bluuebunny/crossref_metadata_2025 huggingface dataset:
SEWING YANG–MILLS MEASURES FOR NON-TRIVIAL BUNDLES
Authors: SENGUPTA AMBAR N.
Published: October 2003

For a closed surface Σ obtained by pasting together two surfaces Σ1 and Σ2 along their boundary components, it is proven that the Yang–Mills measure for a bundle of specified topology over the closed surface Σ results from a "convolution" of the corresponding measures for the surfaces Σ1 and Σ2.
VANISHING THEOREM OF THE HODGE–KODAIRA OPERATOR FOR DIFFERENTIAL FORMS ON A CONVEX DOMAIN OF THE WIENER SPACE
Authors: SHIGEKAWA ICHIRO
Published: October 2003

We discuss the vanishing theorem on a convex domain of the Wiener space. We show that there is no harmonic form satisfying the absolute boundary condition. Our method relies on an expression of the bilinear form associated with the Hodge–Kodaira operator.
Generalizations of Bernoulli numbers and polynomials
Authors: Luo Qiu-Ming , Guo Bai-Ni , Qi Feng , Debnath Lokenath
Published: October 2003

The concepts of Bernoulli numbers Bn, Bernoulli polynomials
Bn(x), and the generalized Bernoulli numbers Bn(a, b) are
generalized to the one Bn(x; a, b, c) which is called the
generalized Bernoulli polynomials depending on three positive
real parameters. Numerous properties of these polynomials and
some relationships between Bn, Bn(x), Bn(a, b), and
Bn(x; a, b, c) are established.
A coefficient inequality for the class of analytic functions inthe unit disc
Authors: Polatoğlu Yaşar , Bolcal Metın
Published: October 2003

The aim of this paper is to give a coefficient inequality for the
class of analytic functions in the unit disc D = {z||z|  < 1}.
On certain Heun functions, associated functions of discrete variables, and applications
Authors: Malits P.
Published: October 2003

Two sets of the Heun functions are introduced via integrals.
Theorems about expanding functions with respect to these sets are
proven. A number of integral and series representations as well
as integral equations and asymptotic formulas are obtained for
these functions. Some of the coefficients of the series are
orthogonal (J‐orthogonal) functions of discrete
variables and may be interpreted as orthogonal polynomials. Other
sets of the coefficients are biorthonormal. Expanding infinite
vectors to series with respect to the coefficients is
discussed. Certain Legendre functions of complex degree are
limiting cases of the studied functions. This leads to new
relations for Legendre functions and associated integral
transforms. The treated Heun functions find a use for solving
dual Fourier series equations which are reduced to the Fredholm
integral equations of the second kind. Explicit solutions are
obtained in a special case.
Coefficients estimates for functions in Bn(α)
Authors: Halim S. Abdul
Published: October 2003

We consider functions f, analytic in the unit disc and of the
normalised form

. For
functions f ∈ Bn(α), the class of functions involving
the Sălăgean differential operator, we give some
coefficient estimates, namely, |a2|, |a3|, and |a4|.
Existence of solutions and controllability ofnonlinear integrodifferential systems in Banach spaces
Authors: Balachandran K. , Park J. Y.
Published: October 2003

We prove the existence of mild and strong solutions of
integrodifferential equations with nonlocal conditions in Banach
spaces. Further sufficient conditions for the controllability of
integrodifferential systems are established. The results are
obtained by using the Schauder fixed‐point theorem. Examples are
provided to illustrate the theory.
Gene Expression in Macrophage-Rich Inflammatory Cell Infiltrates in Human Atherosclerotic Lesions as Studied by Laser Microdissection and DNA Array
Authors: Tuomisto Tiina T. , Korkeela Anna , Rutanen Juha , Viita Helena , Bräsen Jan H. , Riekkinen Mervi S. , Rissanen Tuomas T. , Karkola Kari , Kiraly Zsolt , Kölble Konrad , Ylä-Herttuala Seppo
Published: October 2003

Objective—

Inflammatory cells play an important role in atherogenesis. However, more information is needed about their gene expression profiles in human lesions.

Methods and Results—

We used laser microdissection (LMD) to isolate macrophage-rich shoulder areas from human lesions. Gene expression profiles in isolated cells were analyzed by cDNA array and compared with expression patterns in normal intima and THP-1 macrophages. Upregulation of 72 genes was detected with LMD and included 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interferon regulatory factor-5 (IRF-5), colony stimulating factor (CSF) receptors, CD11a/CD18 integrins, interleukin receptors, CD43, calmodulin, nitric oxide synthase (NOS), and extracellular superoxide dismutase (SOD). Several of these changes were also present in PMA-stimulated THP-1 macrophages in vitro. On the other hand, expression of several genes, such as VEGF, tissue factor pathway inhibitor 2, and apolipoproteins C-I and C-II, decreased.

