bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Importance of Obesity Versus the Metabolic Syndrome in Cardiovascular Risk in Women
Authors: Kip Kevin E. , Marroquin Oscar C. , Kelley David E. , Johnson B. Delia , Kelsey Sheryl F. , Shaw Leslee J. , Rogers William J. , Reis Steven E.
Published: February 2004

Background—

Obesity and the metabolic syndrome frequently coexist. Both are associated with cardiovascular disease (CVD). However, the contribution of obesity to cardiovascular risk, independent of the presence of the metabolic syndrome, remains controversial.

Methods and Results—

From the WISE study, 780 women referred for coronary angiography to evaluate suspected myocardial ischemia were classified by body mass index (BMI; <24.9=normal, n=184; ≥25.0 to ≤29.9=overweight, n=269; ≥30.0=obese, n=327) and presence (n=451) or absence (n=329) of the metabolic syndrome, further classified by diabetes status. Prevalence of significant angiographic coronary artery disease (CAD; ≥50% stenosis) and 3-year risk of CVD were compared by BMI and metabolic status. The metabolic syndrome and BMI were strongly associated, but only metabolic syndrome was associated with significant CAD. Similarly, unit increases in BMI (normal to overweight to obese) were not associated with 3-year risk of death (adjusted hazard ratio [HR] 0.92, 95% CI 0.59 to 1.51) or major adverse cardiovascular event (MACE: death, nonfatal myocardial infarction, stroke, congestive heart failure; adjusted HR 0.95, 95% CI 0.71 to 1.27), whereas metabolic status (normal to metabolic syndrome to diabetes) conferred an approximate 2-fold adjusted risk of death (HR 2.01, 95% CI 1.26 to 3.20) and MACE (HR 1.88, 95% CI 1.38 to 2.57). Levels of C-reactive protein (hs-CRP) were more strongly associated with metabolic syndrome than BMI but were not independently associated with 3-year risk of death or MACE.

Conclusions—

The metabolic syndrome but not BMI predicts future cardiovascular risk in women. Although it remains prudent to recommend weight loss in overweight and obese women, control of all modifiable risk factors in both normal and overweight persons to prevent transition to the metabolic syndrome should be considered the ultimate goal.
Serum Amyloid A as a Predictor of Coronary Artery Disease and Cardiovascular Outcome in Women
Authors: Johnson B. Delia , Kip Kevin E. , Marroquin Oscar C. , Ridker Paul M , Kelsey Sheryl F. , Shaw Leslee J. , Pepine Carl J. , Sharaf Barry , Bairey Merz C. Noel , Sopko George , Olson Marian B. , Reis Steven E.
Published: February 2004

Background—

Serum amyloid-α (SAA) is a sensitive marker of an acute inflammatory state. Like high-sensitivity C-reactive protein (hs-CRP), SAA has been linked to atherosclerosis. However, prior studies have yielded inconsistent results, and the independent predictive value of SAA for coronary artery disease (CAD) severity and cardiovascular events remains unclear.

Methods and Results—

A total of 705 women referred for coronary angiography for suspected myocardial ischemia underwent plasma assays for SAA and hs-CRP, quantitative angiographic assessment, and follow-up evaluation. Cardiovascular events were death, myocardial infarction, congestive heart failure, stroke, and other vascular events. The women’s mean age was 58 years (range 21 to 86 years), and 18% were nonwhite. SAA and hs-CRP were associated with a broad range of CAD risk factors. After adjustment for these risk factors, SAA levels were independently but moderately associated with angiographic CAD (
P
=0.004 to 0.04) and highly predictive of 3-year cardiovascular events (
P
<0.0001). By comparison, hs-CRP was not associated with angiographic CAD (
P
=0.08 to 0.35) but, like SAA, was strongly and independently predictive of adverse cardiovascular outcome (
P
<0.0001).

Conclusions—

Our results show a strong independent relationship between SAA and future cardiovascular events, similar to that found for hs-CRP. Although SAA was independently but moderately associated with angiographic CAD, this association was not found for hs-CRP. These results are consistent with the hypothesis that systemic inflammation, manifested by high SAA or hs-CRP levels, may promote atherosclerotic plaque destabilization, in addition to exerting a possible direct effect on atherogenesis.
Metabolic Syndrome Modifies the Cardiovascular Risk Associated With Angiographic Coronary Artery Disease in Women
Authors: Marroquin Oscar C. , Kip Kevin E. , Kelley David E. , Johnson B. Delia , Shaw Leslee J. , Bairey Merz C. Noel , Sharaf Barry L. , Pepine Carl J. , Sopko George , Reis Steven E.
Published: February 2004

Background—

The metabolic syndrome, which is characterized by a constellation of fasting hyperglycemia, hypertriglyceridemia, low HDL cholesterol, hypertension, and/or abdominal obesity, is a risk factor for the development of coronary artery disease (CAD) and cardiovascular events. The interrelationship between metabolic status and CAD on cardiovascular risk in women is not known.

Methods and Results—

We evaluated interrelationships between angiographic CAD, the metabolic syndrome, and incident cardiovascular events among 755 women from the Women’s Ischemia Syndrome Evaluation (WISE) study who were referred for coronary angiography to evaluate suspected myocardial ischemia; 25% of the cohort had the metabolic syndrome at study entry. Compared with women with normal metabolic status, women with the metabolic syndrome had a significantly lower 4-year survival rate (94.3% versus 97.8%,
P
=0.03) and event-free survival from major adverse cardiovascular events (death, nonfatal myocardial infarction, stroke, or congestive heart failure; 87.8% versus 93.5%,
P
=0.003). When the subjects were stratified by the presence or absence of angiographically significant CAD at study entry, in women with angiographically significant CAD, the metabolic syndrome resulted in significantly higher risk of cardiovascular events than in women with normal metabolic status (hazard ratio 4.93, 95% CI 1.02 to 23.76;
P
=0.05), whereas it did not result in increased 4-year cardiovascular risk in women without angiographically significant CAD (hazard ratio 1.41, 95% CI 0.32 to 6.32;
P
=0.65).

