bluuebunny/crossref_metadata_2025 huggingface dataset:
Flow Cytometric Monitoring of Glycoprotein IIb/IIIa Blockade and Platelet Function in Patients With Acute Myocardial Infarction Receiving Reteplase, Abciximab, and Ticlopidine
Authors: Peter Karlheinz , Kohler Benedikt , Straub Andreas , Ruef Johannes , Moser Martin , Nordt Thomas , Olschewski Manfred , Ohman Magnus E. , Kübler Wolfgang , Bode Christoph
Published: June 2012

Background
—Improvement of thrombolysis may be achieved by concomitant strong platelet inhibition. To monitor platelet function in patients with myocardial infarction (n=46) who were treated with the fibrinolytic agent reteplase, the glycoprotein (GP) IIb/IIIa blocker abciximab, and the ADP receptor antagonist ticlopidine, we developed a flow cytometric assay.

Methods and Results
—Binding of abciximab to platelets was directly monitored as the percentage of platelets stained by a goat anti-mouse antibody. Blood drawn 10 minutes and 2 hours after the start of therapy with reteplase and abciximab and during the 12-hour infusion of abciximab demonstrated a maximal blockade of GP IIb/IIIa (10 minutes, 86.2±10.3%; 12 hours, 85.8±7.1%). Starting at 24 hours, abciximab binding gradually decreased (24 hours, 74.6±16.2%; 48 hours, 66.8±14.9%; 72 hours, 60.5±16.7%; 96 hours, 49.4±17.8%; 120 hours, 35.8±16.4%; and 144 hours, 29.9±15.3%). Binding of a chicken anti-fibrinogen antibody to platelets, indicating the level of functional blockade of GP IIb/IIIa, was inversely correlated with the binding of abciximab (
r
=−0.72,
P
<0.0001). In blood drawn at 10 minutes, platelet aggregation was maximally inhibited but recovered within 48 hours even if the majority of GP IIb/IIIa receptors were still blocked by abciximab. Reteplase did not influence abciximab binding and did not activate platelets, as measured by P-selectin expression, fibrinogen binding, and platelet aggregation. Platelet inhibition that was achieved during the first 24 hours by abciximab was directly maintained by additional treatment with ticlopidine.

Conclusions
—Flow cytometric monitoring of platelet function allows differentiation of the effects of reteplase, abciximab, and ticlopidine. The combination of abciximab and ticlopidine is an attractive therapeutic strategy that provides a fast and continuous platelet inhibition.
Predicting Outcome of Defibrillation by Spectral Characterization and Nonparametric Classification of Ventricular Fibrillation in Patients With Out-of-Hospital Cardiac Arrest
Authors: Eftestøl Trygve , Sunde Kjetil , Ole Aase Sven , Husøy John Håkon , Steen Petter Andreas
Published: June 2012

Background
—In 156 patients with out-of-hospital cardiac arrest of cardiac cause, we analyzed the ability of 4 spectral features of ventricular fibrillation before a total of 868 shocks to discriminate or not between segments that correspond to return of spontaneous circulation (ROSC).

Methods and Results
—Centroid frequency, peak power frequency, spectral flatness, and energy were studied. A second decorrelated feature set was generated with the coefficients of the principal component analysis transformation of the original feature set. Each feature set was split into training and testing sets for improved reliability in the evaluation of nonparametric classifiers for each possible feature combination. The combination of centroid frequency and peak power frequency achieved a mean±SD sensitivity of 92±2% and specificity of 27±2% in testing. The highest performing classifier corresponded to the combination of the 2 dominant decorrelated spectral features with sensitivity and specificity equal to 92±2% and 42±1% in testing or a positive predictive value of 0.15 and a negative predictive value of 0.98. Using the highest performing classifier, 328 of 781 shocks not leading to ROSC would have been avoided, whereas 7 of 87 shocks leading to ROSC would not have been administered.

Conclusions
—The ECG contained information predictive of shock therapy. This could reduce the delivery of unsuccessful shocks and thereby the duration of unnecessary “hands-off” intervals during cardiopulmonary resuscitation. The low specificity and positive predictive value indicate that other features should be added to improve performance.
Confocal Microscopic Localization of Constitutive and Heat Shock–Induced Proteins HSP70 and HSP27 in the Rat Heart
Authors: Leger James P. , Smith Frank M. , Currie R. William
Published: June 2012

Background
—Heat-shock treatment of rats elevates expression of heat-shock proteins, which play a role in improving the contractile recovery and reducing infarct size in hearts after ischemic injury. However, the location of these proteins in the heart is unknown.

Methods and Results
—Anesthetized rats were heat-shocked by elevation of body temperature to 42°C to 42.5°C for 15 minutes, followed by 24 hours of recovery. Control and heat-shocked hearts were extirpated and perfused briefly with saline followed by 2% paraformaldehyde in PBS. Confocal immunofluorescence microscopy of control hearts revealed that HSP27 was localized in cardiomyocytes in a pattern reminiscent of Z bands and was colocalized with neuronal markers in somata and axons. No obvious change in HSP27 content or distribution occurred after heat shock. Confocal microscopy revealed little or no HSP70 in control hearts. After heat shock, HSP70 was detected neither in cardiomyocytes nor in neuronal elements within the heart, but HSP70 was abundant in small blood vessels found between the ventricular cardiomyocytes.