Conclusions—

Overexpression of HMG-CoA reductase in macrophage-rich lesion areas may explain some beneficial effects of statins, which can also modulate increased expression of CD11a/CD18 and CD43 found in microdissected cells. We also found increased expression of CSF receptors, IRF-5, and interleukin receptors, which could become useful therapeutic targets for the treatment of atherosclerotic diseases.
Soy Protein With Isoflavones, but not an Isoflavone-Rich Supplement, Improves Arterial Low-Density Lipoprotein Metabolism and Atherogenesis
Authors: Wagner Janice D. , Schwenke Dawn C. , Greaves Kathryn A. , Zhang Li , Anthony Mary S. , Blair Robert M. , Shadoan Melanie K. , Williams J. Koudy
Published: October 2003

Objective—

We sought to determine if arterial LDL metabolism contributes to the decreased atherosclerosis seen with soy and if isolated isoflavones would have similar effects.

Methods and Results—

Ovariectomized monkeys were fed an atherogenic diet for 20 weeks with a protein source of (1) casein/lactalbumin (CAS, n=20), (2) soy protein isolate (SOY, n=20), or (3) casein/lactalbumin with isolated soy isoflavones (ISO, n=17). Plasma lipoprotein concentrations were improved with SOY but not ISO. Arterial LDL metabolism was characterized with one subset (n=12/group) injected with dual-labeled tyramine-cellobiose (TC)-LDL (
125
I-TC-
131
I-LDL) 24 hours before necropsy to determine LDL degradation and accumulation, while another subset (n=8/group) was injected with
125
I-TC-LDL 1 hour before necropsy to determine LDL permeability and delivery.

Conclusions—

Coronary artery LDL degradation was reduced by 50% (
P
=0.02) with SOY but not with ISO compared with CAS. Neither treatment altered arterial permeability. Reduced LDL degradation with SOY was due to decreased arterial LDL delivery (
P
=0.02). Carotid artery cholesterol ester was also decreased with SOY, but not with ISO. Plasma isoprostanes or plasma markers of inflammation did not differ among treatment groups. Thus, the decreased arterial LDL delivery and subsequent LDL degradation may explain, in part, the atheroprotective effects of soy.
Flow-Induced Vascular Remodeling in the Mouse
Authors: Korshunov Vyacheslav A. , Berk Bradford C.
Published: October 2003

Objective—

Vascular remodeling of the carotid artery with intima-media thickness (IMT) is an important predictive factor for human cardiovascular disease. We characterized a mouse model of vascular remodeling.

Methods and Results—

The left external and internal carotid branches were ligated so that left carotid blood flow was reduced to flow via the occipital artery. In response to partial ligation of the left carotid artery (LCA), blood flow significantly decreased (−90%) in the LCA and increased (+70%) in the right carotid artery (RCA). Morphometry showed that both RCA and LCA underwent outward remodeling that was maximal at one week. Remodeling was greater in the RCA with predominantly increased lumen and very little increase in media or adventitia. In the LCA there was a dramatic increase in media with adventitia growth and intima formation. Correlation analysis indicated that the outward remodeling was more likely due to primary changes in the vessel wall rather than to changes in the lumen, such as shear stress. Mechanistic studies suggested roles for macrophage infiltration, upregulation of matrix metalloproteinase (MMP)-9, extracellular matrix reorganization, and vascular smooth muscle cell proliferation in LCA remodeling.

Conclusions—

The mouse model described here may be useful to define genetic determinants of IMT and identify new targets for therapy based on vascular remodeling.
Hysteresis Effect Implicates Calcium Cycling as a Mechanism of Repolarization Alternans
Authors: Walker Mariah L. , Wan Xiaoping , Kirsch Glenn E. , Rosenbaum David S.
Published: October 2003

Background—

T-wave alternans is due to alternation of membrane repolarization at the cellular level and is a risk factor for sudden cardiac death. Recently, a hysteresis effect has been reported in patients whereby T-wave alternans, once induced by rapid heart rate, persists even when heart rate is subsequently slowed. We hypothesized that alternans hysteresis is an intrinsic property of cardiac myocytes, directly related to an underlying mechanism for repolarization alternans that involves intracellular calcium cycling.

Methods and Results—

Stepwise pacing was used to induce alternans in Langendorff-perfused guinea pig hearts from which optical action potentials were recorded simultaneously at 256 ventricular sites with voltage-sensitive dyes and in whole-cell patch-clamped cardiac myocytes treated with or without BAPTA-AM (1,2-bis[2-aminophenoxy]ethane-
N
,
N
,
N
′,
N
′-tetraacetic acid tetrakis [acetoxymethyl ester]). Alternans hysteresis was observed in every isolated heart: threshold heart rate for alternans was 280±12 bpm, but during subsequent deceleration of pacing, alternans persisted to significantly slower heart rates (238±5 bpm,
P
<0.05). Optical mapping showed that this effect also applied to the threshold for spatially discordant alternans (313±2.2 bpm during acceleration versus 250±6.6 bpm during deceleration,
P
<0.05). Alternans hysteresis was also observed in isolated cardiac myocytes. Moreover, calcium chelation by BAPTA-AM raised the threshold for alternans and inhibited hysteresis in a dose-dependent manner with no effect on baseline action potential duration.

Conclusions—

Alternans hysteresis is an intrinsic property of cardiac myocytes that can lead to persistence of arrhythmogenic discordant alternans even after heart rate is slowed. These results also support an important underlying role of calcium cycling in the mechanism of alternans.
Epiregulin as a Major Autocrine/Paracrine Factor Released From ERK- and p38MAPK-Activated Vascular Smooth Muscle Cells
Authors: Takahashi Masanori , Hayashi Ken’ichiro , Yoshida Kenji , Ohkawa Yasuyuki , Komurasaki Toshi , Kitabatake Akira , Ogawa Akira , Nishida Wataru , Yano Masahiko , Monden Morito , Sobue Kenji
Published: October 2003

Background—

The coordinated activation of extracellular signal–regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non–heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs).