Conclusions—

These data suggest that in women with suspected myocardial ischemia, the metabolic syndrome modifies the cardiovascular risk associated with angiographic CAD. Specifically, the metabolic syndrome was found to be a predictor of 4-year cardiovascular risk only when associated with significant angiographic CAD.
Adenoviral Catheter-Mediated Intramyocardial Gene Transfer Using the Mature Form of Vascular Endothelial Growth Factor-D Induces Transmural Angiogenesis in Porcine Heart
Authors: Rutanen Juha , Rissanen Tuomas T. , Markkanen Johanna E. , Gruchala Marcin , Silvennoinen Päivi , Kivelä Antti , Hedman Antti , Hedman Marja , Heikura Tommi , Ordén Maija-Riitta , Stacker Steven A. , Achen Marc G. , Hartikainen Juha , Ylä-Herttuala Seppo
Published: February 2004

Background—

It is unclear what is the most efficient vector and growth factor for induction of therapeutic vascular growth in the heart. Furthermore, the histological nature of angiogenesis and potential side effects caused by different vascular endothelial growth factors (VEGFs) in myocardium have not been documented.

Methods and Results—

Adenoviruses (Ad) at 2 doses (2×10
11
and 2×10
12
viral particles) or naked plasmids (1 mg) encoding
Lac
Z control, VEGF-A
165
, or the mature, soluble form of VEGF-D (VEGF-D
ΔNΔC
) were injected intramyocardially with the NOGA catheter system into domestic pigs. AdVEGF-D
ΔNΔC
gene transfer (GT) induced a dose-dependent myocardial protein production, as measured by ELISA, resulting in an efficient angiogenic effect 6 days after the injections. Also, AdVEGF-A
165
produced high gene transfer efficacy, as demonstrated with immunohistochemistry, leading to prominent angiogenesis effects. Despite the catheter-mediated approach, angiogenesis induced by both AdVEGFs was transmural, with maximal effects in the epicardium. Histologically, strongly enlarged α-smooth muscle actin–positive microvessels involving abundant cell proliferation were found in the transduced regions, whereas microvessel density did not change. Myocardial contrast echocardiography and microspheres showed marked increases in perfusion in the transduced areas. VEGF-D
ΔNΔC
but not matrix-bound VEGF-A
165
was detected in plasma after adenoviral GT. A modified Miles assay demonstrated myocardial edema resulting in pericardial effusion with the higher AdVEGF doses. All effects returned to baseline by 3 weeks. Naked plasmid–mediated GT did not induce detectable protein production or vascular effects.

Conclusions—

Like AdVEGF-A
165
, AdVEGF-D
ΔNΔC
GT using the NOGA system produces efficient transmural angiogenesis and increases myocardial perfusion. AdVEGF-D
ΔNΔC
could be useful for the induction of therapeutic vascular growth in the heart.
Pressure-Induced Matrix Metalloproteinase-9 Contributes to Early Hypertensive Remodeling
Authors: Lehoux Stéphanie , Lemarié Catherine A. , Esposito Bruno , Lijnen H. Roger , Tedgui Alain
Published: February 2004

Background—

High blood pressure causes a change in vascular wall structure involving altered extracellular matrix composition, but how this process occurs is not fully understood.

Methods and Results—

Using mouse carotid arteries maintained in organ culture for 3 days, we detected increased gelatin zymographic activity of matrix metalloproteinase (MMP)-2 (168±13%,
P
<0.05) in vessels kept at low intraluminal pressure (10 mm Hg) compared with vessels at 80 mm Hg (100%), whereas in vessels maintained at high pressure (150 mm Hg), both MMP-2 and MMP-9 activity was induced (182±32%,
P
<0.05, and 194±21%,
P
<0.01, respectively). MMPs were detected in endothelial and smooth muscle cells by immunohistochemistry and in situ gelatin zymography. In vessels at 150 mm Hg, MMP activation was associated with a shift in the pressure-diameter curve toward greater distensibility (
P
<0.01) compared with vessels at 80 mm Hg. However, distensibility was not altered in vessels at 10 mm Hg, in which only activated MMP-2 was detected. The role of MMPs in high pressure–induced vessel distensibility was confirmed by use of the MMP inhibitor FN-439, which prevented the shift in the pressure-diameter relationship. Furthermore, in carotid arteries from MMP-9–deficient mice, the pressure-dependent increase in MMP-2 and in situ gelatinolytic activity were maintained, but the upward shift in the pressure-diameter curve was abolished.

Conclusions—

MMP-9 seems to play a key role in the early stages of hypertensive vascular remodeling.
Abnormal Coronary Vasomotion as a Prognostic Indicator of Cardiovascular Events in Women
Authors: von Mering Gregory O. , Arant Christopher B. , Wessel Timothy R. , McGorray Susan P. , Bairey Merz C. Noel , Sharaf Barry L. , Smith Karen M. , Olson Marian B. , Johnson B. Delia , Sopko George , Handberg Eileen , Pepine Carl J. , Kerensky Richard A.
Published: February 2004

Background—

Coronary vascular dysfunction has been linked to atherosclerosis and adverse cardiovascular outcomes in men, but these relationships have not been firmly established in women.

