardial synthesis of ET-1 contributes directly to LV contractile dysfunction during the transition from LVH to CHF. Unelevated levels of LV ET-1 at the established LVH stage and lack of effects on LV mass by chronic bosentan treatment suggest that myocardial growth is mediated through alternative pathways. These studies indicate that chronic ET antagonism may provide an additional strategy for heart failure therapy in humans.