Conclusions
—Heat shock induces a cell type–specific expression of HSP70 in blood vessels but not myocytes or intrinsic cardiac neurons, suggesting that blood vessels play a primary role in myocardial protection.
Roles of P-Selectin in Inflammation, Neointimal Formation, and Vascular Remodeling in Balloon-Injured Rat Carotid Arteries
Authors: Hayashi Shin-ichiro , Watanabe Noboru , Nakazawa Koh , Suzuki Junichi , Tsushima Kenji , Tamatani Takuya , Sakamoto Shinji , Isobe Mitsuaki
Published: June 2012

Background
—P-selectin plays key roles in mediating inflammation through promoting adherence of leukocytes to activated platelets and endothelium. This process is one of the initial events in atherosclerosis and restenosis after coronary angioplasty.

Methods and Results
—Using a rat balloon-injury model, we examined the role of P-selectin in vascular inflammatory processes. In the acute phase, immunohistochemistry revealed that P-selectin was intensely expressed on both activated platelets covering the denuded segment and endothelial cells of the inflamed adventitial small vessels. Treatment with an anti–P-selectin monoclonal antibody (MAb) for 8 consecutive days significantly inhibited neointimal formation at day 14 (42% inhibition;
P
<0.05), and this effect persisted at day 56 (40% inhibition;
P
<0.01) compared with the control group. Vascular shrinking accompanying adventitial fibrosis was also attenuated at day 56. Inhibition of both neointimal formation and vascular shrinking resulted in the lumen area of the anti–P-selectin treatment group being ≈3 times larger at day 56 than that of the control group. Accumulation of CD45-positive leukocytes in the developing neointima, media, and adventitia at day 8 was significantly inhibited by treatment with the anti–P-selectin MAb. Scanning electron microscopy demonstrated that anti–P-selectin treatment resulted in a less thrombogenic surface of the arterial intima, which featured a pseudoendothelial appearance at day 14 after injury.

Conclusions
—These results suggest that inhibition of P-selectin–mediated leukocyte recruitment prevents the development of neointimal formation, adventitial inflammation, and vascular shrinking and promotes pseudoendothelialization by luminal smooth muscle cells. This treatment thus beneficially affects vascular remodeling after balloon injury in rats.
Secondary Pulmonary Hypertension in Chronic Heart Failure
Authors: Moraes Denzil L. , Colucci Wilson S. , Givertz Michael M.
Published: June 2012

Abstract
—Pulmonary vascular resistance is frequently elevated in patients with chronic left ventricular failure as a result of dysregulation of vascular smooth muscle tone and structural remodeling. The former is reversible over a period of minutes to days by pharmacological vasodilators, whereas the latter is relatively fixed and may resolve only slowly, over months to years. These abnormalities are due, at least in part, to pulmonary vascular endothelial dysfunction that results in impaired nitric oxide availability and increased endothelin expression. In patients with chronic heart failure, the resulting pulmonary hypertension directly affects right ventricular function and may affect exercise capacity, morbidity, and mortality. New treatment strategies, which include the use of agents that increase nitric oxide availability or oppose the actions of endothelin, may improve the structure and function of the pulmonary vasculature in patients with chronic heart failure.
Polyethylene Glycol–Derivatized Cysteine-Substitution Variants of Recombinant Staphylokinase for Single-Bolus Treatment of Acute Myocardial Infarction
Authors: Collen Désiré , Sinnaeve Peter , Demarsin Eddy , Moreau Huberte , De Maeyer Marc , Jespers Laurent , Laroche Yves , Van de Werf Frans
Published: June 2012

Background
—Thrombolytic therapy of acute myocardial infarction (AMI) is evolving toward bolus administration. Derivatization of proteins with polyethylene glycol (PEG) may reduce their clearance.

Methods and Results
—A staphylokinase (SakSTAR) variant with 12 amino acid substitutions to reduce its antigenicity, SakSTAR (K35A, E65Q, K74R, E80A, D82A, T90A, E99D, T101S, E108A, K109A, K130T, K135R), and with Ser in position 3 mutated into Cys (code SY161), was derivatized with maleimide-PEG with
M
r
of 5000 (P5), 10 000 (P10), or 20 000 (P20). The PEGylated variants recognized only one third of the antibodies elicited with wild-type SakSTAR in AMI patients. In experimental animals, plasma clearances were reduced 2.5- to 5-fold with P5, 5- to 20-fold with P10, and 20-fold with P20, and bolus injection induced pulmonary plasma clot lysis at doses inversely related to their clearance. Intravenous bolus injection of 5 mg of the P5, P10, or P20 variants in AMI patients was associated with plasma half-lives (t
1/2α
) of 13, 30, and 120 minutes and clearances of 75, 43, and 8 mL/min, respectively, compared with 3 minutes and 360 mL/min for SakSTAR. Injection of 5 mg P5 variant restored TIMI-3 flow within 60 minutes in 14 of 18 AMI patients (78%, 95% CI 55% to 91%) and of 2.5 mg in 7 of 11 patients (63%, 95% CI 35% to 85%), both in the absence of fibrinogen degradation. The immunogenicity of the variants was significantly (
P
<0.002) reduced.

Conclusions
—The staphylokinase variant SY161-P5, derivatized with one linear polyethylene glycol molecule of
M
r
5000, is a promising fibrin-selective agent for single-bolus coronary thrombolysis.
Multicenter, Randomized, Controlled Trial of 150-J Biphasic Shocks Compared With 200- to 360-J Monophasic Shocks in the Resuscitation of Out-of-Hospital Cardiac Arrest Victims
Authors: Schneider Thomas , Martens Patrick R. , Paschen Hans , Kuisma Markku , Wolcke Benno , Gliner Bradford E. , Russell James K. , Weaver W. Douglas , Bossaert Leo , Chamberlain Douglas
Published: June 2012

Background
—In the present study, we compared an automatic external defibrillator (AED) that delivers 150-J biphasic shocks with traditional high-energy (200- to 360-J) monophasic AEDs.

