bluuebunny/crossref_metadata_2025 huggingface dataset:
Essential Role of Inducible Nitric Oxide Synthase in Monophosphoryl Lipid A–Induced Late Cardioprotection
Authors: Xi Lei , Jarrett Novlet C. , Hess Michael L. , Kukreja Rakesh C.
Published: June 2012

Background
—Monophosphoryl lipid A (MLA), a nontoxic analogue of endotoxin, is a pharmacological agent that is known to have anti-ischemic effects. Mechanisms involved with the cardioprotection are still unclear. A role for inducible nitric oxide synthase (iNOS) was recently proposed. We tested this hypothesis using
S
-methylisothiourea (SMT), one of the specific pharmacological inhibitors of iNOS, as well as iNOS gene knockout mice.

Methods and Results
—Adult male ICR or B6,129 mice were pretreated with either MLA 35 or 350 μg/kg IP (MLA35 or MLA350) or vehicle 24 hours before global ischemia/reperfusion, which was carried out in a Langendorff isolated perfused heart model (n=8 to 9 per group). Another group of MLA350 mice received SMT 3 mg/kg IP 30 minutes before heart perfusion. Ventricular contractile function and heart rate were not different between the groups during the preischemia and reperfusion periods (
P
>0.05). Preischemic basal coronary flow was significantly increased in all MLA350 but not MLA35 mice. Myocardial infarct size was reduced significantly, from 26.9±2.9% of risk area in vehicle-treated mice to 13.5±2.4% in the MLA350 group (mean±SEM,
P
<0.05). This reduction in infarct size was accompanied by augmented nitrite/nitrate accumulation, from 0.23±0.05 nmol/mg protein in the vehicle group to 0.97±0.27 nmol/mg protein in MLA350 mice (
P
<0.01). Infarct size increased significantly, to 22.2±2.8% after treatment with SMT in the MLA350 group. Furthermore, MLA350 failed to reduce infarct size in iNOS knockout mice (25.5±3.6%).

Conclusions
—These results demonstrate a direct association of infarct size reduction with increased NO production with MLA350. An obligatory role for iNOS in mediating the cardioprotective effect induced by MLA was confirmed with the pharmacological inhibition and gene knockout mice.
Immunolocalization of β
2
-Glycoprotein I (Apolipoprotein H) to Human Atherosclerotic Plaques
Authors: George Jacob , Harats Dror , Gilburd Boris , Afek Arnon , Levy Yair , Schneiderman Jacob , Barshack Iris , Kopolovic Juri , Shoenfeld Yehuda
Published: June 2012

Background
—β
2
-Glycoprotein I (β2GPI) is a major antigenic target of antiphospholipid antibodies, which possesses natural anticoagulant properties. The aim of the present study was to determine its presence and localization within human atherosclerotic plaques and to study its association with endothelial cells and monocyte macrophages in vitro.

Methods and Results
—Human atherosclerotic lesions were obtained after carotid endarterectomies and studied immunohistochemically with anti-β2GPI as well as antibodies to CD4/CD8, macrophages, and adhesion molecules. In vitro, human umbilical vein endothelial cells (HUVECs) and U937 (myelomonocytic cell line) cells were investigated for their ability to associate with radiolabeled β2GPI. We found β2GPI to be abundantly expressed within the subendothelial regions and intimal-medial borders of human atherosclerotic plaques and to colocalize with CD4-positive lymphocytes. This observation was confirmed by Western blot applied on homogenates of atherosclerotic lesions with anti-β2GPI antibodies. Both HUVECs and U937 cells bound labeled β2GPI, and the process was inhibited by oxidized LDL and not by native LDL.

Conclusions
—The abundant presence of human β2GPI within the lesions, its association with endothelial cells and macrophages, and its colocalization with CD4-positive lymphocytes suggests that it may serve as a target for an immune-mediated reaction that can influence lesion progression.
Quantifying GPIIb/IIIa Receptor Binding Using 2 Monoclonal Antibodies
Authors: Quinn Martin , Deering Adele , Stewart Maura , Cox Dermot , Foley Brendan , Fitzgerald Desmond
Published: June 2012

Background
—Dosing of glycoprotein (GP) IIb/IIIa receptor antagonists is frequently based on the inhibition of platelet aggregation, which may be influenced by the agonist used or concurrent medications. Here we describe a monoclonal antibody-based technique to quantify total and ligand-occupied GPIIb/IIIa receptors.

Methods and Results
—In vitro binding of monoclonal antibodies, LYP18 (Mab1) and 4F8 (Mab2), to the GPIIb/IIIa complex, was characterized using purified receptor and to platelets by flow cytometry. Patients undergoing coronary angioplasty received a single 20 mg dose of the oral GPIIb/IIIa antagonist, xemilofiban, or matching placebo, and antibody binding was compared with inhibition of platelet aggregation. Mab1 and Mab2 were bound to purified GPIIb/IIIa and to unoccupied, inactivated receptor on platelets. Mab2 identified the β3 subunit, whereas Mab1 was complex-specific. Neither antibody interfered with the other’s binding, suggesting that they identified distinct sites. Mab1 identified 53 300±5423 GPIIb/IIIa sites per platelet, whereas Mab2 identified 50 120±5066 sites per platelet. Mab1 binding was inhibited by abciximab in a dose dependent manner (IC
50
, 0.85±0.1 μg/mL), whereas Mab2 binding was unaffected. In contrast, the 2 small molecular weight antagonists, SC-57101A (IC
50
, 0.22±0.06 μmol/L) and eptifibatide (IC
50
, 0.35±0.14 μmol/L) inhibited Mab2 but not Mab1 binding. In patients treated with xemilofiban, Mab1 binding was unaltered but Mab2 binding decreased from 37 930±2061 sites per platelet at baseline to 8318±870 sites per platelet 6 hours after dosing (
P
<0.0001). Platelet aggregation to adenosine diphosphate (20 μmol/L) fell to 3±3% of baseline in line with the inhibition of Mab2 binding (correlation coefficient 0.8,
P
<0.0001).