Methods and Results—

As part of the Women’s Ischemia Syndrome Evaluation (WISE) sponsored by the National Heart, Lung, and Blood Institute, 163 women referred for clinically indicated coronary angiography underwent coronary reactivity assessment with quantitative coronary angiography and intracoronary Doppler flow before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin and were then followed up for clinical outcomes. History of hypertension was present in 61%, dyslipidemia in 54%, diabetes in 26%, and current tobacco use in 21% of women enrolled. Seventy-five percent had no or only mild epicardial coronary artery disease (CAD). Over a median follow-up of 48 months, events occurred in 58 women. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area (ΔCSA) in response to acetylcholine (
P
=0.0006) and nitroglycerin (
P
=0.04). In addition, women with abnormal coronary dilator response to acetylcholine had less time free from cardiovascular events (
P
=0.004). In multivariable analysis, after controlling for age, hypertension, diabetes, dyslipidemia, tobacco use, and CAD severity, %ΔCSA with acetylcholine (
P
=0.001) independently predicted events. When the outcome was restricted to only death, myocardial infarction, congestive heart failure, and stroke, %ΔCSA with acetylcholine remained a significant predictor (
P
=0.006).

Conclusions—

In women in this study, impaired coronary vasomotor response to acetylcholine was independently linked to adverse cardiovascular outcomes regardless of CAD severity.
Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model
Authors: Kondo Isao , Ohmori Koji , Oshita Akira , Takeuchi Hiroto , Yoshida Junji , Shinomiya Kaori , Fuke Sachiko , Suzuki Takeo , Mizushige Katsufumi , Kohno Masakazu
Published: February 2004

Background—

Repetitive endomyocardial biopsies are necessary to monitor the effects of immunosuppressants after cardiac transplantation. Contrast ultrasound with microbubble targeting of leukocytes detects acute leukocyte infiltration. We examined whether leukocyte-targeted myocardial contrast echocardiography (MCE) could provide for the quantitative assessment of acute cardiac rejection.

Methods and Results—

Hearts from Brown Norway rats or Lewis rats were transplanted into other Brown Norway rats. Isografts and groups of allografts either untreated or treated with cyclosporin A (CsA) at a low dose (3 mg · kg
−1
· d
−1
) or high dose (10 mg · kg
−1
· d
−1
) from 3 days before transplantation were compared at posttransplantation day 3. Echocardiography-derived left ventricular wall thickening was comparable among the 4 groups. Myocardial blood flow assessed with MCE, relating pulsing intervals with signal intensity (SI), was slightly decreased only in untreated allografts. However, myocardial SI (in gray levels) obtained after a 10-minute period allowing microbubble–leukocyte interactions after contrast injection exhibited a clear gradient in these groups (12±2 in untreated allografts, 9±5 in allografts treated with low-dose CsA, 6±3 in allografts treated with high-dose CsA, and 2±1 in isografts,
P
<0.001). The pattern of difference in SI among the groups agreed well with that in ED-1–positive cell (macrophage) count (25±7, 12±4, 5±3, and 1±0 cells per high-power field, respectively,
P
<0.001), which correlated with CD3-positive cell (T lymphocyte) count (33±5, 22±5, 9±4, and 1±0 cells per high-power field, respectively,
P
<0.001).

Conclusions—

Leukocyte-targeted MCE can noninvasively assess the degree of rejection in transplanted hearts by directly revealing the magnitude of intramyocardial infiltration of macrophages and T lymphocytes.
C-Reactive Protein Upregulates Complement-Inhibitory Factors in Endothelial Cells
Authors: Li Shu-Hong , Szmitko Paul E. , Weisel Richard D. , Wang Chao-Hung , Fedak Paul W.M. , Li Ren-Ke , Mickle Donald A.G. , Verma Subodh
Published: February 2004

Background—

Because complement-mediated vascular injury participates in atherosclerosis and C-reactive protein (CRP) can activate the complement cascade, we sought to determine whether CRP affects the expression of the protective complement-inhibitory factors on the cell surface of endothelial cells (ECs).

Methods and Results—

Human coronary artery or human saphenous vein ECs were incubated with CRP (0 to 100 μg/mL, 0 to 72 hours), and the expression of the complement-inhibitory proteins decay-accelerating factor (DAF), membrane cofactor protein (CD46), and CD59 were measured by flow cytometry. Incubation with CRP resulted in a significant increase in the expression of all 3 proteins. CRP-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. The increased expression of complement-inhibitory proteins was functionally effective, resulting in significant reduction of complement-mediated lysis of antibody-coated human saphenous vein ECs.

Conclusions—

These observations provide evidence for a possible protective role for CRP in atherogenesis.
Predictors of Outcome After Alcohol Septal Ablation Therapy in Patients With Hypertrophic Obstructive Cardiomyopathy
Authors: Chang Su Min , Lakkis Nasser M. , Franklin Jennifer , Spencer William H. , Nagueh Sherif F.
Published: February 2004

Background—

Alcohol septal ablation (ASA) therapy results in clinical and hemodynamic improvement in patients with hypertrophic obstructive cardiomyopathy. However, a subset remains symptomatic afterward, requiring additional procedures. We sought to examine the determinants of an unsatisfactory outcome, defined as unchanged symptoms with <50% reduction of baseline left ventricular outflow tract (LVOT) gradient.

Methods and Results—

Of 173 consecutive hypertrophic obstructive cardiomyopathy patients who underwent ASA, 39 had an unsatisfactory outcome after the first procedure. Patients with an unsatisfactory outcome had a higher baseline LVOT gradient, fewer septal arteries injected with ethanol, lower peak creatine kinase (CK), smaller septal area opacified by contrast echocardiography, and higher residual gradient in the catheterization laboratory after ASA (all
P
<0.05). Symptoms, septal thickness, mitral regurgitation severity, and ventricular function were not determinants of outcome. On multiple logistic regression, LVOT gradient reduction after ASA in the catheterization laboratory to ≥25 mm Hg (OR, 5.5;
P
=0.01) and peak CK <1300 U/L (OR, 2.5;
P
=0.04) were the independent predictors of an unsatisfactory outcome.

