bluuebunny/crossref_metadata_2025 huggingface dataset:
BREATHING: Rhythmicity, Plasticity, Chemosensitivity
Authors: Feldman Jack L. , Mitchell Gordon S. , Nattie Eugene E.
Published: February 2003

▪ Abstract  Breathing is a vital behavior that is particularly amenable to experimental investigation. We review recent progress on three problems of broad interest. (i) Where and how is respiratory rhythm generated? The preBötzinger Complex is a critical site, whereas pacemaker neurons may not be essential. The possibility that coupled oscillators are involved is considered. (ii) What are the mechanisms that underlie the plasticity necessary for adaptive changes in breathing? Serotonin-dependent long-term facilitation following intermittent hypoxia is an important example of such plasticity, and a model that can account for this adaptive behavior is discussed. (iii) Where and how are the regulated variables CO2and pH sensed? These sensors are essential if breathing is to be appropriate for metabolism. Neurons with appropriate chemosensitivity are spread throughout the brainstem; their individual properties and collective role are just beginning to be understood.
Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome
Authors: Takenaka Kotoe , Ai Tomohiko , Shimizu Wataru , Kobori Atsushi , Ninomiya Tomonori , Otani Hideo , Kubota Tomoyuki , Takaki Hiroshi , Kamakura Shiro , Horie Minoru
Published: February 2003

Background—

Experimental studies suggest that the interval between peak and end of T wave (Tpe) in transmural ECGs reflects transmural dispersion of repolarization (TDR), which is amplified by β-adrenergic stimulation in the LQT1 model. In 82 patients with genetically identified long-QT syndrome (LQTS) and 33 control subjects, we examined T-wave morphology and various parameters for repolarization in 12-lead ECGs including corrected QT (QTc; QT/R-R
1/2
) and corrected Tpe (Tpec; Tpe/R-R
1/2
) before and during exercise stress tests.

Methods and Results—

Under baseline conditions, LQT1 (n=51) showed 3 cardinal T-wave patterns (broad-based, normal-appearing, late-onset) and LQT2 (n=31) 3 patterns (broad-based, bifid with a small or large notch). The QTc and Tpec were 510±68 ms and 143±53 ms in LQT1 and 520±61 ms and 195±69 ms in LQT2, respectively, which were both significantly larger than those in control subjects (402±36 ms and 99±36 ms). Both QTc and Tpec were significantly prolonged during exercise in LQT1 (599±54 ms and 215±46 ms) with morphological change into a broad-based T-wave pattern. In contrast, exercise produced a prominent notch on the descending limb of the T wave, with no significant changes in the QTc and Tpec (502±82 ms and 163±86 ms: n=19) in LQT2.

Conclusions—

Tpe interval increases during exercise in LQT1 but not in LQT2, which may partially account for the finding that fatal cardiac events in LQT1 are more often associated with exercise.
Antianginal and Antiischemic Effects of Ivabradine, an I
f
Inhibitor, in Stable Angina
Authors: Borer Jeffrey S. , Fox Kim , Jaillon Patrice , Lerebours Guy
Published: February 2003

Background—

Heart rate reduction should benefit patients with chronic stable angina by improving myocardial perfusion and reducing myocardial oxygen demand. This study evaluated the antianginal and antiischemic effects of ivabradine, a new heart rate–lowering agent that acts specifically on the sinoatrial node.

Methods and Results—

In a double-blind, placebo-controlled trial, 360 patients with a ≥3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2- or 3-month extension on ivabradine (10 mg BID) and a 1-week randomized withdrawal to ivabradine (10 mg BID) or placebo. Primary efficacy criteria were changes in time to 1-mm ST-segment depression and time to limiting angina during bicycle exercise (exercise tolerance tests), performed at trough of drug activity. In the per-protocol population (n=257), time to 1-mm ST-segment depression increased in the 5 and 10 mg BID groups (
P
<0.005); time to limiting angina increased in the 10 mg BID group (
P
<0.05). Deterioration in all exercise tolerance test parameters occurred in patients who received placebo during randomized withdrawal (all
P
<0.02) but not in those still receiving ivabradine. No rebound phenomena were observed on treatment cessation.

Conclusions—

Ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise. These results suggest that ivabradine, representing a novel class of antianginal drugs, is effective and safe during 3 months of use; longer-term safety requires additional assessment.
Quantitative Magnetic Resonance Imaging Analysis of Neovasculature Volume in Carotid Atherosclerotic Plaque
Authors: Kerwin William , Hooker Andrew , Spilker Mary , Vicini Paolo , Ferguson Marina , Hatsukami Thomas , Yuan Chun
Published: February 2003

Background—

Neovasculature within atherosclerotic plaques is believed to be associated with infiltration of inflammatory cells and plaque destabilization. The aim of the present investigation was to determine whether the amount of neovasculature present in advanced carotid plaques can be noninvasively measured by dynamic, contrast-enhanced MRI.

Methods and Results—

A total of 20 consecutive patients scheduled for carotid endarterectomy were recruited to participate in an MRI study. Images were obtained at 15-second intervals, and a gadolinium contrast agent was injected coincident with the second of 10 images in the sequence. The resulting image intensity within the plaque was tracked over time, and a kinetic model was used to estimate the fractional blood volume. For validation, matched sections from subsequent endarterectomy were stained with ULEX and CD-31 antibody to highlight microvessels. Finally, all microvessels within the matched sections were identified, and their total area was computed as a fraction of the plaque area. Results were obtained from 16 participants, which showed fractional blood volumes ranging from 2% to 41%. These levels were significantly higher than the histological measurements of fractional vascular area. Nevertheless, the 2 measurements were highly correlated, with a correlation coefficient of 0.80 (
P
<0.001).