Methods and Results—

We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner. Reverse transcriptase–polymerase chain reaction and/or immunohistological analyses revealed the restricted expression of epiregulin in human atherosclerotic and balloon-injured rat arteries, in which the phenotypic modulation of medial VSMCs occurred in vivo.

Conclusions—

Epiregulin is released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for VSMC dedifferentiation. It may be involved in the progression of vascular remodeling such as atherosclerosis.
Relevance of Monocytic Features for Neovascularization Capacity of Circulating Endothelial Progenitor Cells
Authors: Urbich Carmen , Heeschen Christopher , Aicher Alexandra , Dernbach Elisabeth , Zeiher Andreas M. , Dimmeler Stefanie
Published: October 2003

Background—

Transplantation of ex vivo expanded circulating endothelial progenitor cells (EPCs) from peripheral blood mononuclear cells improves the neovascularization after critical ischemia. However, the origin of the endothelial progenitor lineage and its characteristics have not yet been clearly defined. Therefore, we investigated whether the phenotype and functional capacity of EPCs to improve neovascularization depend on their monocytic origin.

Methods and Results—

Monocytic CD14
+
cells were isolated from mononuclear cells and incubated on fibronectin-coated dishes in endothelial medium in the presence of vascular endothelial growth factor. After 4 days of cultivation, adherent cells deriving from CD14
+
or CD14
−
mononuclear cells showed equal expression of endothelial marker proteins and capacity for clonal expansion as determined by measuring endothelial colony-forming units. In addition, transplanted EPCs (5×10
5
cells) deriving from CD14
+
or CD14
−
cells were incorporated into vascular structures of nude mice after hind-limb ischemia and significantly improved neovascularization from 0.27±0.12 (no cells) to 0.66±0.12 and 0.65±0.17, respectively (
P
<0.001; laser Doppler-derived relative blood flow). In contrast, no functional improvement of neovascularization was detected when freshly isolated CD14
+
mononuclear cells without ex vivo expansion were used (0.33±0.17). Moreover, macrophages or dendritic cells differentiated from isolated CD14
+
cells were significantly less effective in improving neovascularization than EPCs cultivated from the same starting population (
P
<0.01).

Conclusions—

These data demonstrate that EPCs can be generated from nonmonocytic CD14
−
peripheral blood mononuclear cells and exhibit a unique functional activity to improve neovascularization after hind-limb ischemia.
Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro
Authors: Izumi Toshiaki , Kihara Yasuki , Sarai Nobuaki , Yoneda Takeshi , Iwanaga Yoshitaka , Inagaki Koichi , Onozawa Yoko , Takenaka Hiroyuki , Kita Toru , Noma Akinori
Published: October 2003

Background—

In ventricular myocardium, the T-type Ca
2+
current (
I
Ca,T
), which is temporarily observed during fetal and neonatal periods, has been shown to reappear in failing/remodeling hearts. However, its pathophysiological regulation has not been elucidated.

Methods and Results—

We utilized Dahl salt-sensitive (DS) rats with hypertension at the stage of concentric left ventricular (LV) hypertrophy (11 weeks old, LVH) and at the heart failure stage (16 to 18 weeks old, CHF). Some were treated with bosentan (100 mg/kg per day) during the period from LVH to CHF. In LVH, neither the presence of
I
Ca,T
(measured in the freshly isolated LV myocytes) nor an increase in α-1G mRNA expression were detected. This condition was associated with increases in tissue angiotensin II (AII) but not with endothelin (ET)-1 peptides. In contrast, in CHF, when the tissue AII remained elevated and ET-1 de novo increased,
I
Ca,T
was recorded in most of the cells (−0.87±0.18 pA/pF at −30 mV,
P
<0.01 versus LVH). This was associated with a significant increase in the α-1G mRNA level. The chronic bosentan treatment eliminated both the elevation of α-1G mRNA level and
I
Ca,T
from the cells, whereas it did not affect the cell size and membrane capacitance. In addition, 48-hour exposure to ET-1 but not AII induced
I
Ca,T
in normal adult myocytes in culture from Sprague-Dawley rats.

Conclusions—

I
Ca,T
channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.
Multilineage Potential of Cells From the Artery Wall
Authors: Tintut Yin , Alfonso Zeni , Saini Trishal , Radcliff Kristen , Watson Karol , Boström Kristina , Demer Linda L.
Published: October 2003

Background—

In diabetes or atherosclerosis, ectopic bone, fat, cartilage, and marrow often develop in arteries. However the mechanism is unknown. We have previously identified a subpopulation of vascular cells (calcifying vascular cells, CVC), derived by dilutional cloning of bovine aortic medial cells, and showed that they undergo osteoblastic differentiation and mineralization. We now show that CVC have the potential to differentiate along other mesenchymal lineages.