Methods and Results
—AEDs were prospectively randomized according to defibrillation waveform on a daily basis in 4 emergency medical services systems. Defibrillation efficacy, survival to hospital admission and discharge, return of spontaneous circulation, and neurological status at discharge (cerebral performance category) were compared. Of 338 patients with out-of-hospital cardiac arrest, 115 had a cardiac etiology, presented with ventricular fibrillation, and were shocked with an AED. The time from the emergency call to the first shock was 8.9±3.0 (mean±SD) minutes.

Conclusions
—The 150-J biphasic waveform defibrillated at higher rates, resulting in more patients who achieved a return of spontaneous circulation. Although survival rates to hospital admission and discharge did not differ, discharged patients who had been resuscitated with biphasic shocks were more likely to have good cerebral performance.
Effects of Antihypertensive Therapy on Glucose and Insulin Metabolism and on Left Ventricular Mass
Authors: Kuperstein Rafael , Sasson Zion
Published: June 2012

Background
—Glucose and insulin levels are associated with left ventricular mass (LVM) in insulin-resistant individuals. Antihypertensive drugs have different effects on glucose and insulin metabolism (GIM) and on LVM. To evaluate whether the effects of antihypertensive therapy on LVM are associated with its effects on GIM, we compared the effects of atenolol and perindopril on these parameters in a group of insulin-resistant, obese hypertensives.

Methods and Results
—A total of 21 obese, nondiabetic hypertensives who were aged 55±12 years, had a body mass index of 32.8±5.0 kg/m
2
, were free of coronary or valvular heart disease, and had normal LV function were randomized to treatment with atenolol (n=11) or perindopril (n=10). Echocardiographic LVM corrected for height (LVM/height) and GIM (3-hour intravenous glucose tolerance test) were measured after 4 to 6 weeks of washout and 6 months of treatment. Baseline characteristics were similar in both groups. Atenolol and perindopril effectively reduced blood pressure (from 149±13/98±4 to 127±8/82±6 mm Hg and from 148±9/98±4 to 129±9/82±6 mm Hg, respectively, for the atenolol and perindopril groups;
P
=0.002). Atenolol significantly worsened GIM parameters, fasting glucose levels (5.3±0.9 to 6.0±1.5 mmol/L;
P
=0.003), fasting insulin levels (121±121 to 189±228 pmol/L;
P
=0.03), and most other relevant metabolic measures (
P
<0.05 for all). Perindopril did not affect GIM. Atenolol did not affect LVM/height (119±12 to 120±17 g/m;
P
=0.8), whereas perindopril significantly reduced LVM/height (120±13 to 111±19 g/m;
P
=0.04).

Conclusions
—In obese, hypertensive individuals, adequate and similar blood pressure control was achieved with perindopril and atenolol. However, perindopril but not atenolol was associated with a more favorable GIM profile and led to a significant regression of LVM.
Domperidone Should Not Be Considered a No-Risk Alternative to Cisapride in the Treatment of Gastrointestinal Motility Disorders
Authors: Drolet Benoit , Rousseau Guy , Daleau Pascal , Cardinal René , Turgeon Jacques
Published: June 2012

Background
—Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone, a gastrokinetic and antiemetic agent available worldwide but still under investigation in the United States. Although electrolyte disturbances such as hypokalemia could account for some of these events, we hypothesized that domperidone may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia.

Methods and Results
—Studies were undertaken in 9 isolated guinea pig hearts, which demonstrated reverse use–dependent prolongation of cardiac repolarization by 100 nmol/L domperidone. Action potential duration increased 27% from baseline with domperidone (from 114±3 to 145±2 ms) during pacing at a cycle length of 250 ms, and a 9% increase (from 97±2 to 106±3 ms) was seen with pacing at a cycle length of 150 ms. Experiments in human ether-a-go-go–related gene (HERG)-transfected Chinese hamster ovary cells (n=32) demonstrated a concentration-dependent block of the rapid component (I
Kr
) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone.

Conclusions
—Domperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.
Oxidized LDL Upregulates Angiotensin II Type 1 Receptor Expression in Cultured Human Coronary Artery Endothelial Cells
Authors: Li Dayuan , Saldeen Tom , Romeo Francesco , Mehta Jawahar L.
Published: June 2012

Background
—We demonstrated earlier that angiotensin II (Ang II), by AT
1
receptor activation, upregulates oxidized LDL (ox-LDL) endothelial receptor LOX-1 gene expression and uptake of ox-LDL in human coronary artery endothelial cells (HCAECs). In this study, we investigated the regulation of Ang II receptors (AT1R and AT2R) by ox-LDL and the role of the redox-sensitive transcription factor NF-κB in this process.

Methods and Results
—HCAECs were incubated with ox-LDL for 24 hours. Ox-LDL (10 to 40 μg protein/mL) upregulated AT1R but not AT2R, mRNA, or protein. Ox-LDL degraded IκBα in cytoplasm and activated transcription factor NF-κB (P65) in HCAEC nuclear extract. Treatment of cells with the antioxidant α-tocopherol (10 to 50 μmol/L) attenuated ox-LDL–mediated degradation of IκBα and activation of NF-κB (P65) and inhibited the upregulation of AT1R mRNA and protein. The role of NF-κB signal transduction was further examined by use of an NF-κB inhibitor, caffeic acid phenethyl ester (CAPE). Pretreatment of cells with CAPE inhibited ox-LDL–mediated degradation of IκBα and NF-κB activation and inhibited ox-LDL–induced upregulation of AT1R expression. Incubation of cells with both ox-LDL and Ang II increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone. α-Tocopherol as well as the specific AT1R blocker CV11974 (candesartan) attenuated the cell-injurious effects of ox-LDL.