Conclusions—

The residual LVOT gradient in the catheterization laboratory and peak CK leak after ASA are the independent predictors of ASA outcome.
Mortality in Patients After a Recent Myocardial Infarction
Authors: Camm A. John , Pratt Craig M. , Schwartz Peter J. , Al-Khalidi Hussein R. , Spyt Maria J. , Holroyde Michael J. , Karam Roger , Sonnenblick Edmund H. , Brum Jose M.G.
Published: February 2004

Background—

Depressed left ventricular function (LVF) and low heart rate variability (HRV) identify patients at risk of increased mortality after myocardial infarction (MI). Azimilide, a novel class III antiarrhythmic drug, was investigated for its effects on mortality in patients with depressed LVF after recent MI and in a subpopulation of patients with low HRV.

Methods and Results—

A total of 3717 post-MI patients with depressed LVF were enrolled in this randomized, placebo-controlled, double-blind study of azimilide 100 mg on all-cause mortality. Placebo patients with low HRV had a significantly higher 1-year mortality than those with high HRV (>20 U; 15% versus 9.5%,
P
<0.0005) despite nearly identical ejection fractions. No significant differences were observed between the 100-mg azimilide and placebo groups for all-cause mortality in either the “at-risk” patients identified by depressed LVF (12% versus 12%) or the subpopulation of “high-risk” patients identified by low HRV (14% versus 15%) or for total cardiac or arrhythmic mortality. Significantly fewer patients receiving azimilide developed atrial fibrillation than did patients receiving placebo (0.5% versus 1.2%,
P
<0.04). The incidences of torsade de pointes and severe neutropenia (absolute neutrophil count ≤500 cells/μL) were slightly higher in the azimilide group than in the placebo group (0.3% versus 0.1% for torsade de pointes and 0.9% versus 0.2% for severe neutropenia).

Conclusions—

Azimilide did not improve or worsen the mortality of patients after MI. Low HRV independently identified a subpopulation at high risk of mortality.
Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic β-Adrenergic Stimulation
Authors: Engelhardt Stefan , Hein Lutz , Dyachenkow Vitaly , Kranias Evangelia G. , Isenberg Gerrit , Lohse Martin J.
Published: February 2004

Background—

Chronic adrenergic stimulation leads to cardiac hypertrophy and heart failure in experimental models and contributes to the progression of heart failure in humans. The pathways mediating the detrimental effects of chronic β-adrenergic stimulation are only partly understood. We investigated whether genetic modification of calcium handling through deletion of phospholamban in mice would affect the development of heart failure in mice with transgenic overexpression of the β
1
-adrenergic receptor.

Methods and Results—

We crossed β
1
-adrenergic receptor transgenic (β
1
TG) mice with mice homozygous for a targeted deletion of the phospholamban gene (PLB
−/−
). Phospholamban ablation dramatically enhanced survival of β
1
TG mice. The decrease of left ventricular contractility typically observed in β
1
TG mice was reverted back to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis were significantly inhibited in β
1
TG/PLB
−/−
mice compared with β
1
TG mice, and the heart failure–specific gene expression pattern was normalized. Analysis of intracellular calcium transients revealed increased diastolic calcium levels and decreased rate constants of diastolic calcium decline in β
1
TG mice. In β
1
TG/PLB
−/−
mice, diastolic calcium concentration was normal and rate constants of diastolic calcium decline were greater than in wild-type mice.

Conclusions—

We conclude that modification of abnormal calcium handling in β
1
TG mice through ablation of phospholamban resulted in a rescue of functional, morphological, and molecular characteristics of heart failure in β
1
-adrenergic receptor–transgenic mice. These results imply altered calcium handling as critical for the detrimental effects of β
1
-adrenergic signaling.
Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43
Authors: van Rijen Harold V.M. , Eckardt Dominik , Degen Joachim , Theis Martin , Ott Thomas , Willecke Klaus , Jongsma Habo J. , Opthof Tobias , de Bakker Jacques M.T.
Published: February 2004

Background—

Connexin 43 (Cx43) is a major determinant of conduction in the ventricular working myocardium of mammals. We investigated the effect of decreased Cx43 expression on conduction velocity and arrhythmogenesis using adult mice with inducible deletion of Cx43.

Methods and Results—

Cx43
Cre-ER(T)/+
mice, in which 1 coding region of the Cx43 gene was replaced by Cre-ER(T), were mated to Cx43
fl/fl
mice, generating Cx43
Cre-ER(T)/fl
mice. Application of 4-hydroxytamoxifen (4-OHT) induced Cre-ER(T)–mediated deletion of the floxed Cx43 allele. Epicardial ventricular mapping using a 13×19 multiterminal electrode grid (300-μm spacing) was performed on Langendorff-perfused hearts from Cx43
fl/fl
plus carrier (n=10), Cx43
fl/fl
plus 4-OHT (n=10), Cx43
Cre-ER(T)/fl
plus carrier (n=9), and Cx43
Cre-ER(T)/fl
plus 4-OHT (n=10). Cx43 protein amount in group 3 hearts was decreased by ≈50% compared with group 1. 4-OHT did not affect cardiac protein amounts in group 2 but decreased Cx43 expression up to 95% in group 4 compared with group 3. Epicardial activation of both left ventricle (LV) and right ventricle (RV) during sinus rhythm was similar in all groups. Conduction velocity (CV) changed only in group 4 animals. For RV (LV), longitudinal CV decreased from 38 (35) to 31.6 (33.6) and transverse CV from 24.4 (16.8) to 10.1 (11.3) cm/s. Dispersion of conduction in RV (LV) was increased by 91% (38%). Programmed stimulation resulted in ventricular arrhythmias in group 4 (7 of 10 mice) but never in groups 1 through 3.