Conclusions
—Mab1 and Mab2 bind to GPIIb/IIIa and are differentially displaced by abciximab and small molecular weight antagonists. These antibodies may be used to monitor receptor number and occupancy during administration of a GPIIb/IIIa antagonist.
Heritability of Heart Rate Variability
Authors: Singh Jagmeet P. , Larson Martin G. , O’Donnell Christopher J. , Tsuji Hisako , Evans Jane C. , Levy Daniel
Published: June 2012

Background
—There is evolving evidence that heart rate (HR) is genetically determined. Heart rate variability (HRV) measured by power spectral analysis provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HR and HRV only partially explain their variability in the population. The purpose of this study was to assess the heritability of HR and HRV and estimate the contribution of genetic factors to their variance.

Methods and Results
—Subjects who underwent ambulatory recordings at a routine examination were eligible; subjects with congestive heart failure, coronary artery disease, diabetes mellitus, and those taking cardioactive medications were excluded. We analyzed high-frequency power, low-frequency power, very low-frequency power, total power, low-frequency/high-frequency ratio, and the standard deviation of normal R-R intervals from 2-hour continuous ECG recordings. Heritability analysis was done by studying correlations between siblings (n=682, in 291 sibships, 517 pairs) and between spouse pairs (n=206 pairs) after adjusting for important covariates. Results from separate models were combined to estimate the components of variance attributable to measured covariates, additive genetic effects (heritability), and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21 to 0.26) compared with spouses (0.01 to 0.19). The measured covariates in general accounted for 13% to 40% of the total phenotypic variance, whereas genetic factors accounted for 13% to 23% of the variation among HR and HRV measures.

Conclusions
—Heritable factors may explain a substantial proportion of the variance in HR and HRV. These results highlight the contribution of genetic versus environmental factors to autonomic nervous system activity.
Entrainment/Mapping Criteria for the Prediction of Termination of Ventricular Tachycardia by Single Radiofrequency Lesion in Patients With Coronary Artery Disease
Authors: El-Shalakany Ashraf , Hadjis Tomy , Papageorgiou Panos , Monahan Kevin , Epstein Laurence , Josephson Mark E.
Published: June 2012

Background
−A variety of mapping criteria have been proposed to localize critical sites at which radiofrequency (RF) can predictably terminate reentrant ventricular tachycardia (VT) caused by coronary artery disease. The purpose of this study was to determine the accuracy of using a combination of 3 mapping criteria in predicting termination of VT by a single RF lesion.

Methods and Results
−Fifteen consecutive patients with coronary artery disease and recurrent sustained VT underwent an attempted RF ablation of 20 monomorphic VTs. Successful termination of VT by a single RF lesion was predicted if all the following mapping criteria were met: (1) an exact QRS match in the 12-lead ECG during entrainment; (2) a return cycle length ≤10 ms of the VT cycle length; (3) presystolic potentials (<70% of VT cycle length) with an activation time to the QRS within 10 ms of the stimulus to QRS. Inability to meet these 3 criteria was considered to predict failure of VT termination by RF energy at that site. RF ablation was applied to 44 left ventricular sites in 20 VTs at which at least 1 of the mapping criteria was met. VT was terminated with a single RF lesion in 19 of 19 sites meeting all criteria; RF failed to terminate VT at 24 of 25 sites at which all 3 criteria were not met (
P
<0.0005).

Conclusions
−To maximize success and minimize the number of RF lesions in patients with infarct-related VT, all the above 3 mapping criteria should be met before the application of RF energy.
Hemodynamic Changes Induced by Liposomes and Liposome-Encapsulated Hemoglobin in Pigs
Authors: Szebeni Janos , Fontana John L. , Wassef Nabila M. , Mongan Paul D. , Morse David S. , Dobbins David E. , Stahl Gregory L. , Bünger Rolf , Alving Carl R.
Published: June 2012

Background
—Intravenous administration of some liposomal drugs can trigger immediate hypersensitivity reactions that include symptoms of cardiopulmonary distress. The mechanism underlying the cardiovascular changes has not been clarified.

Methods and Results
—Anesthetized pigs (n=18) were injected intravenously with 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynamic, hematologic, and laboratory changes were recorded. The significant (
P
<0.01) alterations included 79±9% (mean±SEM) rise in pulmonary arterial pressure, 30±7% decline in cardiac output, 11±2% increase in heart rate, 236±54% increase in pulmonary vascular resistance, 71±27% increase in systemic vascular resistance, and up to a 100-fold increase in plasma thromboxane B
2
. These changes peaked between 1 and 5 minutes after injection, subsided within 10 to 20 minutes, were lipid dose–dependent (ED
50
=4.5±1.4 mg), and were quantitatively reproducible in the same animal several times over 7 hours. The liposome-induced rises of pulmonary arterial pressure showed close quantitative and temporal correlation with elevations of plasma thromboxane B
2
and were inhibited by an anti-C5a monoclonal antibody (GS1), by sCR1, or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound IgG and IgM natural antibodies. Zymosan- and hemoglobin-containing liposomes and empty liposomes caused essentially identical pulmonary changes.