Conclusions
—These observations suggest an important role of ox-LDL–mediated AT1R upregulation in cell injury. In this process, NF-κB activation seems to play a critical role in signal transduction. These findings provide a basis for the use of antioxidants and AT1R blockers in designing therapy of atherosclerosis.
Single-Beat Estimation of End-Systolic Elastance Using Bilinearly Approximated Time-Varying Elastance Curve
Authors: Shishido Toshiaki , Hayashi Kazuko , Shigemi Kenji , Sato Takayuki , Sugimachi Masaru , Sunagawa Kenji
Published: June 2012

Background
—Although left ventricular end-systolic elastance (E
es
) has often been used as an index of contractility, technical difficulties in measuring volume and in changing loading conditions have made its clinical application somewhat limited. By approximating the time-varying elastance curve by 2 linear functions (isovolumic contraction phase and ejection phase) and estimating the slope ratio of these, we developed a method to estimate E
es
on a single-beat basis from pressure values, systolic time intervals, and stroke volume.

Methods and Results
—In 11 anesthetized dogs, we compared single-beat E
es
with that obtained with caval occlusion. Although the decrease (but not the increase) in contractility (5.3 to 11.4 mm Hg/mL) and the change in loading conditions (3.7 to 34.0 mm Hg/mL) over wide ranges significantly altered the slope ratio, the estimation of E
es
was reasonably accurate (
y
=0.97
x
+0.46,
r
=0.929, SEE=2.1 mm Hg/mL).

Conclusions
—E
es
can be estimated on a single-beat basis from easily obtainable variables by approximating the time-varying elastance curve by a bilinear function.
Calcineurin Inhibitor Attenuates the Development and Induces the Regression of Cardiac Hypertrophy in Rats With Salt-Sensitive Hypertension
Authors: Shimoyama Masaki , Hayashi Doubun , Zou Yunzeng , Takimoto Eiki , Mizukami Miho , Monzen Koshiro , Kudoh Sumiyo , Hiroi Yukio , Yazaki Yoshio , Nagai Ryozo , Komuro Issei
Published: June 2012

Background
—It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.

Methods and Results
—In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.

Conclusions
—These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.
Overexpression of Eotaxin and the CCR3 Receptor in Human Atherosclerosis
Authors: Haley Kathleen J. , Lilly Craig M. , Yang Jeong-Hee , Feng Yajun , Kennedy Scott P. , Turi Thomas G. , Thompson John F. , Sukhova Galina H. , Libby Peter , Lee Richard T.
Published: June 2012

Background
—Unstable atherosclerotic lesions typically have an abundant inflammatory cell infiltrate, including activated T cells, macrophages, and mast cells, which may decrease plaque stability. The pathophysiology of inflammatory cell recruitment and activation in the human atheroma is incompletely described.

Methods and Results
—We hypothesized that differential gene expression with DNA microarray technology would identify new genes that may participate in vascular inflammation. RNA isolated from cultured human aortic smooth muscle cells treated with tumor necrosis factor-α (TNF-α) was examined with a DNA microarray with 8600 genes. This experiment and subsequent Northern analyses demonstrated marked increases in steady-state eotaxin mRNA (>20 fold), a chemokine initially described as a chemotactic factor for eosinophils. Because eosinophils are rarely present in human atherosclerosis, we then studied tissue samples from 7 normal and 14 atherosclerotic arteries. Immunohistochemical analysis demonstrated overexpression of eotaxin protein and its receptor, CCR3, in the human atheroma, with negligible expression in normal vessels. Eotaxin was predominantly located in smooth muscle cells. The CCR3 receptor was localized primarily to macrophage-rich regions as defined by immunopositivity for CD 68; a minority of mast cells also demonstrated immunopositivity for the CCR3 receptor.

Conclusions
—Eotaxin and its receptor, CCR3, are overexpressed in human atherosclerosis, suggesting that eotaxin participates in vascular inflammation. These data demonstrate how genomic differential expression technology can identify novel genes that may participate in the stability of atherosclerotic lesions.
Minimally Invasive Evaluation of Coronary Microvascular Function by Electron Beam Computed Tomography
Authors: Möhlenkamp Stefan , Lerman Lilach O. , Lerman Amir , Behrenbeck Thomas R. , Katušić Zvonimir S. , Sheedy Patrick F. , Ritman Erik L.
Published: June 2012

Background
—We previously demonstrated that in vivo electron-beam computed tomography (EBCT)–based indicator-dilution methods provide an estimate of intramyocardial blood volume (BV) and perfusion (F), which relate as BV=aF+b√F, where a characterizes the recruitable (exchange) and b the nonrecruitable (conduit) component of the myocardial microcirculation. In the present study, we compared BV and F with intracoronary Doppler ultrasound–based coronary blood flow (CBF) as a method for detecting and quantifying differential responses of these microvascular components to vasoactive drugs in normal (control) and hypercholesterolemic (HC) pigs.

Methods and Results
—BV and F values were obtained from contrast-enhanced EBCT studies in 14 HC and 14 control pigs. BV, F, and CBF values were obtained at baseline (intracoronary infusion of saline) and after 5 minutes each of intracoronary infusion of adenosine (100 μg · kg
−
1
· min
−
1
) and nitroglycerin (40 μg/min). BV and CBF reserves in response to adenosine were attenuated in HC pigs compared with controls (90±36% versus 127±42%,
P
<0.03, and 485±182% versus 688±160%,
P
<0.01, respectively). The relationship between BV and F showed consistently lower recruitable BV in HC versus control pigs. Nonrecruitable BV reserve in response to adenosine was attenuated in HC compared with controls (77±20% versus 135±28%,
P
<0.001). Our findings are consistent with HC-induced impairment of intramyocardial resistance vessel function.