Conclusions—

Dynamic contrast-enhanced MRI provides an indication of the extent of neovasculature within carotid atherosclerotic plaque. MRI therefore provides a means for prospectively studying the link between neovasculature and plaque vulnerability.
Pulmonary Vein Diameter Reduction After Radiofrequency Catheter Ablation for Paroxysmal Atrial Fibrillation Evaluated by Contrast-Enhanced Three-Dimensional Magnetic Resonance Imaging
Authors: Dill Thorsten , Neumann Thomas , Ekinci Okan , Breidenbach Christiane , John Anna , Erdogan Ali , Bachmann Georg , Hamm Christian W. , Pitschner Heinz-F.
Published: February 2003

Background—

Radiofrequency catheter ablation (RFCA) is a promising intervention to treat atrial fibrillation. However, pulmonary vein (PV) stenosis after RFCA has been reported. The aim of this study was to investigate the incidence and time course of pulmonary vein stenosis after RFCA within a period of 3 months. Contrast-enhanced magnetic resonance angiography (MRA) was used to visualize pulmonary veins and was compared with radiographic angiography.

Methods and Results—

Forty-six consecutive patients with symptomatic paroxysmal atrial fibrillation had RFCA in the orifice of 138 pulmonary veins. Comparison of diameters measured in 44 untreated vessels either by radiographic angiography or with MRA established the reliability of MRA (
r
=0.934). MRA measurements revealed an incidence of relevant diameter reductions of ≥25% or stenosis of ≥50% after RFCA of 25 of 138 (18.1%) treated vessels 1 day and/or 3 months after ablation. A progression of diameter reduction after RFCA was observed in 8.3% (maximum 75%), whereas a regression was observed in 6.3% of treated PVs. Ablation at a radial angle of >180° of a pulmonary vein orifice increased the risk of diameter reduction significantly compared with ablation at a radial angle ≤180° (
P
=0.002).

Conclusions—

The occurrence and progression of PV stenosis is a potential significant complication of RFCA in the orifice of pulmonary veins. These findings may have an impact on the technical performance of this intervention. In addition, long-term studies will be necessary to evaluate lumen reduction over time. MRA is a noninvasive, reproducible imaging modality for this purpose.
Immunosuppressive Therapy for Active Lymphocytic Myocarditis
Authors: Frustaci Andrea , Chimenti Cristina , Calabrese Fiorella , Pieroni Maurizio , Thiene Gaetano , Maseri Attilio
Published: February 2003

Background—

The beneficial effect of immunosuppressive treatment on myocarditis is still controversial, possibly because the immunologic and virological profile of potential candidates is largely unknown.

Methods and Results—

Out of 652 biopsied patients, 112 had a histological diagnosis of active lymphocytic myocarditis; 41 of these 112 patients were characterized by progressive heart failure despite conventional therapy and were treated with prednisone and azathioprine for 6 months. All were resubmitted to cardiac catheterization, angiography, and endomyocardial biopsy at 1 and 6 months and followed-up for 1 year. A total of 21 patients responded with prompt improvement in left ventricular ejection fraction from 25.7±4.1% to 47.1±4.4% and showed evidence of healed myocarditis at control biopsy. Conversely, 20 patients failed to respond and showed a histological evolution toward dilated cardiomyopathy: 12 remained stationary, 3 underwent cardiac transplantation, and 5 died. We retrospectively performed a polymerase chain reaction on frozen endomyocardial tissue for the most common cardiotropic viruses and assessed circulating serum cardiac autoantibodies. Viral genomes were present in biopsy specimens of 17 nonresponders (85%), including enterovirus (n=5), Epstein-Barr virus (n=5) adenovirus (n=4), both adenovirus and enterovirus (n=1), influenza A virus (n=1), parvovirus-B19 (n=1), and in 3 responders, who were all positive for hepatitis C virus. Cardiac autoantibodies were present in 19 responders (90%) and in none of the nonresponders.

Conclusions—

In patients with active lymphocytic myocarditis, those with circulating cardiac autoantibodies and no viral genome in the myocardium are the most likely to benefit from immunosuppression. The beneficial effect of immunosuppression in hepatitis C virus myocarditis suggests a relevant immunomediated component of damage.
Rapamycin Induces Heme Oxygenase-1 in Human Pulmonary Vascular Cells
Authors: Visner Gary A. , Lu Fuhua , Zhou Hailan , Liu Jun , Kazemfar Kristy , Agarwal Anupam
Published: February 2003

Background—

Rapamycin is an immunosuppressive agent with antiproliferative properties against not only lymphocytes but also vascular endothelial and smooth muscle cells, and it reduces the fibroproliferative response to vascular injury. Heme oxygenase-1 (HO-1) has also been shown to have graft protective effects and to inhibit vascular remodeling. In this study, we evaluated whether there is an interaction between rapamycin and HO-1.

Methods and Results—

In human pulmonary artery endothelial or smooth muscle cells, HO-1 expression was evaluated in response to rapamycin or wortmannin, an inhibitor of the upstream modulator of mammalian target of rapamycin (mTOR) PI-3K. We also evaluated whether the inhibitory actions of rapamycin on platelet-derived growth factor–dependent proliferation was mediated by HO using the chemical inhibitor tin protoporphyrin. Rapamycin induced HO-1 expression in both pulmonary endothelial and smooth muscle cells, whereas no to little increase was seen in response to another immunosuppressive agent, cyclosporin A. HO-1 expression was also increased in response to wortmannin, suggesting that the PI-3K–mTOR pathway is required for this induction. Inhibition of HO activity resulted in a loss of the antiproliferative activity of rapamycin in growth factor–stimulated smooth muscle cells.