Conclusions
—The intense, nontachyphylactic, highly reproducible, complement-mediated pulmonary hypertensive effect of minute amounts of intravenous liposomes in pigs represents a unique, unexplored phenomenon in circulation physiology. The model provides highly sensitive detection and study of cardiopulmonary side effects of liposomal drugs and many other pharmaceutical products due to “complement activation–related pseudoallergy” (CARPA).
Androgen Exposure Increases Human Monocyte Adhesion to Vascular Endothelium and Endothelial Cell Expression of Vascular Cell Adhesion Molecule-1
Authors: McCrohon Jane A. , Jessup Wendy , Handelsman David J. , Celermajer David S.
Published: June 2012

Background
—Male sex is an independent risk factor for coronary artery disease. Owing to the importance of monocyte adhesion to endothelial cells in the development of atherosclerosis, we hypothesized that androgens might promote this process. We therefore studied the effects of the nonaromatizable androgen dihydrotestosterone (DHT) on human monocyte adhesion to human endothelial cells and on endothelial cell–surface expression of adhesion molecules.

Methods and Results
—Human umbilical vein endothelial cells (HUVECs) were grown to confluence in media supplemented with postmenopausal female serum, then exposed for 48 hours to either DHT (40 and 400 nmol/L), with or without the androgen receptor blocker hydroxyflutamide (HF) (4 μmol/L); HF alone; or vehicle control (ethanol 0.1%). Human monocytes obtained by elutriation were incubated for 1 hour with the HUVECs at 37°C, and adhesion was measured by light microscopy. Compared with vehicle control, monocyte adhesion was increased in the androgen-treated HUVECs in a dose-dependent manner (116±6% and 128±3% for DHT 40 and 400 nmol/L respectively;
P
<0.001). HF blocked this increase (
P
≥0.3 compared with control). Surface expression of endothelial cell adhesion molecules was measured by ELISA and revealed an increased expression of vascular cell adhesion molecule-1 (VCAM-1) in the DHT-treated HUVECs (125±5% versus 100±4% in controls;
P
=0.002), an effect also antagonized by HF (
P
≥0.3 compared with controls). Furthermore, the DHT-related increase in adhesion was completely blocked by coincubation with anti–VCAM-1 antibody. Comparable results were obtained in arterial endothelial cells and in endothelium stimulated with the cytokine tumor necrosis factor-α.

Conclusions
—Androgen exposure is associated with increased human monocyte adhesion to endothelial cells, a proatherogenic effect mediated at least in part by an increased endothelial cell–surface expression of VCAM-1.
Automatic Border Detection Identifies Subclinical Anthracycline Cardiotoxicity in Children With Malignancy
Authors: Hashimoto Ikuo , Ichida Fukiko , Miura Masayoshi , Okabe Takashi , Kanegane Hirokazu , Uese Kei-ichiro , Hamamichi Yuji , Misaki Takuro , Koizumi Shoichi , Miyawaki Toshio
Published: June 2012

Background
—Anthracycline drugs for cancer therapy often cause functional myocardial impairment even in relatively low doses. We investigated the left ventricular function in asymptomatic anthracycline-treated children by automatic border detection (ABD) to assess its clinical usefulness for unmasking latent anthracycline-induced myocardial damage.

Methods and Results
—Thirty-four children (0.7 to 17.6 years old) during or after anthracycline chemotherapy (26 to 1100 mg/m
2
) for malignancy (Chemo group) were studied, and 40 children (2.8 to 15.6 years old) without cardiac involvement served as normal control subjects (Control group). All patients underwent complete echocardiographic examination, including M-mode, Doppler, and ABD. Conventional echocardiography disclosed no difference between groups with regard to ejection fraction and the ratio of early to late transmitral flow velocity. In marked contrast, an investigation using ABD revealed that the Chemo group appeared to have some anthracycline-induced myocardial damage. In the apical 4-chamber view, peak filling rate in the Chemo group [2.3±0.4 end-diastolic area (EDA)/s] was significantly lower than that in the Control group (3.1±0.5 EDA/s) (
P
<0.0001), and time to peak filling rate in the Chemo group (106±31 ms) was clearly prolonged compared with that in the Control group (74±22 ms) (
P
<0.0001).

Conclusions
—Echocardiographic ABD may be a sensitive and useful noninvasive approach for evaluating subclinical anthracycline cardiotoxicity.
Association of the α-Fibrinogen Thr312Ala Polymorphism With Poststroke Mortality in Subjects With Atrial Fibrillation
Authors: Carter Angela M. , Catto Andrew J. , Grant Peter J.
Published: June 2012

Background
—The α-fibrinogen Thr312Ala polymorphism occurs in close proximity to several sites important for factor XIIIa–dependent cross-linking, which raises the possibility that it affects fibrin clot stability.

Methods and Results
—We determined the association of this polymorphism with ischemic stroke, stroke subtype, and poststroke mortality. There was no significant difference in the genotype distributions of patients with acute ischemic stroke (n=519) and healthy control subjects (n=423), nor was there any association of this polymorphism with stroke subtype. In a Cox regression model, a significant interaction between Thr312Ala and atrial fibrillation was identified in relation to poststroke mortality (
P
=0.002). In subjects in sinus rhythm (n=418), there was no difference according to genotype in the proportion of subjects who survived (≈60% in each group), whereas in subjects with atrial fibrillation (n=101), there was decreased survival in those possessing the A allele (TT=42.1%, TA=18%, AA=0%).