Conclusions
—EBCT technology allows minimally invasive evaluation of intramyocardial microcirculatory function and permits assessment of microvascular BV distribution in different functional components. This method may be of value in evaluating the coronary microcirculation in pathophysiological states such as hypercholesterolemia.
Cardioprotective Effect of Prior β-Blocker Therapy in Reducing Creatine Kinase-MB Elevation After Coronary Intervention
Authors: Sharma Samin K. , Kini Annapoorna , Marmur Jonathan D. , Fuster Valentin
Published: June 2012

Background
—Both retrospective studies and prospective randomized trials have shown that β-blockers improve survival and reduce the risk of reinfarction in patients with myocardial infarction. To evaluate whether β-blockers exert similar protective benefits during and after coronary intervention, we studied the incidence of postprocedure creatine kinase (CK)-MB elevation in patients with or without prior β-blocker therapy and its effect on intermediate-term (≈1 year) survival.

Methods and Results
—We prospectively analyzed 1675 consecutive patients undergoing coronary intervention; of these patients, 643 (38.4%) were on β-blocker therapy before the intervention. The incidence of CK-MB elevation after coronary intervention was 13.2% in patients on β-blocker therapy before intervention and 22.1% in patients who were not on β-blockers (
P
<0.001). Patients with prior β-blocker therapy had lower persistent/recurrent postprocedure chest pain and lower preprocedure and postprocedure heart rates and mean blood pressures compared with patients who were not on β-blockers (
P
<0.001). Multiple linear regression analysis revealed prior β-blocker therapy as the sole independent factor for lower CK-MB release after coronary intervention. During intermediate-term follow-up at 15±3 months, patients on β-blocker therapy before intervention had lower mortality rates compared with those not on β-blockers (0.78% versus 1.96%;
P
=0.04), although the benefit was independent of the reduction in CK-MB release.

Conclusions
—Our nonrandomized, prospective analysis suggests that prior β-blocker therapy has a cardioprotective effect in limiting CK-MB release after coronary intervention and that it is associated with a lower mortality at intermediate-term follow-up.
Diastolic Biomechanics in Normal Infants Utilizing MRI Tissue Tagging
Authors: Fogel Mark A. , Weinberg Paul M. , Hubbard Anne , Haselgrove John
Published: June 2012

Background
—Most of what is known about diastolic function in normal infants is derived from flow and pressure measurements. Little is known about regional diastolic strain and wall motion.

Methods and Results
—Magnetic resonance tissue tagging was performed in 11 normal infants to determine regional diastolic strain and wall motion. Tracking diastolic motion of the intersection points and finite strain analysis yielded regional rotation, radial displacement, and
E

1

and
E

2

strains at 3 short-axis levels (significance was defined as
P
<0.05).
E

2

“circumferential lengthening” strains were significantly greater at the lateral wall, regardless of short-axis level, whereas
E

1

“radial thinning” strains were similar in all wall regions at all short-axis levels. In general, no differences were noted in strain dispersion within a wall region or in endocardial/epicardial strain at all short-axis levels. At all short-axis levels, septal radial motion was significantly less than in other wall regions. No significant differences in radial wall motion between short-axis levels were noted. Rotation was significantly greater at the apical short-axis level in all wall regions than in other short-axis levels, and it was clockwise. At the atrioventricular valve, septal and anterior walls rotated slightly clockwise, whereas the lateral and inferior walls rotated counterclockwise.

Conclusions
—Diastolic biomechanics in infants are not homogeneous. The lateral walls are affected most by strain, and the septal walls undergo the least radial wall motion. Apical walls undergo the most rotation. These normal data may help in the understanding of diastolic dysfunction in infants with congenital heart disease.
Clinical and Genetic Heterogeneity of Right Bundle Branch Block and ST-Segment Elevation Syndrome
Authors: Priori Silvia G. , Napolitano Carlo , Gasparini Maurizio , Pappone Carlo , Della Bella Paolo , Brignole Michele , Giordano Umberto , Giovannini Tiziana , Menozzi Carlo , Bloise Raffaella , Crotti Lia , Terreni Liana , Schwartz Peter J.
Published: June 2012

Background
—The ECG pattern of right bundle branch block and ST-segment elevation in leads V
1
to V
3
(Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups.

Methods and Results
—Sixty patients (45 males aged 40±15 years) with the typical ECG pattern were clinically evaluated. Events at follow-up were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (30 symptomatic patients) and for patients without previous history of events (30 asymptomatic patients). Prevalence of mutations of the cardiac sodium channel was 15%, demonstrating genetic heterogeneity. During a mean follow-up of 33±38 months, ventricular fibrillation occurred in 5 (16%) of 30 symptomatic patients and in none of the 30 asymptomatic patients. Programmed electrical stimulation was of limited value in identifying patients at risk (positive predictive value 50%, negative predictive value 46%). Pharmacological challenge with sodium channel blockers was unable to unmask most silent gene carriers (positive predictive value 35%).