Conclusions—

The induction of HO-1 expression by rapamycin and, more importantly, the effects of tin protoporphyrin, an inhibitor of HO activity, on the antiproliferative actions of rapamycin suggest that the effects of rapamycin may be, at least in part, modulated by its actions on HO-1.
Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction
Authors: Pacher Pál , Liaudet Lucas , Bai Péter , Mabley Jon G. , Kaminski Pawel M. , Virág László , Deb Amitabha , Szabó Éva , Ungvári Zoltán , Wolin Michael S. , Groves John T. , Szabó Csaba
Published: February 2003

Background—

Increased oxidative stress and dysregulation of nitric oxide have been implicated in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide in various forms of cardiac injury. Using a novel metalloporphyrinic peroxynitrite decomposition catalyst, FP15, and nitric oxide synthase inhibitors or knockout mice, we now delineate the pathogenetic role of peroxynitrite in rodent models of DOX-induced cardiac dysfunction.

Methods and Results—

Mice received a single injection of DOX (25 mg/kg IP). Five days after DOX administration, left ventricular performance was significantly depressed, and high mortality was noted. Treatment with FP15 and an inducible nitric oxide synthase inhibitor, aminoguanidine, reduced DOX-induced mortality and improved cardiac function. Genetic deletion of the inducible nitric oxide synthase gene was also accompanied by better preservation of cardiac performance. In contrast, inhibition of the endothelial isoform of nitric oxide synthase with
N
-nitro-
l
-arginine methyl ester increased DOX-induced mortality. FP15 reduced the DOX-induced increase in serum LDH and creatine kinase activities. Furthermore, FP15 prevented the DOX-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart but not NAD(P)H-driven superoxide generation. Peroxynitrite neutralization did not interfere with the antitumor effect of DOX. FP15 also decreased ischemic injury in rats and improved cardiac function and survival of mice in a chronic model of DOX-induced cardiotoxicity.

Conclusions—

Thus, peroxynitrite plays a key role in the pathogenesis of DOX-induced cardiac failure. Targeting peroxynitrite formation may represent a new cardioprotective strategy after DOX exposure or in other conditions associated with peroxynitrite formation, including myocardial ischemia/reperfusion injury.
Validity of a Simple ST-Elevation Acute Myocardial Infarction Risk Index
Authors: Rathore Saif S. , Weinfurt Kevin P. , Gross Cary P. , Krumholz Harlan M.
Published: February 2003

Background—

Risk-stratification scores derived from randomized clinical trial (RCT) data should be evaluated in community-based populations. A simple risk-stratification index for patients with ST-segment elevation myocardial infarction derived from an RCT population was recently proposed, but it has not been validated in a community-based cohort.

Methods and Results—

We evaluated the simple risk index using data from 49 711 patients ≥65 years of age hospitalized with ST-elevation myocardial infarction. We evaluated the distribution of patients in the 5 simple risk index groups, compared observed and published 30-day mortality rates, and assessed the score’s discrimination and calibration. The simple risk index provided poor discrimination (c=0.62) and calibration (goodness of fit
P
<0.001) for survival at 30 days. Risk score distribution was skewed, because two thirds (66.1%) of all patients were classified in the highest-risk group, whereas fewer than 11.0% were classified in the 3 lowest-risk groups. Thirty-day mortality estimates were lower than those observed in the cohort (risk group 2 to 5: 1.9% to 17.4% versus 5.3% to 27.9%). Risk index discrimination, calibration, score distribution, and mortality estimates were worse among patients who did not receive acute reperfusion therapy than among those who did.

Conclusions—

The limited performance of the simple risk index highlights the limitations of applying prognostic models derived in RCT populations to the general population of patients 65 years and older. Prognostic scores must be validated in community-based cohorts before integration into clinical practice.
Left Ventricular Mass and Systolic Performance in Pediatric Patients With Chronic Renal Failure
Authors: Mitsnefes Mark M. , Kimball Thomas R. , Witt Sandra A. , Glascock Betty J. , Khoury Philip R. , Daniels Stephen R.
Published: February 2003

Background—

Children with chronic renal disease have a high prevalence of left ventricular hypertrophy (LVH), which is thought to be adaptive to improve contractility and lower wall stress in the face of increased afterload and preload. The aim of this study was to determine the association between LV mass, LV performance, and LV contractility in children with chronic renal insufficiency (CRI) and children undergoing chronic dialysis.

Methods and Results—

Twenty-five children with CRI, 12 undergoing chronic dialysis, and 24 controls had echocardiographic evaluation during rest and peak exercise. LV performance was assessed by calculation of shortening fraction and heart rate–corrected velocity of circumferential fiber shortening (VCF). Contractility (VCF difference) was determined based on the relation between VCF and end-systolic wall stress. Contractile reserve was assessed by the difference between contractility at rest and peak exercise. The dialysis group had higher LVM index than the group with CRI (42.9±10.3 versus 29.9±9.4 g/m
2.7
,
P
<0.001). Both groups had higher LVM index compared with controls (22.2±6.1 g/m
2.7
,
P
<0.001). At rest, the CRI and dialysis groups had significantly higher VCF
c
(
P
<0.001) and VCF difference (
P
<0.05) and significantly lower wall stress (
P
<0.01) compared with the control group. Dialysis patients had significantly lower contractile reserve compared with the control group (
P
<0.03).