Conclusions
—The Thr312Ala polymorphism may give rise to an increased susceptibility for embolization of intra-atrial clot, and these findings could have important implications for identifying subjects most at risk of developing thromboembolic complications.
Evidence for Increased Collagenolysis by Interstitial Collagenases-1 and -3 in Vulnerable Human Atheromatous Plaques
Authors: Sukhova Galina K. , Schönbeck Uwe , Rabkin Elena , Schoen Frederick J. , Poole A. Robin , Billinghurst R. Clark , Libby Peter
Published: June 2012

Background
—Several recent studies attempted to classify plaques as those prone to cause clinical manifestations (vulnerable, atheromatous plaques) or those less frequently associated with acute thrombotic complication (stable, fibrous plaques). Defining the cellular and molecular mechanisms that underlie these morphological features remains a challenge. Because interstitial forms of collagen determine the biomechanical strength of the atherosclerotic lesion, this study investigated expression of the collagen-degrading matrix metalloproteinase (MMP) interstitial collagenase-3 (MMP-13) and the previously studied MMP-1 in human atheroma and used a novel technique to test the hypothesis that collagenolysis in atheromatous lesions exceeds that in fibrous human atherosclerotic lesions.

Methods and Results
—Human carotid atherosclerotic plaques, similar in size, were separated by conventional morphological characteristics into fibrous (n=10) and atheromatous (n=10) lesions. Immunohistochemical and Western blot analysis demonstrated increased levels of MMP-1 and MMP-13 in atheromatous versus fibrous plaques. In addition, collagenase-cleaved type I collagen, demonstrated by a novel cleavage-specific antibody, colocalized with MMP-1– and MMP-13–positive macrophages. Macrophages, rather than endothelial or smooth muscle cells, expressed MMP-13 and MMP-1 on stimulation in vitro. Furthermore, Western blot analysis demonstrated loss of interstitial collagen type I and increased collagenolysis in atheromatous versus fibrous lesions. Finally, atheromatous plaques contained higher levels of proinflammatory cytokines, activators of MMPs.

Conclusions
—This report demonstrates that atheromatous rather than fibrous plaques might be prone to rupture due to increased collagenolysis associated with macrophages, probably mediated by the interstitial collagenases MMP-1 and MMP-13.
Platelet Microparticles Promote Platelet Interaction With Subendothelial Matrix in a Glycoprotein IIb/IIIa–Dependent Mechanism
Authors: Merten Michael , Pakala Rajbabu , Thiagarajan Perumal , Benedict Claude R.
Published: June 2012

Background
—Platelets, on activation, release vesicular particles called platelet microparticles. Despite their procoagulant activity, their functional role in platelet–vessel wall interactions is not known.

Methods and Results
—We examined the binding of microparticles to vessel wall components in vitro and in vivo. Microparticles bound to fibrinogen-, fibronectin-, and collagen-coated surfaces. Compared with activated platelets, we observed minimal binding of microparticles to vitronectin and von Willebrand factor. The glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors abciximab and eptifibatide (Integrilin) inhibited the binding to fibrinogen and fibronectin but had minimal effect on binding to collagen. Furthermore, monoclonal antibodies to GP Ib or anionic phospholipid-binding proteins (β
2
-glycoprotein I or annexin V) had no effect in these interactions. Microparticles did not bind to monolayers of resting or stimulated human umbilical vein endothelial cells (HUVECs), even in the presence of fibrinogen or von Willebrand factor. However, under similar conditions, microparticles bound to extracellular matrix produced by cultured HUVECs. Abciximab inhibited this interaction by ≈50%. In a rabbit model of arterial endothelial injury, the infusion of
51
Cr-labeled microparticles resulted in a 3- to 5-fold increase of microparticle adhesion to the injured site compared with the uninjured site (
P
<0.05%). Furthermore, activated platelets bound to surface-immobilized microparticles in a GP IIb/IIIa–dependent mechanism. This binding increased in the presence of fibrinogen by ≈30%.

Conclusions
—Platelet microparticles bind to subendothelial matrix in vitro and in vivo and can act as a substrate for further platelet binding. This interaction may play a significant role in platelet adhesion to the site of endothelial injury.
Evidence for Angiotensin-Converting Enzyme– and Chymase-Mediated Angiotensin II Formation in the Interstitial Fluid Space of the Dog Heart In Vivo
Authors: Wei Chih-Chang , Meng Qing C. , Palmer Ronald , Hageman Gilbert R. , Durand Joan , Bradley Wayne E. , Farrell Diane M. , Hankes Gerald H. , Oparil Suzanne , Dell’Italia Louis J.
Published: June 2012

Background
—We have previously demonstrated that angiotensin II (Ang II) levels in the interstitial fluid (ISF) space of the heart are higher than in the blood plasma and do not change after systemic infusion of Ang I. In this study, we assess the enzymatic mechanisms (chymase versus ACE) by which Ang II is generated in the ISF space of the dog heart in vivo.

Methods and Results
—Cardiac microdialysis probes were implanted in the left ventricular (LV) myocardium (3 to 4 probes per dog) of 12 anesthetized open-chest normal dogs. ISF Ang I and II levels were measured at baseline and during ISF infusion of Ang I (15 μmol/L, n=12), Ang I+the ACE inhibitor captopril (cap) (2.5 mmol/L, n=4), Ang I+the chymase inhibitor chymostatin (chy) (1 mmol/L, n=4), and Ang I+cap+chy (n=4). ISF infusion of Ang I increased ISF Ang II levels 100-fold (
P
<0.01), whereas aortic and coronary sinus plasma Ang I and II levels were unaffected and were 100-fold lower than ISF levels. Compared with ISF infusion of Ang I alone, Ang I+cap (n=4) produced a greater reduction in ISF Ang II levels than did Ang I+chy (n=4) (71% versus 43%,
P
<0.01), whereas Ang I+cap+chy produced a 100% decrease in ISF Ang II levels.

