bluuebunny/crossref_metadata_2025 huggingface dataset:
Tomographic Three-dimensional Echocardiographic Determination of Chamber Size and Systolic Function in Patients With Left Ventricular Aneurysm
Authors: Buck Thomas , Hunold Peter , Wentz Klaus U. , Tkalec Wolfgang , Nesser H. Joachim , Erbel Raimund
Published: June 2012

Background
Two-dimensional (2D) echocardiographic approaches based on geometric assumptions face the greatest limitations and inaccuracies in patients with left ventricular (LV) aneurysms. Three-dimensional (3D) echocardiographic techniques can potentially overcome these limitations; to date, however, although tested in experimental models of aneurysms, they have not been applied to a series of patients with such distortion. The purpose of this study was therefore to validate the clinical application of tomographic 3D echocardiography (3DE) by the routine transthoracic approach to determine LV chamber size and systolic function without geometric assumptions in patients with LV aneurysms.

Methods and Results
In 23 patients with chronic stable LV aneurysms, LV end-systolic and end-diastolic volumes (LVEDV, LVESV) and ejection fraction (LVEF) by tomographic 3DE were compared with results from 3D magnetic resonance tomography (3DMRT) as an independent reference as well as with the conventional techniques of single plane and biplane 2D echocardiography and biplane cineventriculography. Dynamic 3DE image data sets were obtained from a transthoracic apical view with the use of a rotating probe with acquisition gated to control for ECG and respiration (Echoscan, TomTec). Volumes were calculated from the 3D data sets by summating the volumes of multiple parallel disks. 3DE results correlated and agreed well with those by 3DMRT, with better correlation and agreement than provided by other techniques for LVEDV (3DE:
r
=.97, SEE=14.7 mL, SD of differences from 3DMRT=14.5 mL; other techniques:
r
=.84 to .93, SEE=30.7 to 41.6 mL [
P
<.001 versus 3DE by
F
test], SD of differences=31.5 to 40.7 mL [
P
<.001 versus 3DE by
F
test]). The same also pertained to LVESV (3DE:
r
=.97, SEE=12.4 mL, SD of differences=12.9 mL; other techniques:
r
=.81 to .90, SEE=24.7 to 37.2 mL [
P
<.001], SD of differences=27.6 to 36.8 mL [
P
<.005]) and LVEF (3DE:
r
=.74, SEE=5.6%, SD of differences=6.7%; other techniques:
r
=.14 to .59, SEE=9.5% to 10.1% [
P
<.01], SD of differences=9.5% to 12.6% [
P
<.05]). Compared with 3DMRT, 3DE was less time consuming and patient discomfort was less.

Conclusions
Tomographic 3DE is an accurate noninvasive technique for calculating LV volumes and systolic function in patients with LV aneurysm. Unlike current 2D methods, tomographic 3DE requires no geometric assumptions that limit accuracy.
Halothane Protects Cardiomyocytes Against Reoxygenation-Induced Hypercontracture
Authors: Siegmund Berthold , Schlack Wolfgang , Ladilov Yury V. , Balser Claudia , Piper H. Michael
Published: June 2012

Background
Resupply of oxygen to the myocardium after extended periods of ischemia or hypoxia can rapidly aggravate the already existing injury by provoking hypercontracture of cardiomyocytes (acute reperfusion injury). Previous studies indicated that halothane can protect ischemic-reperfused myocardium. The aim of the present study was to analyze on the cellular level the mechanism by which halothane may protect against reoxygenation-induced hypercontracture.

Methods and Results
To simulate ischemia-reperfusion, isolated adult rat cardiomyocytes were incubated at pH 6.4 under anoxia and reoxygenated at pH 7.4 in the presence or absence of 0.4 mmol/L halothane. Reoxygenation was started when intracellular Ca
2+
(measured with fura 2) had increased to ≥10
−5
mol/L and pH
i
(BCECF) had decreased to 6.5. Development of hypercontracture was determined microscopically. In the control group, reoxygenation provoked oscillations of cytosolic Ca
2+
(72±9 per minute at fourth minute of reoxygenation) accompanied by development of hypercontracture (to 65±3% of end-ischemic cell length). When halothane was added on reoxygenation, Ca
2+
oscillations were markedly reduced (4±2 per minute,
P
<.001) and hypercontracture was virtually abolished (90±4% of end-ischemic cell length,
P
<.001). Halothane did not influence the recovery of pH
i
during reoxygenation. Similar effects on Ca
2+
oscillations and hypercontracture were observed when ryanodine (3 μmol/L), an inhibitor of the sarcoplasmic reticulum Ca
2+
release, or cyclopiazonic acid (10 μmol/L), an inhibitor of the sarcoplasmic reticulum Ca
2+
pump, were applied instead of halothane.

Conclusions
Halothane protects cardiomyocytes against reoxygenation-induced hypercontracture by preventing oscillations of intracellular Ca
2+
during the early phase of reoxygenation.
Hydroxychloroquine Reverses Thrombogenic Properties of Antiphospholipid Antibodies in Mice
Authors: Edwards Michael H. , Pierangeli Silvia , Liu XiaoWei , Barker John H. , Anderson Gary , Harris E. Nigel
Published: June 2012

Background
Previous studies have demonstrated that human monoclonal and polyclonal anticardiolipin antibodies have thrombogenic properties in vivo. Using such a model in which these antibodies have been shown to increase both the size of an induced thrombus and the duration of time in which such a clot lasts, we investigated whether hydroxychloroquine alters the dynamics of such thrombus formation.