Conclusions—

These results indicate that children with CRI and undergoing chronic dialysis have increased LVM, LV performance, and contractility at rest. However, dialysis patients have diminished contractile reserve during exercise, which might be an indicator for the development of more severe systolic dysfunction over time.
Myocardial Proinflammatory Cytokine Expression and Left Ventricular Remodeling in Patients With Chronic Mitral Regurgitation
Authors: Oral Hakan , Sivasubramanian Natarajan , Dyke David B. , Mehta Rajendra H. , Grossman P. Michael , Briesmiester Kerri , Fay William P. , Pagani Francis D. , Bolling Steven F. , Mann Douglas L. , Starling Mark R.
Published: February 2003

Background—

In an animal model, stretch was shown to induce myocardial tumor necrosis factor-α (TNF-α) expression. The purposes of this study were to determine whether the left ventricular (LV) volume overload that occurs in patients with chronic mitral regurgitation (MR) can induce myocardial and systemic TNF-α expression and whether there is a relationship between TNF-α expression and LV remodeling.

Methods and Results—

Plasma TNF-α and its receptors were measured before mitral valve (MV) repair surgery in 26 MR patients and 23±12 months after MV repair surgery in 9 MR patients. Myocardial mRNA copies of TNF-α were determined in 11 MR and 10 donor hearts using quantitative RT-PCR. Compared with 15 control subjects, pre-MV repair plasma TNF-α (3.59±1.81 versus 2.03±1.02 pg/mL,
P
<0.005) and its receptor levels were elevated in MR patients. Myocardial TNF-α mRNA copies (corrected for β-actin mRNA expression) in MR patients and donor hearts were 38.96±42.74×10
6
and 0.88±0.75×10
6
, respectively (
P
=0.01). After MV surgery, there was a decrease in the plasma levels of TNF-α (2.79±1.14 versus 3.51±1.34 pg/mL,
P
=0.02) and its receptors. There was a correlation between myocardial TNF-α expression and preoperative LV end-diastolic and end-systolic volumes. Moreover, there was an inverse correlation between myocardial TNF-α expression and regression in LV end-diastolic (
r
=−0.76,
P
=0.007) and end-systolic (
r
=−0.73,
P
=0.01) volumes after MV surgery.

Conclusions—

TNF-α is expressed in the myocardium and plasma of MR patients. Correction of the LV volume overload with MV surgery results in reversal of TNF-α expression. There is a relationship between TNF-α expression and parameters of LV remodeling, suggesting that TNF-α may play a role in the pathogenesis of the LV remodeling that occurs in MR.
Reductions in Systemic and Skeletal Muscle Blood Flow and Oxygen Delivery Limit Maximal Aerobic Capacity in Humans
Authors: González-Alonso José , Calbet José A.L.
Published: February 2003

Background—

A classic, unresolved physiological question is whether central cardiorespiratory and/or local skeletal muscle circulatory factors limit maximal aerobic capacity (V̇
o
2
max) in humans. Severe heat stress drastically reduces V̇
o
2
max, but the mechanisms have never been studied.

Methods and Results—

To determine the main contributing factor that limits V̇
o
2
max with and without heat stress, we measured hemodynamics in 8 healthy males performing intense upright cycling exercise until exhaustion starting with either high or normal skin and core temperatures (+10°C and +1°C). Heat stress reduced V̇
o
2
max, 2-legged V̇
o
2
, and time to fatigue by 0.4±0.1 L/min (8%), 0.5±0.2 L/min (11%), and 2.2±0.4 minutes (28%), respectively (all
P
<0.05), despite heart rate and core temperature reaching similar peak values. However, before exhaustion in both heat stress and normal conditions, cardiac output, leg blood flow, mean arterial pressure, and systemic and leg O
2
delivery declined significantly (all 5% to 11%,
P
<0.05), yet arterial O
2
content and leg vascular conductance remained unchanged. Despite increasing leg O
2
extraction, leg V̇
o
2
declined 5% to 6% before exhaustion in both heat stress and normal conditions, accompanied by enhanced muscle lactate accumulation and ATP and creatine phosphate hydrolysis.

Conclusions—

These results demonstrate that in trained humans, severe heat stress reduces V̇
o
2
max by accelerating the declines in cardiac output and mean arterial pressure that lead to decrements in exercising muscle blood flow, O
2
delivery, and O
2
uptake. Furthermore, the impaired systemic and skeletal muscle aerobic capacity that precedes fatigue with or without heat stress is largely related to the failure of the heart to maintain cardiac output and O
2
delivery to locomotive muscle.
Defining the Transmurality of a Chronic Myocardial Infarction by Ultrasonic Strain-Rate Imaging
Authors: Weidemann Frank , Dommke Christoph , Bijnens Bart , Claus Piet , D’hooge Jan , Mertens Paul , Verbeken Eric , Maes Alex , Van de Werf Frans , De Scheerder Ivan , Sutherland George R.
Published: February 2003

Background—

In a correlative functional/histopathologic study, we investigated the regional deformation characteristics of both chronic nontransmural and transmural infarctions before and after a dobutamine challenge.

Methods and Results—

After stenosing copper-coated stent implantation to produce circumflex artery endothelial proliferation, 18 pigs were followed up for 5 weeks. Posteuthanasia histology showed 10 to have a nontransmural and 8 a transmural infarction. Eight nonstented animals served as controls. Regional radial function was monitored by measuring ultrasound-derived peak systolic strain rates (SR
SYS
) and systolic strains (ε
SYS
) (1) before stent implantation and (2) at 5 weeks, at baseline (bs) and during an incremental dobutamine infusion. In controls, dobutamine induced a linear increase in SR
SYS
(dobutamine: bs, 4.8±0.4 s
−1
; 20 μg · kg
−1
· min
−1
, 9.9±0.7 s
−1
;
P
<0.0001) and an initial increase of ε
SYS
at low dose (bs, 58±5%; at 5 μg · kg
−1
· min
−1
, 78±6%;
P
<0.05) but a subsequent decrease during higher infusion rates. In the nontransmural group, bs SR
SYS
and ε
SYS
were significantly lower than prestent values (SR
SYS
, 2.9±0.5 s
−1
and ε
SYS
, 32±6%,
P
<0.05 versus prestent). During dobutamine infusion, SR
SYS
increased slightly at 5 μg · kg
−1
· min
−1
(4.7±0.6 s
−1
,
P
<0.05) but fell during higher infusion rates, whereas ε
SYS
showed no change. For nontransmural infarctions, transmural scar extension correlated closely with ε
SYS
at bs (
r
=0.88). For transmural infarctions, SR
SYS
at bs was significantly reduced and ε
SYS
was almost not measurable (SR
SYS
, 1.8±0.3 s
−1
; ε
SYS
, 3±4%). Both deformation parameters showed no further change during the incremental dobutamine infusion.