Conclusions—

Heterozygous expression of Cx43 did not affect ventricular conduction velocity. Up to 95% decrease of Cx43 protein in 4-OHT–treated Cx43
Cre-ER(T)/fl
mice reduced conduction velocity and increased dispersion of conduction and propensity for ventricular arrhythmias.
Remnant Lipoprotein Particles Induce Apoptosis in Endothelial Cells by NAD(P)H Oxidase–Mediated Production of Superoxide and Cytokines via Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Activation
Authors: Shin Hwa Kyoung , Kim Yong Ki , Kim Ki Young , Lee Jeong Hyun , Hong Ki Whan
Published: February 2004

Background—

Remnant lipoprotein particles (RLPs), products of lipolytic degradation of triglyceride-rich lipoprotein derived from VLDL, exert atherogenesis. In this study, we observed how RLPs induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and cilostazol prevented cell death.

Methods and Results—

RLPs were isolated from the plasma of hyperlipidemic patients by use of an immunoaffinity gel mixture of anti–apolipoprotein A-1 and anti–apolipoprotein B-100 monoclonal antibodies. RLPs (50 μg/mL) significantly increased superoxide formation in HUVECs associated with elevated gp91phox mRNA and protein expression and Rac1 translocation, accompanied by increased production of tumor necrosis factor (TNF)-α and interleukin-1β, DNA fragmentation, and cell death. Cilostazol (1 to 100 μmol/L) significantly suppressed not only NAD(P)H oxidase–dependent superoxide production but also TNF-α and interleukin-1β release and restored viability. RLPs activated a lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which was not inhibited by cilostazol. Treatment of HUVECs with monoclonal antibody for LOX-1 attenuated RLP-mediated production of superoxide, TNF-α, and interleukin-1β and DNA fragmentation.

Conclusions—

RLPs stimulated NAD(P)H oxidase–dependent superoxide formation and induction of cytokines in HUVECs via activation of LOX-1, consequently leading to reduction in cell viability with DNA fragmentation, and cilostazol exerts a cell-protective effect by suppressing these variables.
Reoxygenation of Hypoxic Coronary Smooth Muscle Cells Amplifies Growth-Retarding Effects of Ionizing Irradiation
Authors: Arab Amina , Grumann Thorsten , Guttenberger Roland , Bode Christoph , Hehrlein Christoph
Published: February 2004

Background—

Hypoxic human coronary smooth muscle cells (HCSMCs) are possible targets for brachytherapy to prevent restenosis after percutaneous transluminal coronary angiography. It is unclear whether growth kinetics and gene expression of these cells undergoing γ-irradiation are changed by reoxygenation.

Methods and Results—

Hypoxic (H) and hypoxia-reoxygenated (H-R) HCSMCs were irradiated with γ-radiation at single doses of 4, 8, and 16 Gy using a
60
Co-source. Vascular endothelial growth factor gene expression of HCSMCs was dramatically suppressed in H-R versus H cells independent of the radiation dose (15±7% versus 2183±2023%,
P
<0.01, H-R versus H cells). An oxygen enhancement ratio of 1.8 was calculated after irradiation from the retarded growth of H-R versus hypoxic HCSMCs. Production of reactive oxygen species by HCSMCs after irradiation increased by 15±2% in H-R cells versus 7±1% in H cells (
P
<0.05).

Conclusions—

Reoxygenation of hypoxic HCSMCs markedly amplifies growth-retarding effects of ionizing irradiation. On the basis of these findings, oxygenating radiosensitizers should be analyzed with regard to suitability for coronary brachytherapy to prevent restenosis.
Mechanisms of Exercise Intolerance
Authors: Skaluba Stanislaw J. , Litwin Sheldon E.
Published: February 2004

Background—

A decreased ratio of early to late diastolic mitral inflow velocities (E/A <1.0) reflects slowing of left ventricular (LV) relaxation. This finding is widely believed to indicate significant diastolic dysfunction. However, E/A <1.0 is common during normal aging and often is not associated with symptoms of heart failure. We asked (1) whether slowed LV relaxation is associated with exercise intolerance and (2) whether tissue Doppler imaging of the early diastolic mitral annular velocity (Ea) is helpful in understanding mechanisms of exercise intolerance.

Methods and Results—

Patients (n=121) underwent echocardiography before maximal exercise testing. Fifty-nine subjects had E/A <1.0, and 36 subjects had E/Ea ≥10. Exercise capacity was similar in the population with a normal mitral inflow pattern and those with a slow relaxation pattern when E/Ea was <10. In contrast, the subjects with slow relaxation and E/Ea ≥10 had reduced exercise tolerance. Of all the echo and clinical parameters assessed, E/Ea had the best correlation with exercise capacity (
r
=−0.684,
P
<0.001) and was the strongest independent predictor of exercise capacity ≤7 METs by multivariate analysis (prevalence-corrected odds ratio=12.6,
P
<0.001). E/Ea continued to be strongly associated with exercise capacity in all age groups and in those with preserved or reduced systolic function.

Conclusions—

Of the subjects with slow LV relaxation, only those with E/Ea ≥10 have objective evidence of reduced exercise tolerance. These data suggest that elevated LV filling pressures rather than slow relaxation per se reduce exercise capacity.
Mechanisms of Myocardial Capture and Temporal Excitable Gap During Spiral Wave Reentry in a Bidomain Model
Authors: Ashihara Takashi , Namba Tsunetoyo , Ikeda Takanori , Ito Makoto , Nakazawa Kazuo , Trayanova Natalia
Published: February 2004

Background—

Recent studies have demonstrated that regional capture during cardiac fibrillation is associated with an elevated capture threshold. It is typically assumed that the temporal excitable gap (capture window) during fibrillation reflects the size of the spatial excitable gap (excitable tissue between fibrillation waves). Because capture threshold is high, virtual electrode polarization is expected to be involved in the process. However, little is known about the underlying mechanisms of myocardial capture during fibrillation.