Conclusions
—At variance with current views, asymptomatic patients are at lower risk for sudden death. Programmed electrical stimulation identifies only a fraction of individuals at risk, and sodium channel blockade fails to unmask most silent gene carriers. This novel evidence mandates a reappraisal of therapeutic management.
Ischemic Inactivation of G Protein–Coupled Receptor Kinase and Altered Desensitization of Canine Cardiac β-Adrenergic Receptors
Authors: Yu Xichun , Zhang Min , Kyker Kimberly , Patterson Eugene , Benovic Jeffrey L. , Kem David C.
Published: June 2012

Background
—G protein–coupled receptor kinases (GRKs) modulate myocardial β-adrenergic receptor (βAR) signaling. We examined whether GRK activity was altered 6, 24, and 96 hours after left anterior descending coronary artery ligation (LAD CAL) in the dog.

Methods and Results
—GRK activity was measured in arrhythmogenic subepicardial border zone (EBZ) tissue overlying the infarct and from nonischemic remote-site (RS) subepicardial tissue from the same animal. GRK activity in the ischemic EBZ was 15% of RS (
P
=0.03, n=6) 24 hours after CAL and appeared to start as early as 6 hours through 96 hours. GRK activity and immunoblot data demonstrated a marked decrease of GRK2 but not GRK5 at 24 hours. EBZ tissue exhibited high-affinity binding for (−)-isoproterenol (
K
i
of 0.076±0.026 nmol/L [SEM]) at 24 hours, which was not significantly different from control tissue from nonoperated animals (1.2±0.8 nmol/L,
P
>0.05, n=6). A significantly lower
K
i
of 13.8±2.8 nmol/L (
P
<0.001, n=6) was observed for RS taken from the ischemic animals. This was reflected by a 4-fold increase in the EC
50
of isoproterenol-stimulated adenylyl cyclase activity from 18 nmol/L in EBZ tissue to 73 nmol/L in RS (
P
<0.05, n=4).

Conclusions
—There is a selective decrease in GRK2 activity and a loss of the ability of the arrhythmia-prone EBZ tissue to desensitize to β-adrenergic stimulation 24 hours after CAL. This correlates temporally with a second (late) peak in sudden cardiac death previously observed between 6 and 24 hours in dog and rat models of myocardial infarction.
Oxidized Low-Density Lipoprotein Is Associated With Apoptosis of Vascular Smooth Muscle Cells in Human Atherosclerotic Plaques
Authors: Okura Yoshifumi , Brink Marijke , Itabe Hiroyuki , Scheidegger Kathrin J. , Kalangos Afksendiyos , Delafontaine Patrice
Published: June 2012

Background
—Cytotoxic oxidized LDL (oxLDL) has been shown to promote apoptosis in cultured vascular smooth muscle cells (VSMCs). We investigated the localization of oxLDL and its association with apoptosis and the expression of apoptosis-related proteins in early and advanced atherosclerotic lesions.

Methods and Results
—Atherosclerotic plaques (n=23) from patients undergoing aortic, carotid, or femoral arterial surgery were studied. In early lesions, oxLDL was located predominantly in the superficial intima and in the media just beneath the internal elastic lamina. Medial VSMCs staining positive for oxLDL showed expression of BAX, a proapoptotic protein of the BCL-2 family. Apoptosis, as detected by DNA in situ terminal deoxynucleotidyl transferase end-labeling (TUNEL), was not present in these early lesions. In advanced plaques, areas of the intima positive for oxLDL showed lower α-smooth muscle actin immunoreactivity (
P
<0.01) and higher BAX immunoreactivity (
P
<0.05). Furthermore, these areas showed an increased number of apoptotic VSMCs (
P
<0.01). Western blot analysis revealed that oxLDL increases BAX expression in cultured human coronary VSMCs.

Conclusions
—We conclude that in early atherosclerotic lesions, oxLDL-positive VSMCs express BAX, which increases the susceptibility of these cells to undergo apoptosis. This could be important in our understanding of the transition of early lesions into advanced atherosclerotic plaques, which are characterized by regions of cell death. In advanced plaques, oxLDL-positive areas of the intima show higher BAX immunoreactivity and TUNEL-positive VSMCs, and this may contribute to plaque instability and rupture.
Exaggerated Vascular and Renal Pathology in Endothelin-B Receptor–Deficient Rats With Deoxycorticosterone Acetate–Salt Hypertension
Authors: Matsumura Yasuo , Kuro Toshihiko , Kobayashi Yutaka , Konishi Fumiko , Takaoka Masanori , Wessale Jerry L. , Opgenorth Terry J. , Gariepy Cheryl E. , Yanagisawa Masashi
Published: June 2012

Background
—Endothelin (ET)-1 plays an important role in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt–induced hypertension. We evaluated the pathological role of ET
B
receptors in DOCA-salt–induced hypertension, cardiovascular hypertrophy, and renal damage by using the spotting-lethal (
sl
) rat, which carries a naturally occurring deletion in the ET
B
receptor gene.

Methods and Results
—Homozygous (
sl
/
sl
) rats exhibit abnormal development of neural crest–derived epidermal melanocytes and the enteric nervous system, and they do not live beyond 1 month because of intestinal aganglionosis and intestinal obstruction. The dopamine β-hydroxylase (DβH) promoter was used to direct ET
B
transgene expression in
sl
/
sl
rats to support normal enteric nervous system development. DβH-ET
B
sl/sl
rats live into adulthood and are healthy, expressing ET
B
receptors in adrenal glands and other adrenergic neurons. When homozygous (
sl
/
sl
) and wild-type (+/+) rats, all of which were transgenic, were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than did wild-type rats. Chronic treatment with ABT-627, an ET
A
receptor antagonist, completely suppressed DOCA-salt–induced hypertension in both groups. Renal dysfunction and histological damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous rats than in wild-type rats. Renal and vascular injuries were significantly improved by ABT-627. In DOCA-salt–treated homozygous rats, there were notable increases in renal, urinary, and aortic ET-1, all of which were normalized by ABT-627.