Conclusions—

Ultrasonic deformation values could clearly differentiate chronic nontransmural from transmural myocardial infarction. The transmural extension of the scar could be defined by the regional deformation response.
Widening of the Excitable Gap and Enlargement of the Core of Reentry During Atrial Fibrillation With a Pure Sodium Channel Blocker in Canine Atria
Authors: Kawase Ayaka , Ikeda Takanori , Nakazawa Kazuo , Ashihara Takashi , Namba Tsunetoyo , Kubota Tetsuya , Sugi Kaoru , Hirai Hironori
Published: February 2003

Background—

This study aimed to assess the effects of pilsicainide, a pure sodium channel blocker, on electrophysiological action and wavefront dynamics during atrial fibrillation (AF).

Methods and Results—

In a newly developed model of isolated, perfused, and superfused canine atria (n=12), the right and left endocardia were mapped simultaneously by use of a computerized mapping system. AF was induced with 1 to 5 μmol/L acetylcholine. The antifibrillatory actions of pilsicainide on AF cycle length (AFCL), refractory period (RP), conduction velocity (CV), excitable gap (EG), and the core of the mother rotor were studied. The RP was defined as the shortest coupling interval that could capture the fibrillating atrium. The EG was estimated as the difference between the AFCL and RP. At baseline, multiple wavefronts were observed. After 2.5 μg/mL infusion of pilsicainide, all preparations showed irregular activity, and AF was terminated in 2 preparations. The AFCL and RP were prolonged, and CV was decreased significantly. The EG was widened (147%;
P
<0.01), and the core perimeter was increased (100%;
P
<0.01). Increasing the dosage either terminated AF (6 preparations) or converted to organized activity (ie, atypical atrial flutter) (4 preparations). On the maps, all “unorganized” AFs were terminated with the excitation of the core of the mother rotor by an outside wavefront, whereas in preparations with atrial flutter, pilsicainide did not terminate its activity.

Conclusions—

Widening of the EG by pilsicainide facilitates the excitation of the core of the mother rotor, leading to the termination of AF. In some experiments, pilsicainide converts AF to persistent atrial flutter.
Failure of Thrombus to Resolve in Urokinase-Type Plasminogen Activator Gene–Knockout Mice
Authors: Singh I. , Burnand K.G. , Collins M. , Luttun A. , Collen D. , Boelhouwer B. , Smith A.
Published: February 2003

Background—

Monocytes may have an important role in the resolution of venous thrombosis. Increased expression of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) is associated with an ingress of monocytes into the thrombus. This study was designed to evaluate the importance of these activators in thrombus resolution.

Methods and Results—

Inferior caval vein thrombosis was induced in cohorts of adult wild-type, uPA gene-knockout (uPA
−/−
), and tPA gene-knockout (tPA
−/−
) mice in a flow model. Thrombi were harvested from wild-type and uPA
−/−
mice (n=60 per group) between 1 and 60 days. Thrombi were also obtained from groups of wild-type and tPA
−/−
mice (n=24 per group) between 1 and 28 days. Thrombus size and macrophage content were measured by computer-assisted image analysis. Thrombus resolution was significantly impaired in the uPA
−/−
mice compared with wild-type controls (
P
<0.0001) but was unaffected in tPA
−/−
mice. Monocyte content in wild-type mice was highest at 14 days after thrombus induction and was ≈4 times greater than in uPA
−/−
mice (
P
=0.0043). Thrombus size in uPA
−/−
mice transplanted with wild-type marrow (0.29±0.06 mm
2
) was significantly smaller than in uPA
−/−
mice given uPA
−/−
bone marrow (3.9±1.1 mm
2
) (
P
=0.0022). Donor bone marrow–derived cells expressing LacZ were present in the thrombus after transplantation.

Conclusions—

The resolution of experimental venous thrombus is dependent on uPA but is unaffected by the absence of tPA. Absence of uPA is also associated with delayed monocyte recruitment into the thrombus. Transplanting wild-type bone marrow restores thrombus resolution in uPA
−/−
animals, suggesting an important role for bone marrow–derived cells in this process.
Alterations in Janus Kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) Signaling in Patients With End-Stage Dilated Cardiomyopathy
Authors: Podewski Edith K. , Hilfiker-Kleiner Denise , Hilfiker Andres , Morawietz Henning , Lichtenberg Artur , Wollert Kai C. , Drexler Helmut
Published: February 2003

Background—

Experimental studies indicate that interleukin-6 (IL-6)–related cytokines, signaling via the shared receptor gp130, Janus kinases (JAKs), and signal transducers and activators of transcription (STATs), provide a critical cardiomyocyte survival pathway in vivo. Little is known about the activation of this signaling pathway in the myocardia of patients with end-stage dilated cardiomyopathy (DCM).