Methods and Results—

To determine the multilineage potential of CVC, molecular and functional markers of multiple mesenchymal lineages were assessed. Chondrogenic potential of CVC was evidenced by expression of types II and IX collagen and cytochemical staining for Alcian blue. Leiomyogenic potential of CVC was evidenced by the expression of smooth muscle-α actin, calponin, caldesmon, and myosin heavy chain. Stromogenic potential of CVC was evidenced by the ability to support growth of colony-forming units of hematopoietic progenitor cells from human CD34
+
umbilical cord blood cells for a period of 5 weeks. Adipogenic potential was not observed. CVC were immunopositive to antigens to CD29 and CD44 but not to CD14 or CD45, consistent with other mesenchymal stem cells. CVC retained multipotentiality despite passaging and expansion through more than 20 to 25 population triplings, indicating a capacity for self-renewal.

Conclusions—

These results suggest that the artery wall contains cells that have the potential for multiple lineages similar to mesenchymal stem cells but with a unique differentiation repertoire.
Aldosterone and Not Plasminogen Activator Inhibitor-1 Is a Critical Mediator of Early Angiotensin II/
N
G
-Nitro-
l
-Arginine Methyl Ester-Induced Myocardial Injury
Authors: Oestreicher Eveline M. , Martinez-Vasquez Diego , Stone James R. , Jonasson Larus , Roubsanthisuk Weranuj , Mukasa Koji , Adler Gail K.
Published: October 2003

Background—

Angiotensin II (Ang II) increases levels of aldosterone and plasminogen activator inhibitor-1 (PAI-1). Both aldosterone and PAI-1 seem to promote cardiovascular (CV) injury. Our objective was to determine the roles of PAI-1 and aldosterone in the development of myocardial and renal damage in a model with high Ang II and low nitric oxide (NO) availability, a pattern seen in patients with heart failure, diabetes mellitus, and arteriosclerosis.

Methods and Results—

Mice on a moderately high sodium diet were treated with the NO synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME) for 14 days plus Ang II during days 8 through 14. The roles of aldosterone and PAI-1 in the development of CV injury were assessed using the mineralocorticoid receptor antagonist spironolactone (0, 1.5, 15, and 50 mg · 100 g
−1
· day
−1
) and PAI-1-deficient mice (PAI-1
−/−
). Ang II/L-NAME-treated mice showed glomerular ischemia, proteinuria, and necrosis of myocytes and vascular smooth muscle cells with an associated mixed inflammatory response, deposition of loose collagen, and neovascularization. Compared with saline-drinking mice, Ang II/L-NAME-treated mice had significantly increased heart to body weight (HW/BW) ratios, cardiac and renal damage assessed by histological examination, PAI-1 immunoreactivity, and proteinuria. Spironolactone treatment decreased PAI-1 immunoreactivity and reduced in a dose-dependent fashion cardiac and renal damage. PAI-1
−/−
animals had a similar degree of CV injury as PAI-1
+/+
animals.

Conclusions—

Mineralocorticoid receptor antagonism, but not PAI-1 deficiency, protected mice from developing Ang II/L-NAME-mediated myocardial and vascular injury and proteinuria, suggesting that aldosterone, but not PAI-1, plays a key role in the development of early Ang II/L-NAME-induced cardiovascular injury.
Characterizing Vulnerable Plaque Features With Intravascular Elastography
Authors: Schaar Johannes A. , de Korte Chris L. , Mastik Frits , Strijder Chaylendra , Pasterkamp Gerard , Boersma Eric , Serruys Patrick W. , van der Steen Anton F.W.
Published: October 2003

Background—

In vivo detection of vulnerable plaques is presently limited by a lack of diagnostic tools. Intravascular ultrasound elastography is a new technique based on intravascular ultrasound and has the potential to differentiate between different plaques phenotypes. However, the predictive value of intravascular elastography to detect vulnerable plaques had not been studied.

Methods and Results—

Postmortem coronary arteries were investigated with intravascular elastography and subsequently processed for histology. In histology, a vulnerable plaque was defined as a plaque consisting of a thin cap (<250 μm) with moderate to heavy macrophage infiltration and at least 40% of atheroma. In elastography, a vulnerable plaque was defined as a plaque with a high strain region at the surface with adjacent low strain regions. In 24 diseased coronary arteries, we studied 54 cross sections. In histology, 26 vulnerable plaques and 28 nonvulnerable plaques were found. Receiver operator characteristic analysis revealed a maximum predictive power for a strain value threshold of 1.26%. The area under the receiver operator characteristic curve was 0.85. The sensitivity was 88%, and the specificity was 89% to detect vulnerable plaques. Linear regression showed high correlation between the strain in caps and the amount of macrophages (
P
<0.006) and an inverse relation between the amount of smooth muscle cells and strain (
P
<0.0001). Plaques, which are declared vulnerable in elastography, have a thinner cap than nonvulnerable plaques (
P
<0.0001).

Conclusions—

Intravascular elastography has a high sensitivity and specificity to detect vulnerable plaques in vitro.
Adverse Prognosis of Patients With Hypertrophic Cardiomyopathy Who Have Epicardial Coronary Artery Disease
Authors: Sorajja Paul , Ommen Steve R. , Nishimura Rick A. , Gersh Bernard J. , Berger Peter B. , Tajik A. Jamil
Published: October 2003

Background—

Adult patients with hypertrophic cardiomyopathy (HCM) may develop concomitant atherosclerotic coronary artery disease (CAD). There is a paucity of data on the clinical outcomes of HCM patients who have CAD.