Conclusions
—This study demonstrates for the first time a very high capacity for conversion of Ang I to Ang II mediated by both ACE and chymase in the ISF space of the dog heart in vivo.
In Vivo Formation of 8-Iso-Prostaglandin F
2α
and Platelet Activation in Diabetes Mellitus
Authors: Davı̀ Giovanni , Ciabattoni Giovanni , Consoli Agostino , Mezzetti Andrea , Falco Antonio , Santarone Stella , Pennese Elsa , Vitacolonna Ester , Bucciarelli Tonino , Costantini Fabrizio , Capani Fabio , Patrono Carlo
Published: June 2012

Background
—Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F
2
-isoprostane 8-iso-prostaglandin (PG)F
2α
, a bioactive product of arachidonic acid peroxidation, is enhanced in DM and contributes to platelet activation.

Methods and Results
—Urine samples were obtained from 85 diabetic patients and 85 age- and sex-matched healthy subjects for measurement of immunoreactive 8-iso-PGF
2α
and 11-dehydro-thromboxane B
2
(TXM), an in vivo index of platelet activation. Sixty-two had non–insulin-dependent (NID)DM, and 23 had insulin-dependent (ID) DM. Vitamin E supplementation, metabolic control, and cyclooxygenase inhibitors were used to investigate the mechanisms of formation of 8-iso-PGF
2α
in this setting. Urinary 8-iso-PGF
2α
excretion was significantly higher (
P
=0.0001) in NIDDM patients (419±208 pg/mg creatinine; range 160 to 1014) than in age-matched control subjects (208±92; 41 to 433). Urinary 8-iso-PGF
2α
was linearly correlated with blood glucose and urinary TXM. 8-iso-PGF
2α
excretion was also significantly (
P
=0.0001) higher in IDDM patients (400±146; 183 to 702) than in control subjects (197±69; 95 to 353). Vitamin E supplementation (600 mg/d for 14 days) was associated with a statistically significant reduction in both urinary 8-iso-PGF
2α
(by 37%) and TXM (by 43%) in 10 NIDDM patients. Improved metabolic control was associated with a significant (
P
=0.0001) reduction in 8-iso-PGF
2α
and TXM excretion by 32% and 41%, respectively, in 21 NIDDM patients. 8-iso-PGF
2α
was unchanged after 2-week dosing with aspirin and indobufen despite profound suppression of TXM excretion.

Conclusions
—We conclude that DM is associated with increased formation of F
2
-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired glycemic control and persistent platelet activation. These results provide a rationale for dose-finding studies of antioxidant treatment in diabetes.
Doppler Estimation of Left Ventricular Filling Pressures in Patients With Hypertrophic Cardiomyopathy
Authors: Nagueh Sherif F. , Lakkis Nasser M. , Middleton Katherine J. , Spencer William H. , Zoghbi William A. , Quiñones Miguel A.
Published: June 2012

Background
—Conventional Doppler parameters are unreliable for estimating left ventricular (LV) filling pressures in hypertrophic cardiomyopathy (HCM). This study was undertaken to evaluate flow propagation velocity by color M-mode and early diastolic annular velocity (Ea) by tissue Doppler 2 new indices of LV relaxation, combined with mitral E velocity for estimation of filling pressures in HCM.

Methods and Results
—Thirty-five HCM patients (52±15 years) underwent LV catheterization simultaneously with 2-dimensional and Doppler echocardiography. Pulsed Doppler echocardiography of mitral and pulmonary venous flows was obtained along with flow propagation velocity and Ea. LV preA pressure had weak or no relations with mitral, pulmonary venous velocities and atrial volumes. In contrast, preA pressure related strongly to E velocity/flow propagation velocity (
r
=0.67; SEE=4) and E/Ea (
r
=0.76; SEE=3.4). In 17 patients with repeat measurements, preA pressure changes were well detected by measuring E velocity/flow propagation velocity (
r
=0.68;
P
=0.01) or E/Ea (
r
=0.8;
P
<0.001). PreA pressure estimation with these 2 methods was tested prospectively in 17 additional HCM patients with good results (E velocity/flow propagation velocity,
r
=0.76; E/Ea,
r
=0.82).

Conclusions
—LV filling pressures can be estimated with reasonable accuracy in HCM patients by measuring E velocity/flow propagation velocity or E/Ea. These ratios also track changes in filling pressures.
Catheter Ablation of Accessory Pathways, Atrioventricular Nodal Reentrant Tachycardia, and the Atrioventricular Junction
Authors: Calkins Hugh , Yong Patrick , Miller John M. , Olshansky Brian , Carlson Mark , Saul J. Philip , Huang Shoei K. Stephen , Liem L. Bing , Klein Lawrence S. , Moser Suzan A. , Bloch Daniel A. , Gillette Paul , Prystowsky Eric
Published: June 2012

Background
—The purpose of this study was to evaluate the safety and efficacy of a temperature-controlled radiofrequency catheter ablation system.

Methods and Results
—The patient population included 1050 patients who had undergone ablation of atrioventricular nodal reentrant tachycardia (AVNRT), an accessory pathway (AP), or the atrioventricular junction (AVJ). Ablation was successful in 996 patients. The probability of success was highest among patients who had undergone ablation of the AVJ, lowest in patients who had undergone ablation of an AP, and in between for patients who had undergone ablation of AVNRT. A major complication occurred in 32 patients. Four variables predicted ablation success (AVJ, AVNRT, or left free wall AP ablation and an experienced center). Four factors predicted arrhythmia recurrence (right free wall, posteroseptal, septal, and multiple APs). Two variables predicted development of a complication (structural heart disease and the presence of multiple targets), and 3 variables predicted an increased risk of death (heart disease, lower ejection fraction, and AVJ ablation).