Methods and Results—

We performed a comprehensive expression and activation analysis of IL-6–related cytokines, receptors, signal transducers, and signal transduction inhibitors in left ventricular (LV) myocardia from patients with DCM (n=10) and non-failing (NF) donor hearts (n=5). Differential expression (DCM versus NF) was observed by immunoblotting at each level of the signaling cascade, including receptor ligands (IL-6: −59%,
P
<0.01; leukemia inhibitory factor [LIF]: +54%,
P
<0.05), receptor subunits (LIF receptor: −16%,
P
<0.05), signaling molecules (the Janus kinase TYK2: −48%,
P
<0.01; STAT3: −47%,
P
<0.01), and suppressors of cytokine signaling (SOCS1: +97%,
P
<0.05; SOCS3: −49%,
P
<0.01). Tyrosine-phosphorylation status of gp130 was increased (+60%,
P
<0.05), whereas tyrosine-phosphorylation status of JAK2 was reduced in DCM (−72%,
P
<0.01). Moreover, as shown by immunohistochemistry, the number of STAT3-positive cardiomyocytes was reduced in DCM (−42%,
P
<0.01).

Conclusion—

Signaling via gp130 and JAK-STAT is profoundly altered in DCM. Importantly, tyrosine-phosphorylation of JAK2 is reduced in the face of increased gp130 phosphorylation, indicating impaired downstream activation of this critical pathway in DCM.
Intracardiac Echocardiography Is Superior to Conventional Monitoring for Guiding Device Closure of Interatrial Communications
Authors: Bartel Thomas , Konorza Thomas , Arjumand Jawed , Ebradlidze Tiko , Eggebrecht Holger , Caspari Guido , Neudorf Ulrich , Erbel Raimund
Published: February 2003

Background—

This study sought to test whether intracardiac echocardiography (ICE) is superior to conventional monitoring in guiding device closure of interatrial communications (atrial septal defect [ASD] and patent foramen ovale [PFO]).

Methods and Results—

Forty-four patients undergoing device closure of ASD (n=6) or PFO (n=38) were randomized to have the procedure guided by either ICE (group 1; n=22) or by transesophageal echocardiography (TEE) (group 2; n=22). All interventions were completed successfully. In 1 patient from group 2, atrial fibrillation occurred 1 day after device implantation; the patient was successfully cardioverted on the next day. There were no other complications. Fluoroscopy time (FT) (6.0±1.7 minutes versus 9.5±1.6 minutes;
P
<0.0001) as well as procedure time (PT) (33.4±4.7 minutes versus 37.8±5.6 minutes;
P
<0.01) were shorter in group 1 than in group 2. Group 2 patients required general anesthesia without (n=19) or with endotracheal intubation (n=3). In contrast, ICE allowed continuous monitoring of the whole procedure, including balloon sizing before device closure, without sedation.

Conclusions—

ICE is a safe tool to guide device closure of PFO and ASD. Supine patients tolerate ICE better than TEE. ICE reduces FT and PT. ICE seems to be advantageous, especially when long continuous or repeated echocardiographic viewing is required.
Angiostatin
Authors: Koshida Ryoji , Ou Jingsong , Matsunaga Toshiro , Chilian William M. , Oldham Keith T. , Ackerman Allan W. , Pritchard Kirkwood A.
Published: February 2003

Background—

Angiostatin is known to inhibit certain aspects of endothelial function, eg, angiogenesis. Here we investigated the effects of angiostatin on another aspect of endothelial function, vasodilation, and examined mechanisms of inhibition—namely, association of heat-shock protein 90 (hsp90) with endothelial nitric oxide synthase (eNOS) and endothelial generation of nitric oxide (·NO) and superoxide anion (

). This avenue of investigation was based on recent reports suggesting that hsp90 modulates NOS production of ·NO and

.

Methods and Results—

Effects of angiostatin on vasodilation were determined in arterioles with the use of videomicroscopy in response to endothelium- and ·NO-dependent vasodilators, acetylcholine (ACh) and vascular endothelial growth factor (VEGF), and an endothelium-independent agonist, papaverine. Association of hsp90 with eNOS was determined in rat aortas and bovine aortic endothelial cells (BAECs). Effects of angiostatin on ·NO and

generation by BAECs were determined by ozone chemiluminescence and superoxide dismutase (SOD)–inhibitable ferricytochrome c reduction, respectively. Angiostatin impaired vasodilation mediated by ACh and VEGF but not papaverine. Pretreating arterioles with polyethylene glycolated–SOD (PEG-SOD) improved vasodilation to ACh and VEGF. Angiostatin decreased the association of hsp90 with eNOS in aortas and BAEC cultures and increased

generation in stimulated BAECs by an Lγ-nitroargininemethylester (L-NAME)–inhibitable mechanism.

Conclusions—

These data indicate angiostatin alters endothelial function by allowing eNOS to generate

on activation. Such changes in enzyme function begin to explain, in part, why angiostatin is antiangiogenic and impairs endothelium-dependent vasodilation.
Inhibitory Effect of Natriuretic Peptides on Aldosterone Synthase Gene Expression in Cultured Neonatal Rat Cardiocytes
Authors: Ito Teruhiko , Yoshimura Michihiro , Nakamura Shota , Nakayama Masafumi , Shimasaki Yukio , Harada Eisaku , Mizuno Yuji , Yamamuro Megumi , Harada Masaki , Saito Yoshihiko , Nakao Kazuwa , Kurihara Hiroki , Yasue Hirofumi , Ogawa Hisao
Published: February 2003

Background—

Although previously thought to be synthesized solely in adrenal cortex, we have recently showed that aldosterone is also produced in and the expression of CYP11B2 mRNA was induced in the failing or hypertensive human ventricle. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones with wide biological effects, including inhibition of renin and aldosterone production. We hypothesized that natriuretic peptides reduce the expression of CYP11B2 mRNA in the heart.