Methods and Results—

We examined the outcome of 433 adult patients with HCM according to the presence and severity of CAD. All patients were aged ≥21 years, had a left ventricular ejection fraction of ≥50%, and were without a history of prior surgical revascularization (mean age, 63 years; 212 men). Compared with HCM patients with mild-to-moderate or no CAD, those with severe CAD demonstrated markedly reduced survival. Ten-year overall survival was 46.1%, 70.5%, and 77.1% for patients with severe, mild-to-moderate, and no CAD, respectively (unadjusted
P
=0.0001; adjusted
P
=0.0006). For the end point of cardiac death, this survival was 62.3%, 81.0%, and 80.9% (unadjusted
P
=0.009; adjusted
P
=0.004). For the end point of sudden cardiac death, this survival was 77.4%, 93.2%, and 90.3% (unadjusted
P
=0.01; adjusted
P
=0.01). The presence of severe CAD also was highly predictive of these events (risk ratio for respective event: 2.31, 2.15, and 2.77) in multivariate models that additionally identified age, prior stroke, hyperlipidemia, and atrial fibrillation as significant covariates.

Conclusions—

Among adult patients with HCM who undergo coronary angiography, those who have concomitant severe CAD are at increased risk of death. This risk far exceeds historical death rates of CAD patients with normal left ventricular function.
Effects of Intense and Prolonged Exercise on Insulin Sensitivity and Glycogen Metabolism in Hypertensive Subjects
Authors: Rhéaume Caroline , Waib Paulo-Henrique , Kouamé N’Guessan , Nadeau André , Lacourcière Yves , Joanisse Denis R. , Simoneau Jean-Aimé , Cléroux Jean
Published: October 2003

Background—

The information that insulin sensitivity and glycogen synthesis are reduced in hypertension arises primarily from studies using insulin infusions. Whether glycogen metabolism is actually altered in a physiological condition, such as during and after prolonged exercise, is currently unknown.

Methods and Results—

To examine this issue, 9 hypertensive and 11 normotensive subjects were evaluated on a rest day and after intense and prolonged exercise on a separate day. Insulin sensitivity and hemodynamic variables were measured on both days. On the exercise day, whole-body substrate utilization was assessed and muscle biopsies were taken in the leg at baseline, immediately after exercise, and 2.5 and 4 hours after exercise. Insulin sensitivity at rest was lower in hypertensive than normotensive subjects (
P
<0.05) and increased after exercise in normotensive (
P
<0.01) but not in hypertensive (
P
=NS) subjects. Leg blood flow increased after exercise in both groups but to a lesser extent in hypertensive than normotensive subjects. Baseline glycogen content and maximal glycogen synthase activity were higher in hypertensive than normotensive subjects (
P
<0.001). Glycogen concentration decreased relatively less (−35 versus −66%) and returned to baseline levels faster in hypertensive subjects after exercise. Hypertensive subjects used ≈40% less carbohydrates during exercise (
P
<0.001) at the expense of greater free fatty acid oxidation.

Conclusions—

It is concluded that increased intramuscular glycogen storage and resynthesis in hypertension are independent of blood flow and may represent compensatory mechanisms for the reduced insulin sensitivity and carbohydrate metabolism in this condition.
Exercise-Induced Pulmonary Edema in Heart Failure
Authors: Agostoni Piergiuseppe , Cattadori Gaia , Bianchi Michele , Wasserman Karlman
Published: October 2003

Background—

In heart failure (HF) patients, exercise may increase pulmonary capillary hydrostatic pressure and thereby generate pulmonary edema. If pulmonary edema developed, alveolar-capillary membrane conductance (D
m
), measured immediately after exercise, would decrease. To test this hypothesis, we measured D
m
before and at 2 and 60 minutes after exercise.

Methods and Results—

We studied 10 HF patients with exercise-induced periodic breathing, 10 with peak V̇
o
2
≤15 mL · min
−1
· kg
−1
(severe HF), 10 with V̇
o
2
=15 to 20 mL · min
−1
· kg
−1
(moderate HF), and 10 normal subjects (control). Using the Roughton-Forster technique, we measured carbon monoxide diffusion capacity (DL
co
) and its components, capillary blood volume (V
c
) and D
m
, at rest and 2 and 60 minutes after exercise. At rest, DL
co
and D
m
were lowest in periodic breathing and highest in control subjects. D
m
decreased in periodic breathing, severe HF, and moderate HF (−7.83±3.98, −5.57±2.03, and −3.85±3.53 mL · min
−1
· mm Hg
−1
, respectively;
P
<0.01) at 2 minutes after exercise but not in control subjects. V
c
increased in all groups at 2 minutes and remained elevated at 60 minutes only in periodic breathing. D
m
/V
c
was decreased in periodic breathing, severe HF, and moderate HF at 2 minutes but not in control subjects. D
m
and D
m
/V
c
remained low at 60 minutes only in periodic breathing.