Methods and Results
Three groups of nine mice were injected with purified immunoglobulin G (IgG) from a patient with the antiphospholipid syndrome (IgG-APS) and then fed with hydroxychloroquine at various doses (100, 6, and 3 mg/kg body wt). Three control groups of mice were also studied, including mice injected with IgG-APS and then fed with placebo, as well as two other groups injected with IgG from normal human serum and fed either hydroxychloroquine or placebo. A standardized thrombogenic injury was subsequently induced in the femoral vein of each mouse and the area (size) of thrombus measured as well as the total period of time that thrombus was present. Mice treated with hydroxychloroquine and IgG-APS showed significantly smaller thrombi that persisted for a shorter period of time compared with animals treated with IgG-APS and placebo.

Conclusions
Hydroxychloroquine significantly diminished both thrombus size and total time of thrombus formation in mice previously injected with IgG-APS.
Electrophysiological Mechanism of the Characteristic Electrocardiographic Morphology of Torsade de Pointes Tachyarrhythmias in the Long-QT Syndrome
Authors: El-Sherif Nabil , Chinushi Masaomi , Caref Edward B. , Restivo Mark
Published: June 2012

Background
The long-QT syndrome (LQTS) is an electrophysiological (EP) entity characterized by prolongation of cardiac repolarization and the occurrence of polymorphic ventricular tachyarrhythmias (VTs), sometimes with a twisting QRS morphology, better known as torsade de pointes (TdP). In the present study, detailed analysis of ventricular tridimensional activation patterns during nonsustained TdP VT was performed to provide an EP mechanism of the periodic transition in QRS axis.

Methods and Results
The studies were conducted with the anthopleurin-A canine model of LQTS. Tridimensional isochronal maps of ventricular activation were constructed from 256 bipolar electrograms obtained from the use of 64 plunge needle electrodes. In 26 episodes of nonsustained TdP VT, detailed activation maps could be accurately constructed during QRS-axis transitions in surface ECGs. The initial beat of all VTs consistently arose as a subendocardial focal activity, whereas subsequent beats were due to reentrant excitation in the form of rotating scrolls. The VT ended when reentrant excitation was terminated. In 22 of 26 episodes, the transition in QRS axis coincided with the transient bifurcation of a predominantly single rotating scroll into two simultaneous scrolls involving both the right ventricle and left ventricle separately. The common mechanism for initiation or termination of bifurcation was the development of functional conduction block between the anterior or posterior right ventricle free wall and the ventricular septum. In 4 of 26 episodes, a fast polymorphic VT, with an apparent shift in QRS axis, was due to a predominantly single localized circuit that varied its location and orientation from beat to beat, with the majority of ventricular myocardium being activated in a centrifugal pattern.

Conclusions
The study provides for the first time an EP mechanism for the characteristic periodic transition of the QRS axis during TdP VT in the LQTS.
Adenovirus-Mediated Gene Transfer Reconstitutes Depressed Sarcoplasmic Reticulum Ca
2+
-ATPase Levels and Shortens Prolonged Cardiac Myocyte Ca
2+
Transients
Authors: Giordano Frank J. , He Huaping , McDonough Patrick , Meyer Markus , Sayen M. Richard , Dillmann Wolfgang H.
Published: June 2012

Background
Decreased expression of the sarcoplasmic reticulum (SR) Ca
2+
-ATPase of the cardiac myocyte (SERCA2) and abnormal Ca
2+
regulation have been independently linked to human heart failure. This study was designed to determine whether expression of a
SERCA2
transgene could reconstitute depressed cardiac myocyte SERCA2 levels, augment SR Ca
2+
uptake, and shorten prolonged excitation-contraction (EC)–associated Ca
2+
transients in neonatal rat cardiac myocytes (NM).

Methods and Results
Cultured NM were treated with phorbol-12-myristate-13-acetate (PMA), a compound that decreases endogenous SERCA2 expression and results in prolongation of EC-associated Ca
2+
transients. PMA-treated NM had a 75% reduction in SERCA2 mRNA and a 40% reduction in SERCA2 protein levels. SERCA2 adenovirus infection increased SERCA2 mRNA expression to 2.5 times control and reconstituted SERCA2 protein levels in PMA-treated cells. This reconstitution was associated with a 32.4% reduction in the time for decline of the Indo-1 Ca
2+
transient to half-maximum levels (
t
1/2
[Ca
2+
]
i
) (
P
<.05). A 34.5% augmentation of oxalate-facilitated SR Ca
2+
uptake was also documented in SERCA2 adenovirus–infected cells (
P
<.05).

Conclusions
Adenovirus-mediated expression of a
SERCA2
transgene can reconstitute depressed endogenous SERCA2 levels, shorten prolonged Ca
2+
transients, and augment SR Ca
2+
uptake. It is conceivable that such an approach might be used in vivo to normalize altered Ca
2+
regulation in human heart failure.
Hormonal Changes and Catabolic/Anabolic Imbalance in Chronic Heart Failure and Their Importance for Cardiac Cachexia
Authors: Anker Stefan D. , Chua Tuan Peng , Ponikowski Piotr , Harrington Derek , Swan Jon W. , Kox Wolfgang J. , Poole-Wilson Philip A. , Coats Andrew J. S.
Published: June 2012

Background
The role of hormonal and cytokine abnormalities in the development of cardiac cachexia remains obscure.

Methods and Results
Healthy control subjects (n=16) and patients with chronic heart failure (CHF), classified clinically as cachectic (8% to 35% weight loss over ≥6 months before study, n=16) or noncachectic (n=37), were assessed for markers of disease severity (maximal oxygen consumption, left ventricular ejection fraction, NYHA functional class). These markers were compared with plasma concentrations of potentially important anabolic and catabolic factors. The degree of neurohormonal activation and catabolic/anabolic imbalance was closely related to wasting but not to conventional measures of the severity of heart failure. Compared with control subjects and noncachectic patients, cachectic patients had reduced plasma sodium and increased norepinephrine, epinephrine (all
P
<.0001), cortisol, tumor necrosis factor (TNF)-α (both
P
<.002), and human growth hormone (
P
<.05). Insulin-like growth factor-1, testosterone, and estrogen were similar in all groups. Insulin was increased only in the noncachectic patients (
P
<.005 versus control subjects). Dehydroepiandrosterone was reduced in the cachectic patients (
P
<.02 versus control subjects). Insulin, cortisol, TNF-α, and norepinephrine correlated independently with wasting in CHF (
P
<.05; multiple regression of these four factors versus percent ideal weight,
R
2
=.50,
P
<.0001).