Methods and Results—

To clarify these issues, we conducted altogether 3168 simulations of single spiral wave capture in a bidomain sheet. Unipolar stimuli of strengths 4, 8, 16, and 24 mA and 2-ms duration were delivered at 99 locations in the sheet. We found that cathode-break rather than cathode-make excitation was the dominant mechanism of myocardial capture. When the stimulation site was located diagonally with respect to the core (upper left or lower right if the spiral wave rotates counterclockwise), the cathode-break excitation easily invaded the spatial excitable gap and resulted in a successful capture as a result of the formation of virtual anodes in the direction of the myocardial fibers. Thus, the spatial distribution of the temporal excitable gap did not reflect the spatial excitable gap.

Conclusions—

The areas exhibiting wide temporal excitable gaps were areas in which the cathode-break excitation wave fronts easily invaded the spatial excitable gap via the virtual anodes. This study provides mechanistic insight into myocardial capture.
Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage
Authors: Niu Pei , Shindo Takayuki , Iwata Hiroshi , Iimuro Satoshi , Takeda Norifumi , Zhang Yuelan , Ebihara Aya , Suematsu Yoshihiro , Kangawa Kenji , Hirata Yasunobu , Nagai Ryozo
Published: February 2004

Background—

Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function. The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice.

Methods and Results—

Mice heterozygous for an AM-null mutation (AM+/−) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-β, collagen type I, brain natriuretic peptide, and c-
fos
. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AM+/− mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK) activation, as did cardiac myocytes from neonates treated acutely with Ang II. Again the effect was more pronounced in AM+/− mice, which showed increases in cardiac myocyte size, protein synthesis, and fibroblast proliferation. ERK activation was suppressed by protein kinase C inhibition to a greater degree in AM+/− myocytes. In addition, treatment of cardiac myocytes with recombinant AM suppressed Ang II-induced ERK activation via a protein kinase A-dependent pathway.

Conclusions—

Endogenous AM exerts a protective effect against stress-induced cardiac hypertrophy via protein kinase C- and protein kinase A-dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.
Simultaneous Evaluation of Infarct Size and Cardiac Function in Intact Mice by Contrast-Enhanced Cardiac Magnetic Resonance Imaging Reveals Contractile Dysfunction in Noninfarcted Regions Early After Myocardial Infarction
Authors: Yang Zequan , Berr Stuart S. , Gilson Wesley D. , Toufektsian Marie-Claire , French Brent A.
Published: February 2004

Background—

The objective of this study was to noninvasively determine the effects of reperfused myocardial infarction (MI) on regional and global left-ventricular (LV) function 24 hours after MI in intact mice with contrast-enhanced cardiac MRI and a single, gradient-echo pulse sequence.

Methods and Results—

Twenty-three mice received baseline MRI scans followed by either 60 minutes of coronary occlusion (MI group, n=15) or thoracotomy without occlusion (sham group, n=8). Gadolinium-DTPA–enhanced magnetic resonance (MR) images were acquired 24 hours after surgery. Hearts were then excised for conventional infarct size determination via 2,3,5-triphenyl tetrazolium chloride (TTC) staining. In addition to infarct size, analysis of the MR images yielded left ventricular (LV) mass, LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), LV ejection fraction (LVEF), cardiac output, and percent LV wall thickening (%WTh). Twenty-four hours after surgery, infarct size was 28.1±1.8% of LV mass by MRI and 27.5±1.7% by TTC (
P
=NS). Bland-Altman analysis revealed close agreement between the results obtained by the 2 methods. MI had little effect on LVEDV but caused a 98% increase in LVESV (from 11.3 to 22.4 μL,
P
<0.05), which resulted in a significant reduction in LVEF (from 70% to 37%,
P
<0.05). Compared with LV regional function at baseline, %WTh 24 hours after MI was significantly depressed, not only in infarcted myocardium but also in regions remote from the infarct zone. In contrast, sham-operated mice showed a small but significant increase in %WTh 24 hours after surgery (
P
<0.05).

Conclusions—

MRI can accurately assess both infarct size and cardiac function in intact mice early after large, reperfused MI, revealing the existence of contractile dysfunction in noninfarcted regions of the heart.
Asymptotic Dental Score and Prevalent Coronary Heart Disease
Authors: Janket Sok-Ja , Qvarnström Markku , Meurman Jukka H. , Baird Alison E. , Nuutinen Pekka , Jones Judith A.
Published: February 2004

Background—

Oral infections have been postulated to produce cytokines that may contribute to the pathogenesis of coronary heart disease (CHD). We hypothesized that by estimating the combined production of inflammatory mediators attributable to several oral pathologies, we might be able to explain CHD with better precision.

Methods and Results—

A total of 256 consecutive Finnish cardiac patients from Kuopio University Hospital with angiographically confirmed CHD and 250 age-, gender-, and residence-matched noncardiac patients (controls) were recruited. All dental factors expected to generate inflammatory mediators, including pericoronitis, dental caries, dentate status, root remnants, and gingivitis, were examined, and an asymptotic dental score (ADS) was developed by logistic regression analyses with an appropriate weighting scheme according to the likelihood ratio. We validated the explanatory ability of ADS by comparing it to that of the Total Dental Index and examining whether the ADS was associated with known predictors of CHD. A model that included ADS, C-reactive protein, HDL, and fibrinogen offered an explanatory ability that equaled or exceeded that of the Framingham heart score (C statistic=0.82 versus 0.80). When ADS was removed from this model, the C-statistic decreased to 0.77, which indicates that the ADS was a significant contributor to the explanatory ability of a logistic model.