Conclusions
—These findings may serve as a guide to clinicians considering therapeutic options in patients who are candidates for ablation.
Lesion Dimensions During Temperature-Controlled Radiofrequency Catheter Ablation of Left Ventricular Porcine Myocardium
Authors: Petersen Helen Høgh , Chen Xu , Pietersen Adrian , Svendsen Jesper Hastrup , Haunsø Stig
Published: June 2012

Background
—It is important to increase lesion size to improve the success rate for radiofrequency ablation of ischemic ventricular tachycardia. This study of radiofrequency ablation, with adjustment of power to approach a preset target temperature, ie, temperature-controlled ablation, explores the effect of catheter-tip length, ablation site, and convective cooling on lesion dimensions.

Methods and Results
—In vitro strips of porcine left ventricular myocardium during different levels of convective cooling and in vivo pig hearts at 2 or 3 left ventricular sites were ablated with 2- to 12-mm-tip catheters. We found increased lesion volume for increased catheter-tip length ≤8 mm in vitro (
P
<0.05) and 6 mm in vivo (
P
<0.0001), but no further increase was found for longer tips. For the 4- to 10-mm catheter tips, we found smaller lesion volume in low-flow areas (apex) than in high-flow areas (free wall and septum) (
P
<0.05). Increasing convective cooling of the catheter tip in vitro increased lesion volume (
P
<0.0005) for the 4- and 8-mm tips but not for the 12-mm tip as the generator reached maximum output. In contrast to power-controlled ablation, we found a negative correlation between tip temperature reached and lesion volume for applications in which maximum generator output was not achieved (
P
<0.0001), whereas delivered power and lesion volume correlated positively (
P
<0.0001).

Conclusions
—Lesion size differs in different left ventricular target sites, which is probably related to convective cooling, as illustrated in vitro. Longer electrode tips increase lesion size for tip lengths ≤6 to 8 mm. For temperature-controlled ablation, the tip temperature achieved is a poor predictor of lesion size.
Glycometabolic State at Admission: Important Risk Marker of Mortality in Conventionally Treated Patients With Diabetes Mellitus and Acute Myocardial Infarction
Authors: Malmberg Klas , Norhammar Anna , Wedel Hans , Rydén Lars
Published: June 2012

Background
—The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study addressed prognostic factors and the effects of concomitant treatment and glycometabolic control in diabetic patients with myocardial infarction (AMI).

Methods and Results
—Of 620 diabetic patients with AMI, 306 were randomly assigned to a ≥24-hour insulin-glucose infusion followed by multidose subcutaneous insulin. Three hundred fourteen patients were randomized as controls, receiving routine antidiabetic therapy. Thrombolysis and β-blockers were administered when possible. Univariate and multivariate statistical analyses were applied to study predictors of long-term mortality. During an average follow-up of 3.4 years (range, 1.6 to 5.6 years), 102 patients (33%) in the intensive insulin group and 138 (44%) in the control group died (
P
=0.011). Old age, previous heart failure, diabetes duration, admission blood glucose, and admission Hb A
Ic
were independent predictors of mortality in the total cohort, whereas previous AMI, hypertension, smoking, or female sex did not add independent predictive value. Metabolic control, mirrored by blood glucose and Hb A
Ic
, improved significantly more in patients on intensive insulin treatment than in the control group. β-Blockers improved survival in control subjects, whereas thrombolysis was most efficient in the intensive insulin group.

Conclusions
—Mortality in diabetic patients with AMI is predicted by age, previous heart failure, and severity of the glycometabolic state at admission but not by conventional risk factors or sex. Intensive insulin treatment reduced long-term mortality despite high admission blood glucose and Hb A
Ic
.
Long-Term Survival and Valve-Related Complications in Young Women With Cardiac Valve Replacements
Authors: North Robyn A. , Sadler Lynn , Stewart Alistair W. , McCowan Lesley M.E. , Kerr Alan R. , White Harvey D.
Published: June 2012

Background
—The type of cardiac valve replacement associated with the lowest health risks for young women who may undergo pregnancies is unknown. We investigated which valve type was associated with greatest patient and valve survival and the effect of pregnancy on valve loss.

Methods and Results
—In this retrospective study, all women 12 to 35 years old who underwent valve replacements between 1972 and 1992 at Greenlane Hospital were identified, and follow-up was available in 93%. The 232 women were followed up for 1499 patient-years. Ten-year survival of women with mechanical (n=178), bioprosthetic (n=73), and homograft (n=72) valves was 70% (95% CI, 59% to 83%), 84% (95% CI, 72% to 99%), and 96% (95% CI, 91% to 100%),
P
=0.002. After adjustment for confounding variables, the relative risk (RR) of death with mechanical compared with bioprosthetic valves was 2.17 (95% CI, 0.78 to 5.88). Thromboembolic events occurred in 45% of women with mechanical valves within 5 years, compared with 13% with bioprosthetic valves,
P
=0.0001. Valve loss at 10 years was higher in bioprosthetic valves [82% (95% CI, 62% to 92%)] than in mechanical [29% (95% CI, 17% to 39%)] or homograft [28% (95% CI, 12% to 41%)] valves,
P
=0.0001. Pregnancy was not associated with increased bioprosthetic (RR, 0.96; 95% CI, 0.68 to 1.35), homograft (RR, 0.65; 95% CI, 0.37 to 1.13), or mechanical (RR, 0.54; 95% CI, 0.27 to 1.08) valve loss.