Conclusions
Cachexia is more closely associated with hormonal changes in CHF than conventional measures of the severity of CHF. This study suggests that the syndrome of heart failure progresses to cardiac cachexia if the normal metabolic balance between catabolism and anabolism is altered.
Weaning From Mechanical Cardiac Support in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Müller Johannes , Wallukat Gerd , Weng Yu-Guo , Dandel Michael , Spiegelsberger Susanne , Semrau Sabine , Brandes Kersten , Theodoridis Vassilis , Loebe Matthias , Meyer Rudolf , Hetzer Roland
Published: June 2012

Background
Implantation of mechanical cardiac support systems (MCSS) in patients with idiopathic dilated cardiomyopathy (IDC) may improve cardiac function and allow explantation of the device. We report of long-term effects of ventricular unloading on cardiac function, humoral anti-β1-adrenoceptor autoantibodies (A-β
1
-AABs), and myocardial fibrosis.

Methods and Results
Seventeen patients in New York Heart Association functional class IV with nonischemic IDC received MCSS. All had a cardiac index of <1.6 L · min
−1
· m
−2
of body surface area, a left ventricular ejection fraction (LVEF) of <16%, and a left ventricular internal diameter in diastole (LVIDd) of >68 mm and tested positive for A-β
1
-AABs. Echocardiographic evaluation, serum tests for A-β
1
-AABs, and histological assessment of myocardial fibrosis were performed before and after MCSS implantation. The mean support duration was 230±201 days. Six patients died, four were transplanted, and two are still on MCSS. Five patients with significant cardiac recovery (mean LVIDd, 54±2.3 mm; LVEF, 47±3.7%) were weaned after 160 to 794 days and are now device free for 51 to 592 days. A-β
1
-AABs disappeared gradually during MCSS without increase after weaning; cardiac function and volume density of fibrosis remained normal. Nine patients’ cardiac function hardly improved during ventricular unloading.

Conclusions
Cardiac function can be normalized in selected patients with end-stage IDC by MCSS. The degree of preoperative myocardial fibrosis may be an indicator for outcome; A-β
1
-AABs can be used to monitor myocyte recovery. Weaning from MCSS offers an alternative to cardiac transplantation in certain patients.
Congenital Heart Defects
Authors: Yagel Simcha , Weissman Ariel , Rotstein Zeev , Manor Moshe , Hegesh Julius , Anteby Eyal , Lipitz Shlomo , Achiron Reuwen
Published: June 2012

Background
Most congenital heart defects (CHDs) are diagnosed on targeted prenatal transvaginal (TVS) or transabdominal (TAS) ultrasonography during the early second trimester or at midgestation. Nevertheless, delayed diagnosis in some cardiac malformations still remains despite detailed echocardiographic examination. The present study was conducted to evaluate the evolution of fetal cardiac anomalies and assess their development in utero.

Methods and Results
We retrospectively reviewed 22 050 pregnant women who were divided into two groups: 6924 who had initial TVSs at 13 to 16 weeks’ gestation, followed by TASs at 20 to 22 weeks, and 15 126 who had initial TASs at 20 to 22 weeks. Both groups were subsequently examined in their third trimester. All newborns were examined by certified pediatricians. CHD was diagnosed in 168 babies: 66 in group A and 102 in group B. In group A, 42 malformations (64%) were detected at the first TVS examination, and 11 (17%) were found during the subsequent TAS. Three additional anomalies (4%) were found during the third trimester, and 10 malformations (15%) were detected postnatally. In group B, 80 malformations (78%) were detected in the initial examination at midtrimester, and an additional 7 (7%) were found in the third trimester, whereas 15 (15%) were diagnosed postnatally. The 10 anomalies (group A, n=3; group B, n=7) that were detected only during the third trimester comprised aortic stenosis (n=2), cardiac rhabdomyoma (n=2), subaortic stenosis (n=1), tetralogy of Fallot (n=1), aortic coarctation (n=1), sealed foramen ovale (n=1), ventricular septal defects (n=1), and hypertrophic cardiomyopathy (n=1).

Conclusions
Although most fetal cardiac anomalies are detectable early in gestation, some may evolve in utero at different stages of pregnancy.
Monitoring Considerations for Port-Access Cardiac Surgery
Authors: Siegel Lawrence C. , St. Goar Frederick G. , Stevens John H. , Pompili Mario F. , Burdon Thomas A. , Reitz Bruce A. , Peters William S.
Published: June 2012

Background
A method for monitoring patients was evaluated in a clinical trial of minimally invasive port-access cardiac surgery with closed chest endovascular cardiopulmonary bypass.

Methods and Results
Cardiopulmonary bypass was conducted in 25 patients through femoral cannulas. An endovascular pulmonary artery vent was placed in the main pulmonary artery through a jugular vein. For mitral valve surgery, a catheter was placed in the coronary sinus for delivery of cardioplegia. A balloon catheter (“endoaortic clamp,” EAC) used for occlusion of the ascending aorta, delivery of cardioplegia, aortic root venting, and pressure measurement was inserted through a femoral artery and initially positioned by use of fluoroscopy and transesophageal echocardiography (TEE). Potential migration of the EAC was monitored by (1) TEE of the ascending aorta, (2) pulsed-wave Doppler of the right carotid artery, (3) balloon pressure, (4) comparison of aortic root pressure and right radial artery pressure, and (5) fluoroscopy. TEE, fluoroscopy, and pressure measurement were effective in monitoring catheter insertion and position. With inadequate balloon inflation, migration of the EAC toward the aortic valve could be detected with TEE. During administration of cardioplegia, TEE showed movement of the balloon away from the aortic valve, and migration into the aortic arch was detectable with loss of carotid Doppler flow. Stability of EAC position was demonstrated with appropriate balloon volume. Cardioplegic solution was visualized in the aortic root, and aortic root pressure changed appropriately during administration of cardioplegia. Venous cannula position was optimized with TEE and endopulmonary vent flow measurement.