Conclusions—

ADS may be useful as a prescreening tool to promote proactive cardiac evaluation among individuals without overt symptoms of CHD. However, additional prospective study is needed to validate the use of an oral health score as a predictor of incident CHD.
Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin and Oral Anticoagulants for Prevention of Thromboembolic Complications in Cardioversion of Nonvalvular Atrial Fibrillation
Authors: Stellbrink Christoph , Nixdorff Uwe , Hofmann Thomas , Lehmacher Walter , Daniel Werner Günther , Hanrath Peter , Geller Christoph , Mügge Andreas , Sehnert Walter , Schmidt-Lucke Caroline , Schmidt-Lucke Jan-André
Published: February 2004

Background—

Anticoagulation in cardioversion of atrial fibrillation is currently performed with unfractionated heparin (UFH) and oral anticoagulants, with or without guidance by transesophageal echocardiography (TEE). Low-molecular-weight heparins may reduce the risk of bleeding, may obviate the need for intravenous access, and do not require frequent anticoagulation monitoring.

Methods and Results—

In a randomized, prospective multicenter trial, we compared the safety and efficacy of enoxaparin administered subcutaneously with intravenous UFH followed by the oral anticoagulant phenprocoumon in 496 patients scheduled for cardioversion of atrial fibrillation of >48 hours’ and ≤1 year’s duration. Patients were stratified to cardioversion with (n=431) and without (n=65) guidance by TEE. The study aimed to demonstrate noninferiority of enoxaparin compared with UFH+phenprocoumon with regard to the incidence of embolic events, all-cause death, and major bleeding complications. Secondary end points included successful cardioversion, maintenance of sinus rhythm until study end, and minor bleeding complications. Of 496 randomized patients, 428 were analyzed per protocol. Enoxaparin was noninferior to UFH+phenprocoumon with regard to the incidence of the composite primary end point in a per-protocol analysis (7 of 216 patients versus 12 of 212 patients, respectively;
P
=0.016) and in an intention-to-treat analysis (7 of 248 patients versus 12 of 248 patients, respectively;
P
=0.013). There was no significant difference between the 2 groups in the number of patients reverted to sinus rhythm.

Conclusions—

Enoxaparin is noninferior to UFH+phenprocoumon for prevention of ischemic and embolic events, bleeding complications, and death in TEE-guided cardioversion of atrial fibrillation. Its easier application and more stable anticoagulation may make it the preferred drug for initiation of anticoagulation in this setting.
Combination of Renin-Angiotensin System Polymorphisms Is Associated With Altered Renal Sodium Handling and Hypertension
Authors: Siani Alfonso , Russo Paola , Paolo Cappuccio Francesco , Iacone Roberto , Venezia Antonella , Russo Ornella , Barba Gianvincenzo , Iacoviello Licia , Strazzullo Pasquale
Published: February 2004

Genes of the renin-angiotensin–aldosterone system (RAAS) are natural candidates for sodium homeostasis and blood pressure regulation. To investigate the effect of a combination of polymorphisms of RAAS genes on renal sodium handling and blood pressure, 918 participants to the Olivetti Heart Study were genotyped for the following polymorphisms: I/D of angiotensin converting enzyme (
ACE
), M235T of angiotensinogen (
AGT
), A1166C of angiotensin II type-1 receptor (
AT1R
), and C-344T of aldosterone synthase (
CYP11B2
). The segmental renal sodium handling was evaluated by the fractional excretions of exogenous lithium (FE-Li), uric acid (FE-UA), and sodium (FE-Na). Twenty-eight carriers of triple homozygosity for M (
AGT
), A (
AT1R
), and C (
CYP11B2
) in the presence of the D allele of
ACE
(DD/ID) showed lower FE-Li (20.0%±5.9% versus 25.0%±7.5%;
P
=0.004; mean±
s
D), FE-UA (6.3%±2.0% versus 8.2%±2.7%;
P
=0.001), and FE-Na (0.96%±0.41% versus 1.22%±0.61%;
P
=0.004) as compared with all other allelic combinations (n=890), independently from age and body mass, suggesting an enhanced rate of proximal tubular sodium reabsorption. The carriers of the MM, AA, CC, DD/ID combination showed a substantially higher probability of being hypertensive (OR: 3.4 [(99% CI: 1.1 to 10.1]), independently of age and body mass. This relatively rare combination of allelic variants of candidate genes of the RAAS is associated with a significant alteration in proximal renal sodium handling and with higher risk of hypertension, suggesting that a combination of polymorphic variants at different candidate loci may affect phenotypic expression even in the absence of detectable effects of each variant at any single locus.
Hypertensive Myocardial Fibrosis and Diastolic Dysfunction
Authors: Kuwahara Fumitaka , Kai Hisashi , Tokuda Keisuke , Takeya Motohiro , Takeshita Akira , Egashira Kensuke , Imaizumi Tsutomu
Published: February 2004