Conclusions—

D
m
decreases after exercise in HF patients but not in control subjects, which suggests a decrease in conductance across the alveolar-capillary barrier, as with pulmonary edema. The reductions were most marked in HF patients with periodic breathing and less reduced in less severe HF.
Crucial Role of Stromal Cell–Derived Factor-1α in Neointima Formation After Vascular Injury in Apolipoprotein E–Deficient Mice
Authors: Schober Andreas , Knarren Sandra , Lietz Michael , Lin Elisa A. , Weber Christian
Published: October 2003

Background—

Recent evidence indicates that stromal cell–derived factor-1α (SDF-1α) is expressed in human atherosclerotic plaques, whereas high plasma levels are clinically associated with stable coronary artery disease. Herein, we investigate the involvement of SDF-1α in neointimal formation after vascular injury.

Methods and Results—

SDF-1α was detected by immunohistochemistry in carotid arteries of apolipoprotein E–deficient (apoE
−/−
) mice at various stages of neointima formation after wire-induced injury. Double immunofluorescence revealed that SDF-1α staining was mostly confined to smooth muscle cells (SMCs). Furthermore, SDF-1α plasma levels peaked 1 day after vascular injury. Treatment of apoE
−/−
mice after carotid injury with a neutralizing SDF-1α monoclonal antibody for 3 weeks reduced neointimal lesion area by 44% (n=5,
P
<0.05) compared with isotype control. In SDF-1α antibody–treated apoE
−/−
mice, neointimal SMC content was decreased (21.7±2% versus 39.4±4%, n=5,
P
=0.005), whereas the relative content of neointimal macrophages remained unchanged. As shown by flow cytometry, carotid injury resulted in a marked expansion of circulating Sca-1
+
lineage
−
progenitor cells (PBPCs) in the peripheral blood of apoE
−/−
mice after 1 day, which was mediated by SDF-1α. Systemic injection of isolated PBPCs after vascular injury demonstrated their recruitment to neointimal lesions, where they can adopt an SMC-like phenotype.

Conclusions—

SDF-1α plays an instrumental role in neointimal formation after vascular injury in apoE
−/−
mice by regulating neointimal SMC content. This contribution appears to be attributable to SDF-1α–dependent recruitment of circulating SMC progenitor cells.
Interleukin-18 and the Risk of Coronary Heart Disease in European Men
Authors: Blankenberg Stefan , Luc Gérald , Ducimetière Pierre , Arveiler Dominique , Ferrières Jean , Amouyel Philippe , Evans Alun , Cambien François , Tiret Laurence
Published: October 2003

Background—

Interleukin (IL)-18 promotes atherosclerotic plaque growth and vulnerability. It is unknown, however, whether elevations of circulating IL-18 precede the onset of coronary events in apparently healthy individuals.

Methods and Results—

We evaluated the relationship between baseline plasma levels of IL-18 and the subsequent incidence of coronary events over a 5-year follow-up in the Prospective Epidemiological Study of Myocardial Infarction (PRIME),which included 10 600 healthy European men aged 50 to 59 years at baseline. Analysis was performed in a nested case-control manner comparing 335 cases with a coronary event to 670 age-matched controls. Baseline levels of IL-18 were significantly higher in men who developed a coronary event than in controls (225.1 versus 203.9 pg/mL,
P
=0.005). After adjustment for most potential confounders, including C-reactive protein, IL-6, and fibrinogen, the relative risk of future coronary events associated with increasing tertiles of IL-18 was 1.65 (95% CI 1.14 to 2.40,
P
=0.008) in Northern Ireland, 1.29 (95% CI 0.96 to 1.73,
P
=0.09) in France, and 1.42 (95% CI 1.13 to 1.79,
P
=0.003) in both populations combined (
P
=0.31 for the test of homogeneity between populations). In all models, IL-18 made an independent contribution to the prediction of risk over lipids or other inflammatory markers such as C-reactive protein, IL-6, or fibrinogen.

Conclusions—

Plasma IL-18 level was identified as an independent predictor of coronary events in healthy, middle-aged European men. Determination of circulating IL-18 might improve the prediction of coronary events.
Reactive Oxygen Species in the Vasculature
Authors: Taniyama Yoshihiro , Griendling Kathy K.
Published: October 2003

Accumulating evidence indicates that reactive oxygen species (ROS) play major roles in the initiation and progression of cardiovascular dysfunction associated with diseases such as hyperlipidemia, diabetes mellitus, hypertension, ischemic heart disease, and chronic heart failure. ROS produced by migrating inflammatory cells as well as vascular cells (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) have distinct functional effects on each cell type. These include cell growth, apoptosis, migration, inflammatory gene expression, and matrix regulation. ROS, by regulating vascular cell function, can play a central role in normal vascular physiology, and can contribute substantially to the development of vascular disease.
αB-Crystallin Modulates Protein Aggregation of Abnormal Desmin
Authors: Wang Xuejun , Klevitsky Raisa , Huang Wei , Glasford Joseph , Li Faqian , Robbins Jeffrey
Published: October 2003