Conclusions
An effective method has been developed for monitoring patients and the catheter system during port-access cardiac surgery.
Inhibition of Vascular Smooth Muscle Cell Proliferation and Neointimal Accumulation by Adenovirus-Mediated Gene Transfer of Cytosine Deaminase
Authors: Harrell Robert L. , Rajanayagam M. A. Sharmini , Doanes A. Masharn , Guzman Raul J. , Hirschowitz Edward A. , Crystal Ronald G. , Epstein Stephen E. , Finkel Toren
Published: June 2012

Background
Restenosis remains a significant problem after balloon angioplasty. Previous studies have demonstrated that recombinant adenoviruses are efficient vectors for gene transfer to the arterial wall and can be used to inhibit the proliferative aspect of restenosis. We sought to extend these observations using AdCMV.CD, an adenovirus that encodes cytosine deaminase (CD) and is capable of metabolizing 5-fluorocytosine (5-FC) to 5-fluorouracil.

Methods and Results
Infection of vascular smooth muscle cells (VSMC) with AdCMV.CD increases by two to three orders of magnitude the growth-inhibitory effects of 5-FC. The degree of VSMC inhibition in vitro was a function of 5-FC concentration and the level of CD expression. Cells infected with AdCMV.CD exhibited a profound bystander effect on the growth of neighboring cells, which did not require direct cell-to-cell contact. The predominant effect of AdCMV.CD on growth of VSMC appeared to be cytostatic, not cytotoxic. Assessment of this strategy in a rabbit femoral artery model of balloon-induced injury demonstrated that compared with animals in either of two control groups, animals treated with the active combination of infection with AdCMV.CD and 1-week treatment with parenteral 5-FC had a significant reduction at 30 days in the neointimal-to-medial ratio.

Conclusions
Our results suggest that adenovirus-mediated gene transfer of CD along with 5-FC administration may be a useful strategy to treat the proliferative aspects of restenosis.
Paclitaxel Inhibits Arterial Smooth Muscle Cell Proliferation and Migration In Vitro and In Vivo Using Local Drug Delivery
Authors: Axel Dorothea I. , Kunert Wolfgang , Göggelmann Christoph , Oberhoff Martin , Herdeg Christian , Küttner Axel , Wild Doris H. , Brehm Bernhard R. , Riessen Reimer , Köveker Gerhard , Karsch Karl R.
Published: June 2012

Background
The antineoplastic compound paclitaxel (Taxol) causes an increased assembly of extraordinarily stable microtubules. The present study was designed to characterize the effects of paclitaxel on proliferation and migration of human arterial smooth muscle cells (haSMCs) in vitro and on neointima formation in an in vivo experimental rabbit model.

Methods and Results
Both monocultures of haSMCs and cocultures with human arterial endothelial cells (haECs) were used. Cell growth after 4, 8, and 14 days was determined in the absence or presence of platelet-derived growth factor-AB (PDGF-AB), basic fibroblast growth factor (bFGF), or thrombin. Nonstop paclitaxel exposure, as well as single-dose applications of paclitaxel for 24 hours or even 20 minutes (0.1 to 10.0 μmol/L), caused a complete and prolonged inhibition of haSMC growth up to day 14, with an IC
50
of 2.0 nmol/L. Mitogens or cocultures with stimulating haECs did not significantly attenuate paclitaxel-induced effects. Immunohistochemistry showed characteristic cytoskeletal changes predominantly in the microtubule network. Additionally, in 20 male New Zealand White rabbits, intimal plaques were produced by electrical stimulation. In 10 animals, paclitaxel was locally applied by use of microporous balloons. Histologically, the intima wall area, wall thickness, and degree of stenosis were reduced significantly in paclitaxel-treated animals compared with controls.

Conclusions
Our data show that paclitaxel inhibits haSMC proliferation and migration in a dose-dependent manner in monocultures and cocultures even in the presence of mitogens. Furthermore, paclitaxel prevents neointima formation in rabbits after balloon angioplasty. The long-lasting effect after just several minutes’ exposure time makes this lipophilic substance a promising candidate for local antiproliferative therapy of restenosis.
Glycogen Metabolism in the Aerobic Hypertrophied Rat Heart
Authors: Allard Michael F. , Henning Sarah L. , Wambolt Richard B. , Granleese Shaun R. , English Dean R. , Lopaschuk Gary D.
Published: June 2012

Background
Rates of glycolysis from exogenous glucose are accelerated in hypertrophied hearts. In this study, we determined whether alterations in the metabolism of glycogen, an endogenous storage form of glucose, also occur in hypertrophied hearts.