Conclusions
—ET
B
-mediated actions are protective in the pathogenesis of DOCA-salt–induced hypertension. Enhanced ET-1 production and ET
A
-mediated actions are responsible for the increased susceptibility to DOCA-salt hypertension and tissue injuries in ET
B
receptor–deficient rats.
Cryothermal Ablation of the Slow Pathway for the Elimination of Atrioventricular Nodal Reentrant Tachycardia
Authors: Skanes Allan C. , Dubuc Marc , Klein George J. , Thibault Bernard , Krahn Andrew D. , Yee Raymond , Roy Denis , Guerra Peter , Talajic Mario
Published: June 2012

Background
—We report the first successful slow pathway ablation using a novel catheter-based cryothermal technology for the elimination of atrioventricular nodal reentrant tachycardia (AVNRT).

Methods and Results
—Eighteen patients with typical AVNRT underwent cryoablation. Reversible loss of slow pathway (SP) conduction during cryothermy (ice mapping) was demonstrated in 11 of 12 patients. Because of time constraints, only 2 sites were ice mapped in 1 patient. Seventeen of 18 patients had successful cryoablation of the SP. One patient had successful ice mapping of the SP, but inability to cool beyond −38°C prevented successful cryoablation. A single radiofrequency lesion at this site eliminated SP conduction. No patient has had recurrent AVNRT over 4.9±1.7 months of follow-up. During cryoablation, accelerated junctional tachycardia was not seen and was therefore not available to guide lesion delivery. Adherence of the catheter tip during cryothermy (cryoadherence) allowed atrial pacing to test for SP conduction. Cryoablation in the anterior septum produced inadvertent transient PR prolongation consistent with loss of fast pathway conduction in 1 patient and transient (6.5 seconds) 2:1 AV block in another. On rewarming, the PR interval returned to normal, and the AV nodal effective refractory period was unchanged in both. Accelerated junctional tachycardia was seen on rewarming in both but not during cryothermy.

Conclusions
—Cryothermal ablation of the SP was achieved in patients with this novel technique. Successful ice mapping of both the SP and fast pathway was demonstrated. The ability to test the functionality of specific ablation sites before production of a permanent lesion may eliminate inadvertent AV block.
Are Patients With Renal Failure Good Candidates for Percutaneous Coronary Revascularization in the New Device Era?
Authors: Rubenstein Mark H. , Harrell Lari C. , Sheynberg Boris V. , Schunkert Heribert , Bazari Hasan , Palacios Igor F.
Published: June 2012

Background
—Patients with end-stage renal disease undergoing conventional balloon angioplasty have reduced procedural success and increased complication rates. This study was designed to determine the immediate and long-term outcomes of patients with varying degrees of renal failure undergoing percutaneous coronary intervention in the current device era.

Methods and Results
—We compared the immediate and long-term outcomes of 362 renal failure patients (creatinine >1.5 mg/dL) with those of 2972 patients with normal renal function who underwent percutaneous coronary intervention between 1994 and 1997. Patients with renal failure were older and had more associated comorbidities. They had reduced procedural success (89.5% versus 92.9%,
P
=0.007) and greater in-hospital combined major event (death, Q-wave myocardial infarction, emergent CABG; 10.8% versus 1.8%;
P
<0.0001) rates. Renal failure was an independent predictor of major adverse cardiac events (MACEs) (OR, 3.41; 95% CI, 1.84 to 6.22;
P
<0.00001). Logistic regression analysis identified shock, peripheral vascular disease, balloon angioplasty strategy, and unstable angina as independent predictors of in-hospital MACEs in the renal group. Compared with 362 age- and sex-matched patients selected from the control group, patients with renal failure had a lower survival rate (27.7% versus 6.1%,
P
<0.0001) and a greater MACE rate (51% versus 33%,
P
<0.001) at long-term follow-up. Cox regression analysis identified age and PTCA strategy as independent predictors of long-term MACEs in the renal group. Finally, within the renal failure population, the dialysis and nondialysis patients experienced remarkably similar immediate and long-term outcomes.

Conclusions
—Although patients with renal failure can be treated with a high procedural success rate in the new device era, they have an increased rate of major events both in hospital and at long-term follow-up. Nevertheless, utilization of stenting and debulking techniques improves immediate and long-term outcomes.
Risks of Morbidity and Mortality in Dialysis Patients Undergoing Coronary Artery Bypass Surgery
Authors: Liu Jean Y. , Birkmeyer Nancy J. O. , Sanders John H. , Morton Jeremy R. , Henriques Horace F. , Lahey Stephen J. , Dow Richard W. , Maloney Christopher , DiScipio Anthony W. , Clough Robert , Leavitt Bruce J. , O’Connor Gerald T.
Published: June 2012

Background
—Although dialysis patients are undergoing CABG with increasing frequency, large studies specifically comparing patient characteristics and procedure-related risks in this population have not been performed.