Excessive myocardial fibrosis deteriorates diastolic function in hypertensive hearts. Involvement of macrophages is suggested in fibrotic process in various diseased situations. We sought to examine the role of macrophages in myocardial remodeling and cardiac dysfunction in pressure-overloaded hearts. In Wistar rats with suprarenal aortic constriction, pressure overload induced perivascular macrophage accumulation and fibroblast proliferation with a peak at day 3, decreasing to lower levels by day 28. Myocyte chemoattractant protein (MCP)-1 mRNA was upregulated after day 1, peaking at day 3 and returning to insignificant levels by day 28, whereas transforming growth factor (TGF)-β induction was observed after day 3, with a peak at day 7, and remained relatively elevated at day 28. After day 7, concentric left ventricular (LV) hypertrophy developed, associated with reactive fibrosis and myocyte hypertrophy. At day 28, echocardiography showed normal LV fractional shortening but decreased ratio of early to late filling wave of transmitral Doppler velocity, and hemodynamic studies revealed elevated LV end-diastolic pressure, suggesting normal systolic but impaired diastolic function. Chronic treatment with an anti-MCP-1 monoclonal neutralizing antibody inhibited not only macrophage accumulation but also fibroblast proliferation and TGF-β induction. Furthermore, the neutralizing antibody attenuated myocardial fibrosis, but not myocyte hypertrophy, and ameliorated diastolic dysfunction without affecting blood pressure and systolic function. In conclusion, roles of MCP-1-mediated macrophage accumulation are suggested in myocardial fibrosis in pressure-overloaded hearts through TGF-β-mediated process. Inhibition of inflammation may be a new strategy to prevent myocardial fibrosis and resultant diastolic dysfunction in hypertensive hearts.
Evidence for a Gene on Chromosome 13 Influencing Postural Systolic Blood Pressure Change and Body Mass Index
Authors: North Kari E. , Rose Kathryn M. , Borecki Ingrid B. , Oberman Albert , Hunt Steven C. , Miller Michael B. , Blangero John , Almasy Laura , Pankow James S.
Published: February 2004

Previous analysis in the Hypertension Genetic Epidemiology Network (HyperGEN) of the National Heart Lung and Blood Institute (NHLBI) Family Blood Pressure Program, a multicenter study of genetic and environmental factors related to hypertension, indicated regions of linkage for blood pressure traits together with several coincident regions for phenotypically correlated traits, including systolic blood pressure (SBP) response to a postural challenge and body mass index (BMI). Motivated by these findings and by our desire to better understand the physiology of these traits, we conducted bivariate linkage analysis of postural SBP change and BMI. Sibships in HyperGEN were recruited from 5 field centers in Massachusetts, North Carolina, Minnesota, Utah, and Alabama. All available affected siblings, their parents, and selected nonmedicated offspring were recruited. Among 1636 whites and 1747 blacks, we performed a maximum likelihood bivariate genome scan for quantitative trait loci influencing postural SBP change and BMI, similarly adjusted for race, study center, sex, age, and age-by-sex interactions. Genome scans were performed using SOLAR (version 2.0) and race-specific marker allele frequencies derived from founders. The maximum genome-wide logarithm of odds (LOD) score of 3.2 was detected on chromosome 13 at 24 cM. This marker (D13S493) lies within 20 cM of a marker previously linked to BMI in the Family Heart Study and is substantially higher than the univariate linkage for each trait (LOD scores for BMI and postural SBP change were 2.4 and 0.9, respectively). These findings suggest that a gene(s) on chromosome 13q jointly regulates the SBP response to postural change and BMI.
Focal Adhesion Protein Zyxin Is a Mechanosensitive Modulator of Gene Expression in Vascular Smooth Muscle Cells
Authors: Cattaruzza Marco , Lattrich Claus , Hecker Markus
Published: February 2004

Excessive deformation of vascular smooth muscle cells (SMCs) caused by a prolonged increase in blood pressure (eg, in hypertension) results in an adaptive remodeling of the vessel wall that is characterized by SMC hypertrophy or hyperplasia and contributes to fixation of the increase in blood pressure. The onset of this process is characterized by a unique change in gene expression in the SMC. However, thus far, no transcription factor has been identified that specifically mediates mechanosensitive gene expression in these cells. Therefore, the role of a putative mechanotransducer, the cytoskeletal protein zyxin, was investigated in rat aortic cultured SMCs. Immunofluorescence and Western blot analysis revealed that on exposure to cyclic stretch, but not to osmotic stress or treatment with proinflammatory cytokines, zyxin dissociates from focal adhesions and accumulates in the nucleus. Unlike zyxin, vinculin, another focal adhesion-associated protein, did not translocate. Moreover, antisense oligonucleotide downregulation of zyxin protein abundance suggested that zyxin accumulation in the nucleus is a prerequisite for mechanosensitive gene expression in these cells. Thus, stretch-induced endothelin B receptor expression, for example, was attenuated, whereas that of tenascin-C was augmented after zyxin suppression. The data are consistent with a role for zyxin in transducing mechanical stimuli from the cell membrane to the nucleus in vascular SMCs and in controlling the expression of mechanosensitive genes that have been implicated in hypertension-induced arterial remodeling.
Elevated BSC-1 and ROMK Expression in Dahl Salt-Sensitive Rat Kidneys
Authors: Hoagland Kimberly M. , Flasch Averia K. , Dahly-Vernon Annette J. , dos Santos Elisabete Alcantara , Knepper Mark A. , Roman Richard J.
Published: February 2004

This study compared the expression of enzymes and transport and channel proteins involved in the regulation of sodium reabsorption in the kidney of Dahl salt-sensitive (DS) and salt-resistant Brown-Norway (BN) and consomic rats (SS.BN13), in which chromosome 13 from the BN rat has been introgressed into the DS genetic background. The expression of the Na
+
/K
+
/2Cl
−
(BSC-1) cotransporter, Na
+
/H
+
exchanger (NHE3), and Na
+
-K
+
-ATPase proteins were similar in the renal cortex of DS, BN, and SS.BN13 rats fed either a low-salt (0.1% NaCl) or a high-salt (8% NaCl) diet. The expression of the BSC-1 and the renal outer medullary K
+
channel (ROMK) were higher, whereas the expression of the cytochrome P4504A proteins responsible for the formation of 20-hydroxyeicosatetraenoic (20-HETE) was lower in the outer medulla of the kidney of DS than in BN or SS.BN13 rats fed either a low-salt or a high-salt diet. In addition, the renal formation and excretion of 20-HETE was lower in DS than in BN and SS.BN13 rats. These results suggest that overexpression of ROMK and BSC-1 in the thick ascending limb combined with a deficiency in renal formation of 20-HETE may predispose Dahl S rats fed a high-salt diet to Na
+
retention and hypertension.