Methods and Results
Rates of glycolysis ([
3
H]H
2
O production) and oxidation ([
14
C]CO
2
production) from exogenous glucose and glycogen were measured in isolated working hearts from control and aortic-banded rats. Hearts in which glycogen was prelabeled with [5-
3
H]- or [U-
14
C]glucose were perfused with buffer containing 11 mmol/L [5-
3
H]- or [U-
14
C]glucose (different from the isotope used to prelabel glycogen), 0.4 mmol/L palmitate, 0.5 mmol/L lactate, and 100 μU/mL insulin. Rates of glycolysis from exogenous glucose were greater (3471±114 versus 2665±194 nmol glucose·min
−1
·g dry wt
−1
,
P
<.05, n=4 to 6, mean±SEM) and rates of exogenous glucose oxidation (445±36 versus 619±16 nmol glucose·min
−1
·g dry wt
−1
,
P
<.05, n=4 to 6) were lower in hypertrophied hearts than in control hearts. Rates of glycolysis and oxidation from glycogen were not different between hypertrophied and control hearts. A greater proportion of glycogen was oxidized (80% to 100%) than the proportion of exogenous glucose oxidized (13% to 24%) in both groups. Additionally, 10.5±1.4 and 12.3±1.0 μmol/g dry wt of glycogen was synthesized in hypertrophied and control hearts, respectively, indicating that simultaneous synthesis and degradation (ie, glycogen turnover) occurred in both groups.

Conclusions
Thus, aerobic myocardial glycogen metabolism in the hypertrophied heart is similar to that observed in the normal heart even though exogenous glucose metabolism is altered in the hypertrophied heart.
Prolonged Administration of
l
-Arginine Ameliorates Chronic Pulmonary Hypertension and Pulmonary Vascular Remodeling in Rats
Authors: Mitani Yoshihide , Maruyama Kazuo , Sakurai Minoru
Published: June 2012

Background
Endothelium-dependent nitric oxide–mediated vasodilation is impaired in rats with pulmonary hypertension (PH) induced by chronic hypoxia or by monocrotaline injection. We therefore investigated whether the prolonged administration of the nitric oxide precursor
l
-arginine would alleviate PH in both rat models.

Methods and Results
Fifty-nine rats were exposed to hypobaric hypoxia (380 mm Hg, 10 days) or room air and injected intraperitoneally with
l
-arginine (500 mg/kg),
d
-arginine (500 mg/kg), or saline once daily from day −3 to day 10. An additional 38 rats injected subcutaneously with monocrotaline (60 mg/kg) or saline were treated similarly with
l
-arginine or saline from day −3 to day 17. At the end of the experiment, awake mean pulmonary arterial pressure was determined. The heart was dissected to weigh the right ventricle, and the lungs were obtained for vascular morphometric analysis. Hypoxic rats developed PH (30.8±0.7 versus 19.2±0.4 mm Hg in controls;
P
<.05) and right ventricular hypertrophy. Their pulmonary arterial wall thickness and the proportion of muscular arteries in the peripheral arteries increased.
l
-Arginine but not
d
-arginine reduced PH (24.8±0.7 mm Hg;
P
<.05), right ventricular hypertrophy, and pulmonary vascular disease. Monocrotaline rats developed PH (34.9±2.1 versus 18.8±1.2 mm Hg in controls;
P
<.05), right ventricular hypertrophy, and pulmonary vascular disease. Again,
l
-arginine reduced PH (24.3±1.7 mm Hg;
P
<.05), right ventricular hypertrophy, and pulmonary vascular disease.

Conclusions
We conclude that
l
-arginine ameliorated the changes associated with PH in rats, perhaps by modifying the endogenous nitric oxide production.
Association of Angiotensin-Converting Enzyme Gene
I/D
Polymorphism With Change in Left Ventricular Mass in Response to Physical Training
Authors: Montgomery Hugh E. , Clarkson Peter , Dollery Clare M. , Prasad Krishna , Losi Maria-Angela , Hemingway Harry , Statters Deborah , Jubb Mick , Girvain Martin , Varnava Amanda , World Michael , Deanfield John , Talmud Phillipa , McEwan Jean R. , McKenna William J. , Humphries Stephen
Published: June 2012

Background
The absence (deletion allele [
D
]) of a 287–base pair marker in the
ACE
gene is associated with higher ACE levels than its presence (insertion allele [
I
]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of
DD
genotype might show a greater hypertrophic response than those of
II
genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy.

Methods and Results
Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all
P
<.0001). Response magnitude was strongly associated with
ACE
genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in
II
,
ID
and
DD
, respectively (
P
<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of
DD
genotype (from 6 of 24 before training to 11 of 24 after training,
P
<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for
DD
and
II
, respectively (
P
<.001).

Conclusions
Exercise-induced LV growth in young males is strongly associated with the
ACE I/D
polymorphism.
C-Reactive Protein as a Predictor of Infarct Expansion and Cardiac Rupture After a First Q-Wave Acute Myocardial Infarction
Authors: Anzai Toshihisa , Yoshikawa Tsutomu , Shiraki Hiroto , Asakura Yasushi , Akaishi Makoto , Mitamura Hideo , Ogawa Satoshi
Published: June 2012

Background
Pump failure after acute myocardial infarction (AMI) can be predicted by several indices that estimate infarct size. However, there are few indices that predict infarct expansion and cardiac rupture. We focused on the prognostic significance of serum C-reactive protein (CRP) after AMI.

Methods and Results
Serum CRP levels were measured every 24 hours in 220 patients with a first Q-wave AMI. In-hospital complications, predischarge left ventriculographic findings, and long-term prognosis were assessed in relation to peak CRP levels. Peak levels of both CRP and creatine kinase (CK) were higher in patients with pump failure than in those without pump failure. In patients with cardiac rupture, peak CRP levels were higher than in those without rupture (
P
=.001); peak CK levels were not predictive. Higher CRP levels were found in patients with left ventricular aneurysm (
P
=.001 versus those without), aggravated heart failure (
P
=.03 versus those without), and cardiac death (
P
<.0001 versus survivors) during the first year after AMI. Multivariate analysis confirmed that an elevation of the peak CRP level ≥20 mg/dL was an independent predictor of cardiac rupture (relative risk, 4.72;
P
=.004), left ventricular aneurysmal formation (relative risk, 2.11;
P
=.03), and 1-year cardiac death (relative risk, 3.44;
P
<.0001).