Methods and Results—

To test this hypothesis, we examined whether endogenous or exogenous natriuretic peptides reduce the expression of CYP11B2 mRNA using real-time reverse transcription-polymerase chain reaction. By using HS 142–1, a functional guanylyl cyclase-A type receptor antagonist, we showed that angiotensin II (AngII) pretreated with HS 142–1 increased CYP11B2 mRNA expression (1.62±0.12-fold, HS 142–1+AngII 10
−7
mol/L versus AngII 10
−7
mol/L alone,
P
<0.0001). The treatment with exogenous (10
−6
mol/L) ANP and BNP reduced CYP11B2 mRNA expression (ANP,
P
=0.0042; BNP,
P
=0.0012).

Conclusions—

We showed that endogenous and exogenous natriuretic peptides reduced CYP11B2 mRNA expression in cultured neonatal rat cardiocytes. This may inhibit the cardiac renin-angiotensin-aldosterone system by suppressing the gene expression of CYP11B2 and restraining cardiac hypertrophy and fibrosis.
¿Distorsiona la prensa la percepción social que la opinión pública construye acerca del delito, la violencia y la inseguridad?
Authors: D'Adamo Orlando , García Virginia
Published: February 2003

La percepción de la opinión pública acerca de la violencia y de la inseguridad social es una construcción psicológica, construidaparcialmente a partir de las noticias publicadas en los medios de comunicación. Este trabajo muestra que las variaciones en el tratamiento del delito en los periódicos no se ajustan a su ascenso o descenso real. Más bien, los medios explotan «sobretodo» los casos más llamativos. Los datos presentados en el trabajo se obtienen con el «Índice de Violencia Social Percibida» y se comparan con los datos oficiales que el departamento Argentino de Justicia proporciona sobre el delito (años 2000 y 2001).
Un modelo psicosociológico para el estudio de la salud mental
Authors: Sánchez Esteban , Garrido Alicia , Alvaro José Luis
Published: February 2003

En este artículo presentamos un modelo explicativo de la salud mental. Para ello se ha adoptado un enfoque psicosociológico en el que se han tenido en cuenta las variables asociadas al deterioro psicológico que han mostrado su relevancia en investigaciones anteriores. A través de un análisis de ecuaciones estructurales se analiza el peso que factores como los sucesos vitales estresantes, la alienación, la autoestima, el apoyo social percibido y las estrategias de afrontamiento tienen en la explicación del deterioro en la salud mental. Dichos factores tienen un papel mediador entre la posición social y el deterioro psicológico. Como conclusión se da cuenta de los resultados obtenidos en una muestra de 401 sujetos y su interpretación desde un enfoque centrado en un modelo de causación social.
Efectos de los talleres de ocio sobre el bienestar subjetivo y la soledad en las personas mayores
Authors: García Miguel Ángel , Gómez Luis
Published: February 2003

En el presente trabajo se estudian los efectos psicológicos que los talleres de actividades de ocio desarrollados en un Centro de Día para Mayores tienen sobre el bienestar subjetivo de sus usuarios. Sobre una muestra de 122 personas de edades comprendidas entre los 50 y 82 años (edad media = 67.6), repartidas en cinco grupos—gimnasia, manualidades, informática, dibujo-pintura y control—, utilizando un diseño cuasiexperimental pre-test/post-test, se analizan las siguientes variables: satisfacción vital, depresión y soledad. Los resultados hallados confirman que estas actividades de ocio hacen disminuir los niveles de depresión y soledad entre sus usuarios, al tiempo que ayudan a incrementar su satisfacción vital. Estos beneficios se mantienen tres meses después de la conclusión de los talleres.
Factores individuales, familiares y educativos asociados al consumo de alcohol en jóvenes
Authors: García J. Miguel Ángel , Carrasco Ana María
Published: February 2003

El objetivo de este trabajo es analizar la relación entre el consumo de alcohol en jóvenes y diversos factores de riesgo individuales (patrón de conducta Tipo A, autoestima), familiares (satisfacción con el entorno familiar, nivel de estudios de los padres y nivel socioeconómico familiar percibido) y educativos (rendimiento académico y satisfacción con los estudios). La muestra estuvo configuradapor 413 jóvenes de 18 a 20 años, quienes respondieron distintas escalas e instrumentos relativos a las variables estudiadas. Se obtuvieron diferencias significativas entre consumidores y no consumidores de alcohol en las dimensiones de impaciencia, hostilidad, rendimiento académico y satisfacción con los estudios, en el sentido de que los jóvenes que consumen alcohol diaria o sema- nalmentepresentan, respecto a los no consumidores, mayores niveles de hostilidad e impaciencia, menor rendimiento académico y menor satisfacción respecto a los estudios. Finalmente, los resultados obtenidos a través de análisis de regresión logística indican que las variables psicosociales que mejor predicen el consumo de alcohol son el nivel de impaciencia y el rendimiento académico.
Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL-8: novel mechanisms for modulation of hematopoiesis
Authors: Dudek Arkadiusz Z. , Nesmelova Irina , Mayo Kevin , Verfaillie Catherine M. , Pitchford Simon , Slungaard Arne
Published: February 2003