Conclusions
—Although 10-year valve survival was greater with mechanical than bioprosthetic valves, mechanical valves may be associated with reduced patient survival in young women. Thromboembolic complications, often with long-term sequelae, were common with mechanical valves. Pregnancy did not increase structural deterioration or reduce survival of bioprosthetic valves.
Abciximab Facilitates the Rate and Extent of Thrombolysis
Authors: Antman Elliott M. , Giugliano Robert P. , Gibson C. Michael , McCabe Carolyn H. , Coussement Patrick , Kleiman Neal S. , Vahanian Alec , Adgey A. A. Jennifer , Menown Ian , Rupprecht Hans-Jürgen , Van der Wieken R. , Ducas John , Scherer Joel , Anderson Keaven , Van de Werf Frans , Braunwald Eugene
Published: June 2012

Background
—The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI.

Methods and Results
—Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 μg · kg
−1
· min
−1
) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U · kg
−1
· h
−1
), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U · kg
−1
· h
−1
). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion (
P
<0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U · kg
−1
· h
−1
) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%;
P
=0.0009) and 90 minutes (77% versus 62%;
P
=0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70).

Conclusions
—Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.
Multicenter Clinical Trial to Evaluate the Efficacy of Correction for Photon Attenuation and Scatter in SPECT Myocardial Perfusion Imaging
Authors: Hendel Robert C. , Berman Daniel S. , Cullom S. James , Follansbee William , Heller Gary V. , Kiat Hosen , Groch Mark W. , Mahmarian John J.
Published: June 2012

Background
—Soft tissue attenuation is a prominent cause of single-photon emission computed tomography (SPECT) imaging artifacts, which may result in reduced diagnostic accuracy of myocardial perfusion imaging. A method incorporating simultaneously acquired transmission data permits nonuniform attenuation correction and when incorporating scatter correction and resolution compensation may substantially reduce interpretive errors.

Methods and Results
—A prospective multicenter trial was performed recruiting patients with angiographically documented coronary disease (n=96) and group of subjects with a low likelihood of disease (n=88). The uncorrected and attenuation/scatter corrected images were read independently, without knowledge of the patient’s clinical data. The detection of ≥50% stenosis was similar using uncorrected perfusion data or with attenuation/scatter correction and resolution compensation (visual or visual plus quantitative analysis), 76% versus 75% versus 78%, respectively (
P
=NS). The normalcy rate, however, was significantly improved with this new methodology, using either the corrected images (86% vs 96%;
P
=0.011) or with the corrected data and quantitative analysis (86% vs 97%;
P
=0.007). The receiver operator characteristic curves were also found to be marginally but not significantly higher with attenuation/scatter correction than with tradition SPECT imaging. However, the ability to detect multivessel disease was reduced with attenuation/scatter correction. Regional differences were also noted, with reduced sensitivity but improved specificity for right coronary lesions using attenuation/scatter correction methodology.

Conclusions
—This multicenter trial demonstrates the initial clinical results of a new SPECT perfusion imaging modality incorporating attenuation and scatter correction in conjunction with
99m
Tc sestamibi perfusion imaging. Significant improvements in the normalcy rate were noted without a decline in overall sensitivity but with a reduction in detection of extensive coronary disease.
Dilated Cardiomyopathy Is Associated With Significant Changes in Collagen Type I/III ratio
Authors: Pauschinger Matthias , Knopf Dagmar , Petschauer Simone , Doerner Andrea , Poller Wolfgang , Schwimmbeck Peter L. , Kühl Uwe , Schultheiss Heinz-P.
Published: June 2012

Background
—It is controversial whether myocardial fibrosis in end-stage dilated cardiomyopathy (DCM) is associated with altered collagen type I/type III (Col I/Col III) ratio.

Methods and Results
—Patients with DCM (ejection fraction [EF] <50%, n=12) and with mild global left ventricular dysfunction (EF >50%, n=18) were examined. Col I, Col III, and transforming growth factors-β
1
(TGF-β
1
) and -β
2
(TGF-β
2
) gene expression in endomyocardial biopsies was evaluated by quantitative competitive reverse transcriptase–polymerase chain reaction (qRT-PCR). Collagen content was quantified after picrosirius red and immunohistological staining and by hydroxyproline assay. In patients with EF <50%, there was a pronounced 2- to 6-fold increase of myocardial Col I mRNA abundance (
P
<0.01), with a corresponding 1.6-fold increase at the protein level versus that found in patients with EF >50%. The Col III mRNA abundance showed a 2.0-fold increase (
P
<0.04). There was a relevant shift in the Col I/Col III mRNA ratio for DCM patients (Col I/Col III, 8.2) compared with patients with an EF >50% (Col I/Col III, 6.4). In addition, total collagen content was increased in patients with EF <50% (n=3) (4.3±0.1%) compared with patients with EF >50% (n=8) (2.7±0.9%) (
P
<0.004). The biochemically determined ratio of hydroxyproline/total protein (n=12) was correlated to the Col I mRNA abundance (
P
<0.05,
r
=0.77). TGF-β
1
and TGF-β
2
showed elevated myocardial mRNA abundances (1- to 7-fold and 4- to 5-fold, respectively) in DCM patients.

Conclusions
—Differential increase of Col I and Col III leads to an increased Col I/Col III ratio in DCM myocardium. Because Col I provides substantial tensile strength and stiffness, this may contribute to systolic and in particular diastolic dysfunction in DCM.
Free-Floating Thrombi in the Right Heart
Authors: Chartier Ludovic , Béra Jérôme , Delomez Maxence , Asseman Philippe , Beregi Jean-Paul , Bauchart Jean-Jacques , Warembourg Henri , Théry Claude
Published: June 2012

Background
—Floating right heart thrombi (FRHTS) are a rare phenomenon, encountered almost exclusively in patients with suspected or proven pulmonary embolism and diagnosed by transthoracic echocardiography. Their management remains controversial.