Conclusions
Cardiac rupture, left ventricular aneurysmal formation, and 1-year cardiac death were associated with an elevation of serum CRP early after AMI, suggesting that elevation of CRP levels after AMI may predict infarct expansion.
Detection of Coronary Artery Disease With Myocardial Contrast Echocardiography
Authors: Kaul Sanjiv , Senior Roxy , Dittrich Howard , Raval Usha , Khattar Raj , Lahiri Avijit
Published: June 2012

Background
The purpose of this study was to determine whether myocardial contrast echocardiography (MCE) can be used to detect coronary artery disease (CAD) during rest and pharmacological stress in humans through the use of venous injections of contrast.

Methods and Results
Thirty patients with known or suspected CAD underwent MCE and
99m
Tc-sestamibi single-photon emission computed tomography (SPECT) at baseline and after dipyridamole (0.56 mg · kg
−1
) infusion. Ten myocardial segments (5 each in the apical two- and four-chamber views) from the two sets of images using both methods were scored for myocardial perfusion as follows: 1=normal, 0.5=mildly reduced, and 0=severely reduced. The information from baseline and postdipyridamole images was then used to determine whether an abnormal segment was irreversible (similar abnormal perfusion at baseline and after dipyridamole) or reversible (perfusion better at baseline compared with after dipyridamole). Concordance between segmental scores was 92% (κ=.99) for both methods. Concordance between normal perfusion and reversible or irreversible segmental defects was 90% (κ=.80). Agreement between the two methods for each of the three vascular territories in each patient was 90% (κ=.77), while agreement for the presence or absence of CAD in each patient was 86% (κ=.86). In the 4 patients with disagreement, the perfusion scores were 0.5 for SPECT and 1.0 for MCE.

Conclusions
This study shows that MCE, with venous injection of contrast, can define the presence of CAD during rest and pharmacological stress. The location of perfusion abnormalities and their physiologic relevance (reversible or irreversible) by MCE is similar to that provided by SPECT. MCE, therefore, holds promise for the noninvasive assessment of myocardial perfusion in humans.
Insulin Sensitivity, Vascular Reactivity, and Clamp-Induced Vasodilatation in Essential Hypertension
Authors: Natali Andrea , Taddei Stefano , Galvan Alfredo Quiñones , Camastra Stefania , Baldi Simona , Frascerra Silvia , Virdis Agostino , Sudano Isabella , Salvetti Antonio , Ferrannini Ele
Published: June 2012

Background
Insulin resistance and vascular abnormalities have both been described in patients with essential hypertension. Whether these defects are associated with one another in the same individual has not been established.

Methods and Results
Whole-body insulin sensitivity (by the insulin clamp technique), forearm minimal vascular resistances, and the dose-response curve to acetylcholine, sodium-nitroprusside, and norepinephrine were measured in a group of 29 male patients with untreated essential hypertension. When the patients were divided into tertiles according to their level of insulin sensitivity, resistant and sensitive hypertensives were matched on several potential confounders of insulin action and vascular function. These subgroups showed similar minimal vascular resistances (2.5±0.2 versus 3.2±0.6 mm Hg per mL · min
−1
· dL
−1
) and superimposable responses to graded intraarterial infusions of acetylcholine, sodium-nitroprusside, and norepinephrine. No correlation was found between the vascular parameters (slope of the curve or maximal response) and insulin-mediated glucose uptake in the whole group. During the clamp, insulin sensitive patients tended to have greater increments in forearm blood flow when compared to their insulin resistant counterparts (+53±21 versus +9±7%,
P
=.06); in the whole group, clamp-induced vasodilatation was weakly related to insulin-mediated glucose uptake (
r
=.44,
P
<.02) as well as to the slope of the acetylcholine dose-response curve (
r
=.40,
P
<.04). Together, these two responses explained 30% (multiple
r
=.55,
P
<.01) of the variability in insulin-induced vasodilatation.

Conclusions
Metabolic insulin resistance in essential hypertension is not associated with abnormalities in vascular structure, acetylcholine or nitroprusside-induced vasodilatation, or vascular adrenergic reactivity. Degree of insulin sensitivity and acetylcholine sensitivity explain a small portion of the variability of the clamp-induced vasodilatation in hypertensive patients.
Inhibition of Red Cell Aggregation Prevents Spontaneous Echocardiographic Contrast Formation in Human Blood
Authors: Fatkin Diane , Loupas Thanasis , Low Joyce , Feneley Michael
Published: June 2012

Background
Spontaneous echocardiographic contrast (SEC) is a pattern of blood echogenicity that has been attributed to ultrasonic backscatter from blood cell aggregates that form under low shear conditions. Patients with left atrial SEC have an increased thromboembolic risk. This study examined the role of red cell and platelet aggregates in the pathogenesis of SEC in human blood and the effects on SEC of antithrombotic therapy and red cell disaggregatory agents.

Methods and Results
Blood echogenicity was examined with the use of quantitative videodensitometry over a controlled range of flow velocities in an in vitro model characterized by nonlaminar flow conditions. One hundred ninety study samples were prepared from single fresh blood donations (40 to 120 mL) from 24 healthy volunteers and 11 patients. Whole blood echogenicity was unaltered by depletion of platelets, stimulation of platelet aggregation with adenosine diphosphate, or inhibition of platelet aggregation with aspirin. Low flow–related echogenicity increased with increasing hematocrit (
P
<.001) but was abolished when red cells were lysed selectively with saponin (
P
<.001). In the presence of red cells, low flow–related echogenicity increased with increasing fibrinogen concentration (
P
<.001) and with plasma paraproteins. Low flow–related echogenicity in whole blood was unaltered by heparin and warfarin but was reduced in a dose-dependent manner by dextran 40 (40 mg/mL, 70% reduction,
P
<.001) and poloxamer 188 (8 mg/mL, 47% reduction,
P
<.001), which inhibited red cell aggregation.