αB-crystallin (CryAB) is the most abundant small heat shock protein in the heart. Upregulation of CryAB in desmin-related myopathy and its downregulation in end-stage congestive heart failure have both been reported. We previously demonstrated via cardiac-specific transgenesis that modest increases in normal CryAB are not detrimental to the heart, whereas expression of the R120G mutation of CryAB caused a desminopathy. It is generally believed that CryAB plays an important role in protecting the intermediate filaments, but the underlying mechanism is unclear. We hypothesized that CryAB protects the desmin filaments via preventing abnormal desmin protein from aggregating adversely. To test this hypothesis in vivo, mice expressing a desmin mutation that causes a desmin-related cardiomyopathy (D7) were bred into the R120G-CryAB transgenic (TG) background to examine the accumulation and aberrant aggregation of desmin protein. Despite lower mRNA expression of D7-des than in the D7-des TG hearts, the double-TG myocardium exhibited significantly higher desmin protein levels and dramatically more aberrant desmin aggregates than the D7-des TG hearts. The double-TG mice displayed a significantly stronger cardiac hypertrophic response, with the mice dying of congestive heart failure before 7 weeks. To explore the ability of wild-type (WT) CryAB to protect against mutant desmin, a desmin mutant was expressed in both the conventional and WT-CryAB stably transfected HEK cells. Significantly less aberrant desmin aggregation was observed in the WT-CryAB–overexpressing cells than in the HEK cells. The results suggest that CryAB modulates abnormal desmin aggregation and can serve a cardioprotective role.
Influence of Na
+
-Independent Cl
−
-HCO
3
−
Exchange on the Slow Force Response to Myocardial Stretch
Authors: Cingolani Horacio E. , Chiappe Gladys E. , Ennis Irene L. , Morgan Patricio G. , Alvarez Bernardo V. , Casey Joseph R. , Dulce Raúl A. , Pérez Néstor G. , Camilión de Hurtado María C.
Published: October 2003

Previous work demonstrated that the slow force response (SFR) to stretch is due to the increase in calcium transients (Ca
2+
T) produced by an autocrine-paracrine mechanism of locally produced angiotensin II/endothelin activating Na
+
-H
+
exchange. Although a rise in pH
i
is presumed to follow stretch, it was observed only in the absence of extracellular bicarbonate, suggesting pH
i
compensation through the Na
+
-independent Cl
−
-HCO
3
−
exchange (AE) mechanism. Because available AE inhibitors do not distinguish between different bicarbonate-dependent mechanisms or even between AE isoforms, we developed a functional inhibitory antibody against both the AE3c and AE3fl isoforms (anti-AE3Loop III) that was used to explore if pH
i
would rise in stretched cat papillary muscles superfused with bicarbonate after AE3 inhibition. In addition, the influence of this potential increase in pH
i
on the SFR was analyzed. In this study, we present evidence that cancellation of AE3 isoforms activity (either by superfusion with bicarbonate-free buffer or with anti-AE3Loop III) results in pH
i
increase after stretch and the magnitude of the SFR was larger than when AE was operative, despite of similar increases in [Na
+
]
i
and Ca
2+
T under both conditions. Inhibition of reverse mode Na
+
-Ca
2+
exchange reduced the SFR to the half when the AE was inactive and totally suppressed it when AE3 was active. The difference in the SFR magnitude and response to inhibition of reverse mode Na
+
-Ca
2+
exchange can be ascribed to a pH
i
-induced increase in myofilament Ca
2+
responsiveness.
Pharmacological Activation of Normal and Arrhythmia-Associated Mutant KCNQ1 Potassium Channels
Authors: Seebohm Guiscard , Pusch Michael , Chen Jun , Sanguinetti Michael C.
Published: October 2003

KCNQ1 α-subunits coassemble with KCNE1 β-subunits to form channels that conduct the slow delayed rectifier K
+
current (
I
Ks
) important for repolarization of the cardiac action potential. Mutations in
KCNQ1
reduce
I
Ks
and cause long-QT syndrome, a disorder of ventricular repolarization that predisposes affected individuals to arrhythmia and sudden death. Current therapy for long-QT syndrome is inadequate. R-L3 is a benzodiazepine that activates
I
Ks
and has the potential to provide gene-specific therapy. In the present study, we characterize the molecular determinants of R-L3 interaction with KCNQ1 channels, use computer modeling to propose a mechanism for drug-induced changes in channel gating, and determine its effect on several long-QT syndrome–associated mutant KCNQ1 channels heterologously expressed in
Xenopus
oocytes. Scanning mutagenesis combined with voltage-clamp analysis indicated that R-L3 interacts with specific residues located in the 5th and 6th transmembrane domains of KCNQ1 subunits. Most KCNQ1 mutant channels responded to R-L3 similarly to wild-type channels, but one mutant channel (G306R) was insensitive to R-L3 possibly because it disrupted a key component of the drug-binding site.
Cell Type–Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1
Authors: Kelly Brian D. , Hackett Sean F. , Hirota Kiichi , Oshima Yuji , Cai Zheqing , Berg-Dixon Shannon , Rowan Ashley , Yan Zhijiang , Campochiaro Peter A. , Semenza Gregg L.
Published: October 2003

Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1α–null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1α is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.
Novel Polypyrimidine Variation (IVS46: del T −39…−46) in
ABCA1
Causes Exon Skipping and Contributes to HDL Cholesterol Deficiency in a Family With Premature Coronary Disease
Authors: Ho Hong Seung , Rhyne Jeffrey , Miller Michael
Published: October 2003