Methods and Results
—We conducted a regional prospective cohort study of 15 500 consecutive patients undergoing CABG in northern New England from 1992 to 1997. We used multiple logistic regression analysis to examine associations between preoperative dialysis-dependent renal failure and postoperative events and to adjust for potentially confounding variables. The 279 dialysis-dependent renal failure patients (1.8%) were 4.4 times more likely to experience in-hospital mortality than were other CABG patients (12.2% versus 3.0%, respectively;
P
<0.001). Dialysis-dependent renal failure patients were older and had more comorbidities and more severe cardiac disease than did other CABG patients. After adjusting for these factors in multivariate analysis, however, dialysis-dependent renal failure patients remained 3.1 times more likely to die after CABG (adjusted odds ratio [OR] 3.1, 95% CI 2.1 to 4.7;
P
<0.001). Dialysis-dependent renal failure patients compared with other CABG patients also had a substantially increased risk of postoperative mediastinitis (3.6% versus 1.2%, respectively; adjusted OR 2.4, 95% CI 1.2 to 4.7;
P
=0.011) and postoperative stroke (4.3% versus 1.7%, respectively; adjusted OR 2.1, 95% CI 1.1 to 3.9;
P
=0.016), even after controlling for potentially confounding variables. Risks of reexploration for bleeding were similar for patients with and without dialysis-dependent renal failure.

Conclusions
—Preoperative dialysis-dependent renal failure is a strong independent risk factor for in-hospital mortality and mediastinitis after CABG.
Evidence of
Trypanosoma cruzi
Infection (Chagas’ Disease) Among Patients Undergoing Cardiac Surgery
Authors: Leiby David A. , Rentas Francisco J. , Nelson Kenrad E. , Stambolis Veronica A. , Ness Paul M. , Parnis Cheryl , McAllister Hugh A. , Yawn David H. , Stumpf Robert J. , Kirchhoff Louis V.
Published: June 2012

Background
—
Trypanosoma cruzi
, the agent of Chagas’ heart disease, is transmitted by triatomine insects and by blood transfusion. The emigration of several million people from
T cruzi
–endemic countries to the United States has raised concerns regarding a possible increase in cases of Chagas’ heart disease here, as well as an increased risk of transfusion-transmitted
T cruzi
. To investigate these 2 possible outcomes, we tested a repository of blood specimens from multiply transfused cardiac surgery patients for antibodies to
T cruzi
.

Methods and Results
—Postoperative blood specimens from 11 430 cardiac surgery patients were tested by enzyme immunoassay, and if repeat-reactive, were confirmed by radioimmunoprecipitation. Six postoperative specimens (0.05%) were confirmed positive. Corresponding preoperative specimens, available for 4 of these patients, were also positive. The other 2 patients had undergone heart transplantations. Tissue samples from their excised hearts were tested for
T cruzi
by polymerase chain reaction and were positive. Despite the fact that several of these 6 patients had histories and clinical findings suggestive of Chagas’ disease, none of them were diagnosed with or tested for it. Patient demographics showed that 5 of 6 positive patients were Hispanic, and overall, 2.7% of Hispanic patients in the repository were positive.

Conclusions
—No evidence for transfusion-transmitted
T cruzi
was found. All 6 seropositive patients apparently were infected with
T cruzi
before surgery; however, a diagnosis of Chagas’ disease was not known or even considered in any of these patients. Indeed, Chagas’ disease may be an underdiagnosed cause of cardiac disease in the United States, particularly among patients born in countries in which
T cruzi
is endemic.
Gene Expression of Brain Natriuretic Peptide in Isolated Atrial and Ventricular Human Myocardium
Authors: Wiese Stephan , Breyer Tobias , Dragu Adrian , Wakili Reza , Burkard Thilo , Schmidt-Schweda Stephan , Füchtbauer Ernst-Martin , Dohrmann Ulrike , Beyersdorf Friedhelm , Radicke Dirk , Holubarsch Christian J.F.
Published: June 2012

Background
—We studied the effects of angiotensin II (Ang II) and diastolic overstretch on the induction of cardiac growth in isometrically contracting muscle preparations from human right atria and left ventricles. We used the gene expression of brain natriuretic peptide (BNP) as a molecular marker of cardiac hypertrophy.

Methods and Results
—Northern blot analysis was performed in human atrial muscle preparations, which were either incubated in 10
−6
mol/L Ang II for 45 minutes or diastolically stretched to 120% of optimum muscle length. Similar experiments were performed with human left ventricular muscle preparations. Results were as follows: (1) BNP gene expression increased in human atrial myocardium 4-fold when stimulated by Ang II (n=7,
P
<0.001). (2) Diastolic overstretch increased BNP expression in a time-dependent manner. The linear regression equations for the BNP/GAPDH ratio as a function of time (hours) were y=1.21+0.62x (
P
<0.001) for overstretched preparations and y=1.07−0.01x (
P
=NS) for atrial preparations kept at physiological muscle length. (3) In left ventricular human muscle preparations, diastolic overstretch and Ang II increased BNP gene expression as well. (4) In addition, the Ang II subtype 1 receptor blocker losartan was able to block the effects of Ang II and diastolic overstretch.

Conclusions
—Cardiac hypertrophy can be induced in isolated human atrial and left ventricular intact myocardium by Ang II and diastolic overstretch but not by isometric afterload. The fact that the induction of cardiac growth is inhibited by the blockade of Ang II subtype 1 receptors is of scientific and clinical importance.
Trastuzumab in the Treatment of Metastatic Breast Cancer
Authors: Feldman Arthur M. , Lorell Beverly H. , Reis Steven E.
Published: June 2012

Abstract
—Trastuzumab, a monoclonal antibody against the HER2 receptor, was recently approved for the treatment of metastatic breast cancer. However, 28% of patients receiving both an anthracycline and trastuzumab developed heart failure. Although HER2 overexpression has been associated with the development of cancer, HER2 receptors seem to be cardioprotective because they mediate the activation of important cardiac survival pathways. Because the morbidity and mortality of heart failure surpasses that of many cancers, prudent medical practice mandates that physicians learn more about the mechanisms of trastuzumab-induced cardiotoxicity and develop algorithms for assessing risk/benefit ratios before extending the use of this agent to patients with less invasive forms of breast cancer.