Conclusions
These results support protein-mediated red cell aggregation as the mechanism of SEC in human blood. Inhibition of red cell aggregation, indexed by resolution of SEC, may provide an alternative to anticoagulant and antiplatelet therapy to reduce cardiac thromboembolic risk.
Nitric Oxide Regulates Monocyte Chemotactic Protein-1
Authors: Tsao Philip S. , Wang Bing-yin , Buitrago Ricardo , Shyy John Y.-J. , Cooke John P.
Published: June 2012

Background
Monocyte chemotactic protein-1 (MCP-1) is a 76-amino-acid chemokine thought to be the major chemotactic factor for monocytes. We and others have demonstrated that NO inhibits monocyte–endothelial cell interactions and atherogenesis. We hypothesize that the antiatherogenic effect of NO may be due in part to its inhibition of MCP-1 expression.

Methods and Results
Smooth muscle cells (SMCs) were isolated from normal rabbit aortas by the explant method. Cells were then exposed to LPS (10 μg/mL), native LDL, or oxidized LDL (30 μg/mL) for 6 hours. The expression of MCP-1 in SMCs and chemotactic activity in the conditioned medium were induced by lipopolysaccharide (LPS) or by oxidized LDL but not native LDL. The induction of MCP-1 by cytokines or oxidized lipoproteins was associated with an increased generation of superoxide anion by the SMCs and increased activity of the transcriptional protein nuclear factor-κB (NFκB). The induced expression of MCP-1 and activation of NFκB were reduced by previous exposure of the SMCs to the NO donor DETA-NONOate (100 μmol/L) (
P
<.05). To determine whether NO exerted its effect at a transcriptional level, SMCs and COS cells were transfected with a 400-bp fragment of the MCP-1 promoter. Promoter activity was enhanced by oxidized LDL, and LPS was inhibited by DETA-NO. Nuclear run-on assays confirmed that the effect of NO occurred at a transcriptional level. To investigate the role of endogenous NO in the regulation of MCP-1 in vivo, New Zealand White rabbits were fed normal chow, normal chow plus nitro-
l
-arginine (LNA), high-cholesterol diet (Chol), or high-cholesterol diet supplemented with
l
-arginine (Arg). After 2 weeks, thoracic aortas were harvested and total RNA was isolated. Northern analysis using full-length MCP-1 cDNA demonstrated increased expression in Chol and LNA aortas; this expression was decreased in aortas from Arg animals.

Conclusions
These studies indicate that the antiatherogenic effect of NO may be mediated in part by its inhibition of MCP-1 expression.
Prospective Study of Hemostatic Factors and Incidence of Coronary Heart Disease
Authors: Folsom Aaron R. , Wu Kenneth K. , Rosamond Wayne D. , Sharrett A. Richey , Chambless Lloyd E.
Published: June 2012

Background
Although hemostatic factors contribute to acute coronary syndromes and atherogenesis, few studies have prospectively evaluated the association between multiple hemostatic factors and coronary heart disease incidence.

Methods and Results
The Atherosclerosis Risk in Communities Study recruited 14 477 adults from 45 to 64 years of age who were initially free of coronary heart disease. Coronary disease risk factors and several plasma hemostatic factors were measured, and incidence of coronary heart disease was ascertained during an average follow-up of 5.2 years. Age-, race-, and field center–adjusted relative risks of coronary heart disease were significantly elevated (
P
≤.05) per higher value of fibrinogen (relative risk: men, 1.76; women, 1.54), white blood cell count (men, 1.68; women, 2.23), factor VIII coagulant activity (women, 1.25), and von Willebrand factor antigen (men, 1.20; women, 1.18). Adjustment for other risk factors attenuated these associations for fibrinogen (adjusted relative risk: men, 1.48; women, 1.21), and it eliminated the white blood cell count, factor VIII, and von Willebrand factor associations, consistent with the other risk factors either confounding or partly operating through their effects on the hemostatic variables. Adjusted standardized relative risks of total mortality, ranging from 1.13 to 1.37, were also elevated (
P
<.05) in relation to these four factors. There was no association of coronary disease incidence with factor VII, protein C, antithrombin III, or platelet count.

Conclusions
Elevated levels of fibrinogen, white blood cell count, factor VIII, and von Willebrand factor are risk factors and may play causative roles in coronary heart disease. However, their measurement in healthy adults appears to add little to prediction of coronary events beyond that of more established risk factors.
Electron Beam Computed Tomographic Coronary Calcium as a Predictor of Coronary Events
Authors: Secci Angelo , Wong Nathan , Tang Weiyi , Wang Shaojun , Doherty Terence , Detrano Robert
Published: June 2012

Background
We assessed the accuracy of two electron beam computed tomography (EBCT) protocols for predicting coronary events.

Methods and Results
In 1994, 24 months after enrollment in a longitudinal study, 326 high-risk adults underwent both 3- and 6-mm image-slice thickness EBCT scanning and were followed up for 32.0±4.0 additional months. Events were defined as either coronary death, myocardial infarction, or revascularization. We monitored these subjects for the 32-month postscanning period with yearly phone calls and acquisition of records for all hospital admissions. At the time of scanning, 11 subjects (3%) had already suffered 12 events (5 infarctions and 7 revascularizations) during the 24-month prescanning period. During the postscanning period, 18 subjects (6%) suffered 23 events (5 coronary deaths, 6 infarctions, and 12 revascularizations). Thus, 28 subjects (9%) suffered 35 events. Calcium quantities calculated for both protocols, performed on the same subjects, were sorted in ascending order and divided into equal quartiles. When revascularizations were included, there was a significant trend toward higher frequencies of events with increasing calcium quantity (
P
<.01). However, coronary death and infarction were not significantly more frequent in higher quartiles. These relationships were preserved in the subjects without prior events at the time of scanning.