Recent studies have implicated mutations in the ATP-binding cassette transporter A1,
ABCA1
, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the
ABCA1
gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3′ acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T −39…−46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11±5 mg/dL) and ApoA-I (35±15 mg/dL) compared with wild-type (n=25) (HDL-C 51±14 mg/dL; ApoA-I 133±21 mg/dL) (
P
<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36±8; ApoA-I 117±19) or IVS46: del T −39…−46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (
P
<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.
Transcriptional Profiling of the Heart Reveals Chamber-Specific Gene Expression Patterns
Authors: Tabibiazar Raymond , Wagner Roger A. , Liao Arnold , Quertermous Thomas
Published: October 2003

Cardiac chamber-specific gene expression is critical for the normal development and function of the heart. To investigate the genetic basis of cardiac anatomical specialization, we have undertaken a nearly genome-wide transcriptional profiling of the four heart chambers and the interventricular septum. Rigorous statistical analysis has allowed the identification of known and novel members of gene families that are felt to be important in cardiac development and function, including LIM proteins, homeobox proteins, wnt and T-box pathway proteins, as well as structural proteins like actins and myosins. In addition, these studies have allowed the identification of thousands of additional differentially expressed genes, for which there is little structural or functional information. Clustering of genes with known and unknown functions provides insights into signaling pathways that are essential for development and maintenance of chamber-specific features. To facilitate future research in this area, a searchable internet database has been constructed that allows study of the chamber-specific expression of any gene represented on this comprehensive microarray. It is anticipated that further study of genes identified through this effort will provide insights into the specialization of heart chamber tissues, and their specific roles in cardiac development, aging, and disease.
Impaired Acetylcholine-Induced Release of Nitric Oxide in the Aorta of Male Aromatase-Knockout Mice
Authors: Kimura Masahiko , Sudhir Krishnankutty , Jones Margaret , Simpson Evan , Jefferis Ann-Maree , Chin-Dusting Jaye P.F.
Published: October 2003

The consequences of estrogen deficiency on the cardiovascular system have been widely examined in females. The effects of endogenous estrogen deficiency in males are less clear. The aromatase-knockout (ArKO) mouse lacks a functional
Cyp19
gene, which encodes aromatase, and is thus incapable of synthesizing endogenous estrogen. In the present study, we examined the effect of lack of endogenous estrogens on vascular function in aortic rings isolated from male ArKO mice and compared these effects to rings from wild-type (WT) littermates. Full concentration-response curves to norepinephrine, acetylcholine, isoprenaline, and sodium nitroprusside were obtained in the absence and presence of the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine in aortic segments set up in isometric myographs. Responses to noradrenaline were not different in aorta from ArKO compared with WT mice. Both
N
ω
-nitro-
l
-arginine and endothelium denudation significantly shifted the noradrenaline concentration-response curve to the left; however, this shift was not different in ArKO compared with WT. Responses to the endothelium-dependent vasodilator acetylcholine were significantly blunted in aortic rings from ArKO mice (E
max
, 58.2±0.9% and 34.0±0.5% in wild-type and ArKO, respectively;
P
<0.05), whereas responses to the endothelium-independent agonist sodium nitroprusside and to the partial endothelium-dependent agonist isoprenaline were not affected. These findings suggest that endogenous estrogen facilitate vasorelaxation in males. This may be via modulating endothelial function rather than vascular smooth muscle cell responsiveness.
Effect of Basic Fibroblast Growth Factor Treatment on Brain Progenitor Cells After Permanent Focal Ischemia in Rats
Authors: Wada Kuniyasu , Sugimori Hiroshi , Bhide Pradeep G. , Moskowitz Michael A. , Finklestein Seth P.
Published: October 2003

Background and Purpose—

Intracisternal basic fibroblast growth factor (bFGF) enhances sensorimotor recovery after focal cerebral infarction in rats. One possible mechanism is stimulation of endogenous progenitor cells in brain. We investigated the effects of intracisternal bFGF on brain progenitor cells after stroke.

Methods—

Proliferating brain cells were labeled with bromodeoxyuridine (BrdU) before middle cerebral artery (MCA) occlusion or sham surgery in rats. bFGF (0.5 μg) or vehicle was administered intracisternally at 24 and 48 hours after MCA occlusion, and rats were killed at 7, 14, or 21 days after stroke. Immunohistochemistry for BrdU and neuron- or astrocyte-specific markers was used to characterize progenitor cells and their progeny in the subventricular zone and dentate gyrus of the hippocampus.

Results—

Infarct size did not differ among rats with or without bFGF treatment. MCA occlusion alone increased the number of BrdU-labeled cells in the ipsilateral subventricular zone at days 7 to 21, and there was a trend toward increased cell proliferation with bFGF treatment. In the dentate gyrus, the number of BrdU-labeled cells was increased bilaterally after MCA occlusion (peak at day 7). This increase was greater after bFGF treatment. In the subventricular zone, 30% of BrdU-labeled cells were immunopositive for the immature neuron-specific marker doublecortin at day 7, and their number declined to 2% at day 21. In the dentate gyrus, the majority of BrdU-labeled cells colabeled with doublecortin at day 7, becoming NeuN positive at day 21.

Conclusions—

Stroke produces significant changes in progenitor cells in brain that are augmented by bFGF treatment.