Methods and Results
—We report on a series of 38 consecutive patients encountered over the past 12 years. Thirty-two patients were in NYHA class IV, 20 in cardiogenic shock. Echocardiography usually demonstrated signs of cor pulmonale: right ventricular overload (91.7% of the population), paradoxical interventricular septal motion (75%), and pulmonary hypertension (86.1%). The thrombus was typically wormlike (36 of 38 patients). It extended from the left atrium through a patent foramen ovale in 4 patients. Pulmonary embolism was confirmed in all but 1. Mortality was high (17 of 38 patients) irrespective of the therapeutic option chosen: surgery (8 of 17), thrombolytics (2 of 9), heparin (5 of 8), or interventional percutaneous techniques (2 of 4). The in-hospital mortality rate was significantly linked with the occurrence of cardiac arrest. Conversely, the outcome after discharge was usually good, because 18 of 21 patients were still alive 47.2 months later (range, 1 to 70 months).

Conclusions
—Severe pulmonary embolism was the rule in our series of FRHTS (mortality rate, 44.7%). The choice of therapy had no effect on mortality. Emergency surgery is usually advocated. However, thrombolysis is a faster, readily available treatment and seems promising either as the only treatment or as a bridge to surgery. In patients with contraindications to surgery or lytic therapy, interventional techniques may be proposed.
Acetylsalicylic Acid Reduces Vegetation Bacterial Density, Hematogenous Bacterial Dissemination, and Frequency of Embolic Events in Experimental
Staphylococcus aureus
Endocarditis Through Antiplatelet and Antibacterial Effects
Authors: Kupferwasser Leon Iri , Yeaman Michael R. , Shapiro Shelley M. , Nast Cynthia C. , Sullam Paul M. , Filler Scott G. , Bayer Arnold S.
Published: June 2012

Background
—Platelets are integral to cardiac vegetations that evolve in infectious endocarditis. It has been postulated that the antiplatelet aggregation effect of aspirin (ASA) might diminish vegetation evolution and embolic rates.

Methods and Results
—Rabbits with
Staphylococcus aureus
endocarditis were given either no ASA (controls) or ASA at 4, 8, or 12 mg · kg
−1
· d
−1
IV for 3 days beginning 1 day after infection. Vegetation weights and serial echocardiographic vegetation size, vegetation and kidney bacterial densities, and extent of renal embolization were evaluated. In addition, the effect of ASA on early
S aureus
adherence to sterile vegetations was assessed. In vitro, bacterial adherence to platelets, fibrin matrices, or fibrin-platelet matrices was quantified with either platelets exposed to ASA or
S aureus
preexposed to salicylic acid (SAL). ASA at 8 mg · kg
−1
· d
−1
(but not at 4 or 12 mg · kg
−1
· d
−1
) was associated with substantial decreases in vegetation weight (
P
<0.05), echocardiographic vegetation growth (
P
<0.001), vegetation (
P
<0.05) and renal bacterial densities and renal embolic lesions (
P
<0.05) versus controls. Diminished aggregation resulted when platelets were preexposed to ASA or when
S aureus
was preexposed to SAL (
P
<0.05).
S aureus
adherence to sterile vegetations (
P
<0.05) or to platelets in suspension (
P
<0.05), fibrin matrices (
P
<0.05), or fibrin-platelet matrices (
P
<0.05) was significantly reduced when bacteria were preexposed to SAL.

Conclusions
—ASA reduces several principal indicators of severity and metastatic events in experimental
S aureus
endocarditis. These benefits involve ASA effects on both the platelet and the microbe.
Differential
18
F-2-Deoxyglucose Uptake in Viable Dysfunctional Myocardium With Normal Resting Perfusion
Authors: Fallavollita James A. , Canty John M.
Published: June 2012

Background
—Viable, chronically dysfunctional myocardium can have normal or reduced resting flow. We previously produced hibernating myocardium with reduced resting flow in pigs with a chronic stenosis and hypothesized that hibernation is preceded by chronic stunning with normal resting perfusion.

Methods and Results
—Pigs instrumented with a proximal left anterior descending coronary artery (LAD) stenosis were studied 1 or 2 months later in the closed-chest anesthetized state. Stenosis severity increased from 74±5% at 1 month to 83±6% at 2 months and was accompanied by anteroapical hypokinesis (wall motion score, 2.1±0.1 at 1 month and 1.5±0.3 at 2 months; normal=3). Resting perfusion was similar in normal and dysfunctional regions, but the deposition of
18
F-2-deoxyglucose (FDG) varied. At 1 month, subendocardial FDG deposition by excised tissue counting was similar in each region (0.034±0.006 mL · g
−1
· min
−1
LAD region versus 0.032±0.004 mL · g
−1
· min
−1
in normal regions,
P
=NS). At 2 months, subendocardial FDG deposition was increased (0.084±0.025 mL · g
−1
· min
−1
LAD region versus 0.042±0.017 mL · g
−1
· min
−1
in normal regions,
P
<0.05). Increases in FDG uptake were inversely related to LAD subendocardial flow reserve during adenosine (3.5±0.6 at 1 month versus 1.4±0.2 at 2 months,
P
<0.01).

Conclusions
—These data indicate a progression of physiological adaptations in pigs with viable, chronically dysfunctional myocardium. As coronary flow reserve decreases, fasting FDG uptake increases. Flow at rest remains normal, consistent with “chronic stunning,” and contrasts with reduced flow and increased FDG characteristic of hibernating myocardium in similarly instrumented pigs after 3 months. This temporal progression of adaptations supports the hypothesis of a transition from a physiological phenotype of stunning to hibernation.