Platelet factor 4 (PF4) is an abundant platelet α-granule C-X-C chemokine that has weak chemotactic potency but strongly inhibits hematopoiesis through an unknown mechanism. We find that PF4 binds to human CD34+ hematopoietic progenitor cells (HPCs) with a median effective concentration of 1 μg/mL but not after exposure to chondroitinase ABC. PF4 enhances adhesion of HPCs to intact stroma. Committed progenitors also adhere avidly to immobilized PF4. This adhesion is time-dependent, requires metabolic activity, causes cytoskeletal rearrangement, and induces cell-cycle inhibition. Using extracellular acidification rate to indicate transmembrane signaling, we find that interleukin-8 (IL-8), but not PF4, activates CD34+ progenitors, and PF4 blocks IL-8–mediated activation. Surface plasmon resonance analysis shows that PF4 binds IL-8 with high (dissociation constant [Kd] = 42 nM) affinity. Nuclear magnetic resonance analysis of IL-8 and PF4 in solution confirms this interaction. We conclude that PF4 has the capacity to influence hematopoiesis through mechanisms not mediated by a classical high-affinity, 7-transmembrane domain chemokine receptor. Instead, PF4 may modulate the hematopoietic milieu both directly, by promoting progenitor adhesion and quiescence through interaction with an HPC chondroitin sulfate–containing moiety, and indirectly, by binding to or interfering with signaling caused by other, hematopoietically active chemokines, such as IL-8.
Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1α (HIF-1α) accumulation via redox-dependent mechanisms
Authors: Shatrov Vladimir A. , Sumbayev Vadim V. , Zhou Jie , Brüne Bernhard
Published: February 2003

Oxidized low-density lipoprotein (oxLDL) and macrophages play a central role in atherosclerosis. Here, we obtained evidence that oxLDL induced hypoxia-inducible factor-1α (HIF-1α) protein accumulation in human macrophages (Mono-Mac-6) under normoxia. HIF-1α accumulation was attenuated by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC), the nitric oxide (NO) donor S-nitrosoglutathione (GSNO), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors such as diphenyleniodonium (DPI) or 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), thus implicating the contribution of oxLDL-generated reactive oxygen species (ROS). Whereas oxLDL did not modulate HIF-1α mRNA levels, experiments with cycloheximide pointed to a translational mechanism in oxLDL action. HIF-1–dependent luciferase reporter gene analysis underscored HIF-1 transactivation. Our results indicate that oxLDL induced HIF-1α accumulation and HIF-1–dependent reporter gene activation in human macrophages via a redox-mediated pathway. This finding may suggest a role of HIF-1 in atherosclerosis and oxLDL-induced pathogenesis.
Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells
Authors: Witcher Michael , Ross Douglas T. , Rousseau Caroline , Deluca Leslie , Miller Wilson H.
Published: February 2003

The nuclear receptor ligand all-trans retinoic acid (ATRA) causes dramatic terminal differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients, but it is less active in other malignancies. However, downstream mediators of the effects of ATRA are not well understood. We used a cDNA microarray to search for ATRA-regulated genes in the APL cell line NB4 and found that ATRA regulated several members of the tumor necrosis factor (TNF) pathway. Here we show that TNF can synergize with ATRA to induce differentiation, showing monocytic characteristics more typical of differentiation mediated by TNF than by ATRA. ATRA and TNF can also induce differentiation of the non-APL cell line U937. Underlying this response was an increase in TNF-induced nuclear factor-κB (NF-κB) DNA binding within 2 hours in the presence of ATRA and activation of NF-κB DNA binding and transcriptional activity in response to ATRA alone within 48 hours of ATRA treatment. Furthermore, we found a synergistic induction of the NF-κB target genes BCL-3, Dif-2, and TNF receptor 2 (TNFR2) in response to the combination of TNF and ATRA. These genes have been previously shown to play a role in TNF signaling, and amplification of such genes may represent a mechanism whereby TNF and ATRA can act synergistically. We propose that ATRA can prime cancer cells for differentiation triggered by TNF and suggest that targeting the TNF pathway in combination with ATRA may represent a novel route to treat leukemias. (Blood. 2003;102:237-245)
Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation
Authors: Jin Yixin , Knudsen Eirunn , Wang Ling , Bryceson Yenan , Damaj Bassam , Gessani Sandra , Maghazachi Azzam A.
Published: February 2003

Sphingosine 1-phosphate (S1P) is a pleiotropic lysosphingophospholipid stored and secreted by platelets. Using reverse transcription–polymerase chain reaction and flow cytometric analyses, we determined the expression of S1P receptors (S1P1, S1P3, S1P4, and S1P5) in peripheral blood T cells. T cells were induced to proliferate in the presence of phorbol 12-myristate 13-acetate (PMA) plus ionomycin, anti-CD3 plus anti-CD28, and allogeneic immature or mature dendritic cells. This activity was inhibited by the addition of S1P. Enhanced T-cell proliferation was observed when these cells were stimulated with the same stimuli, but were incubated in serum-free media (SFM). Addition of S1P to SFM inhibited the stimulation of T cells induced by T-cell stimuli, suggesting that S1P is an important inhibitory molecule present in the serum. T-cell proliferation was also inhibited by the addition of dihydrosphingosine 1-phosphate (DHS1P), sphingosine, and ceramide; however, the latter 2 sphingolipids required higher concentrations than S1P. Pretreatment of T cells with pertussis toxin (PTX) blocked the inhibitory effect of S1P on activation with PMA plus ionomycin, but not on activation with anti-CD3 plus anti-CD28. This is corroborated with the down-regulation of S1P1 in T cells stimulated with anti-CD3 plus anti-CD28. Similarly, PTX did not affect the inhibitory effect of S1P on T-cell proliferation when dendritic cells were used as stimuli. Further, S1P or DHS1P but not ceramide or sphingosine enhanced rather than decreased secretion of interleukin 2 and interferon γ by T cells stimulated with anti-CD3 plus anti-CD28. These results show differential effects of S1P on polyclonal T-cell proliferation and cytokine secretion.