Conclusions
Calcium quantities from the 3-mm and the more reproducible 6-mm scanning are equally accurate for predicting events. Coronary calcium amount appears to be a weak predictor of coronary death and infarction. Its predictive accuracy is superior for predicting revascularization.
Glucose-Insulin-Potassium Therapy for Treatment of Acute Myocardial Infarction
Authors: Fath-Ordoubadi Farzin , Beatt Kevin J.
Published: June 2012

Background
Glucose-insulin-potassium (GIK) therapy has been advocated for the treatment of acute myocardial infarction. However, the results from the clinical trials have been inconclusive, largely because of the small number of patients recruited and discrepancies between protocols used in these studies.

Method and Results
A systematic MEDLINE search for all the randomized placebo-controlled studies of GIK therapy in acute myocardial infarction was made, and a meta-analysis of the mortality data was performed. Fifteen trials were identified, 5 were excluded because of poor randomization, and 1 was excluded because recruitment was limited to diabetic patients. The 9 remaining trials with a total of 1932 patients were included in the analysis. Hospital mortality was reduced from 21% (205 of 972 patients) in the placebo group to 16.1% (154 of 956) in the GIK group (
P
=.004; odds ratio, 0.72; 95% confidence interval [CI], 0.57 to 0.90). The proportional mortality reduction was 28% (CI, 10% to 43%). The number of lives saved per 1000 patients treated was 49 (95% CI, 14 to 83).

Conclusions
The findings indicate that GIK therapy may have an important role in reducing the in-hospital mortality after acute myocardial infarction. The value of this therapy in the era of thrombolysis and acute revascularization by primary angioplasty can be fully resolved only by conducting a large randomized mortality study.
Anatomic Features and Surgical Strategies in Double-Outlet Right Ventricle
Authors: Kleinert S. , Sano T. , Weintraub R.G. , Mee R.B.B. , Karl T.R. , Wilkinson J.L.
Published: June 2012

Background
The objective of this study was to review anatomic features and surgical strategies in children with double-outlet right ventricle (DORV) and to assess risk factors for early mortality.

Methods and Results
Records were reviewed of all children with DORV undergoing surgery between 1978 and 1993. Noncomplex patients (group 1) had atrioventricular (AV) concordance, a single ventricular septal defect (VSD), balanced ventricles, no straddling AV valves, and no major pulmonary artery anomaly. Group 2 (complex) comprised all remaining patients. Independent risk factors analyzed included location of the main VSD, presence of additional VSDs, coarctation, ventricular outflow obstruction, ventricular hypoplasia, age at operation, operation before 1985, previous palliation, and type of definitive operation. Of 193 patients, 117 were in group 1 and 76 in group 2. In 148 patients, biventricular repair was undertaken, including 111 of 117 group 1 patients and 37 of 76 group 2 patients. Early mortality was higher among group 2 patients undergoing biventricular repair than among group 1 patients (8 of 37 versus 4 of 111,
P
<.005) and higher than group 2 patients undergoing a Fontan procedure (none of 29,
P
<.01). Aortic arch obstruction, operation before 1985, and multiple VSDs were significant risk factors for mortality. Age <1 month (
P
<.05) and multiple VSDs (
P
<.005) were independent risk factors after definitive repair. Up-to-date follow-up is available on 144 surviving patients, with 127 (88%) in New York Heart Association class I and the remaining 17 in class II. Overall 10-year survival probability was 81%, whereas probability of survival, free from reoperation (after definitive surgery), was 65% at 10 years.

Conclusions
Biventricular repair can be achieved in most patients with DORV with low risk. In complex DORV, a Fontan procedure is associated with a lower surgical mortality.
Withdrawal of Acetylcholine Elicits Ca
2+
-Induced Delayed Afterdepolarizations in Cat Atrial Myocytes
Authors: Wang Y.G. , Hüser J. , Blatter L.A. , Lipsius S.L.
Published: June 2012

Background
Recent experiments in atrial myocytes indicate that withdrawal of cholinergic agonist can directly increase Ca
2+
influx via L-type Ca
2+
current and stimulate Ca
2+
uptake into the sarcoplasmic reticulum (SR), thereby increasing intracellular Ca
2+
. Overload of cellular Ca
2+
within the SR can initiate various types of atrial dysrhythmias. The present study was designed to determine whether withdrawal of acetylcholine (ACh) can elicit Ca
2+
-induced delayed afterdepolarizations (DADs) in atrial myocytes.

Methods and Results
A nystatin perforated-patch whole-cell method and fluorescence microscopy (indo 1) were used to measure electrical activities and intracellular free Ca
2+
([Ca
2+
]
i
), respectively. Withdrawal of ACh (1 μmol/L) increased action potential duration, shifted plateau voltage toward positive, and generated DADs that initiated spontaneous action potentials. Voltage-clamp analysis revealed that withdrawal of ACh elicited a rebound stimulation of L-type Ca
2+
current (
I
Ca,L
) (+45%) and Na/Ca exchange current (
I
NaCa
) (+16%) and the appearance of transient inward current (
I
ti
) and spontaneous [Ca
2+
]
i
transients. Each of these changes induced by withdrawal of ACh was abolished by Rp-cAMPs (50 to 100 μmol/L) or H-89 (2 μmol/L), inhibitors of cAMP-dependent protein kinase A. Ryanodine (1 μmol/L) abolished
I
NaCa
and the appearance of
I
ti
without decreasing the rebound stimulation of
I
Ca,L
elicited by withdrawal of ACh.

Conclusions
Withdrawal of ACh can elicit cAMP-mediated stimulation of Ca
2+
influx via
I
Ca,L
and uptake of SR Ca
2+
. As a result, cellular Ca
2+
overload causes enhanced SR Ca
2+
release and the initiation of DADs. These mechanisms may generate triggered and/or spontaneous atrial depolarizations elicited by withdrawal of vagal nerve activity.