bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic Inflammation Induced by Lipopolysaccharide Increases Neointimal Formation After Balloon and Stent Injury in Rabbits
Authors: Danenberg Haim D. , Welt Frederick G. P. , Walker Matthew , Seifert Philip , Toegel Greg S. , Edelman Elazer R.
Published: July 2002

Background
—

Emerging data indicate that the inflammatory response after mechanical arterial injury correlates with the severity of neointimal hyperplasia in animal models and postangioplasty restenosis in humans. The present study was designed to examine whether a nonspecific stimulation of the innate immune system, induced in close temporal proximity to the vascular injury, would modulate the results of the procedure.

Methods and Results
—

Rabbits subjected to iliac artery balloon injury (balloon denudation with or without stent deployment) were injected twice with a bacterial lipopolysaccharide (LPS) (500 ng/rabbit) before and after surgery. The dose was chosen to be sufficient to induce systemic inflammation but not septic shock. A systemic marker of inflammation (serum interleukin-1β levels measured by ELISA) and monocytic stimulation (CD14 levels on monocytes measured by flow cytometry) were increased after LPS administration. Arterial macrophage infiltration at 7 days after injury was 1.7±1.2% of total cells in controls and 4.2±1.8% in LPS-treated rabbits (n=4,
P
<0.05). Morphometric analysis of the injured arteries 4 weeks after injury revealed significantly increased luminal stenosis (38±4.2% versus 23±2.6, mean± SEM; n=8,
P
<0.05) and neointima-to-media ratio (1.26±0.21 versus 0.66± 0.09,
P
<0.05) in LPS-treated animals compared with controls. This effect was abolished by anti-CD14 Ab administration. Serum interleukin-1β levels and monocyte CD14 expression were significantly increased in correlation with the severity of intimal hyperplasia. LPS treatment increased neointimal area after stenting from 0.57±0.07 to 0.77± 0.1 mm
2
and stenosis from 9±1% to 13±1.7% (n=5,
P
< 0.05).

Conclusions
—

Nonspecific systemic stimulation of the innate immune system concurrently with arterial vascular injury facilitates neointimal formation, and conditions associated with increased inflammation may increase restenosis.
Adipocyte-Derived Plasma Protein Adiponectin Acts as a Platelet-Derived Growth Factor-BB–Binding Protein and Regulates Growth Factor–Induced Common Postreceptor Signal in Vascular Smooth Muscle Cell
Authors: Arita Yukio , Kihara Shinji , Ouchi Noriyuki , Maeda Kazuhisa , Kuriyama Hiroshi , Okamoto Yoshihisa , Kumada Masahiro , Hotta Kikuko , Nishida Makoto , Takahashi Masahiko , Nakamura Tadashi , Shimomura Iichiro , Muraguchi Masahiro , Ohmoto Yasukazu , Funahashi Tohru , Matsuzawa Yuji
Published: July 2002

Background
—

Vascular smooth muscle cell proliferation plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the human injured artery and suppressed endothelial inflammatory response as well as macrophage-to-foam cell transformation. The present study investigated the effects of adiponectin on proliferation and migration of human aortic smooth muscle cells (HASMCs).

Methods and Results
—

HASMC proliferation was estimated by [
3
H] thymidine uptake and cell number. Cell migration assay was performed using a Boyden chamber. Physiological concentrations of adiponectin significantly suppressed both proliferation and migration of HASMCs stimulated with platelet-derived growth factor (PDGF)-BB. Adiponectin specifically bound to
125
I-PDGF-BB and significantly inhibited the association of
125
I-PDGF-BB with HASMCs, but no effects were observed on the binding of
125
I-PDGF-AA or
125
I-heparin–binding epidermal growth factor (EGF)–like growth factor (HB-EGF) to HASMCs. Adiponectin strongly and dose-dependently suppressed PDGF-BB–induced p42/44 extracellular signal–related kinase (ERK) phosphorylation and PDGF β-receptor autophosphorylation analyzed by immunoblot. Adiponectin also reduced PDGF-AA–stimulated or HB-EGF–stimulated ERK phosphorylation in a dose-dependent manner without affecting autophosphorylation of PDGF α-receptor or EGF receptor.

Conclusions
—

The adipocyte-derived plasma protein adiponectin strongly suppressed HASMC proliferation and migration through direct binding with PDGF-BB and generally inhibited growth factor–stimulated ERK signal in HASMCs, suggesting that adiponectin acts as a modulator for vascular remodeling.
Carotid Plaques Increase the Risk of Stroke and Subtypes of Cerebral Infarction in Asymptomatic Elderly
Authors: Hollander M. , Bots M.L. , del Sol A. Iglesias , Koudstaal P.J. , Witteman J.C.M. , Grobbee D.E. , Hofman A. , Breteler M.M.B.
Published: July 2002

Background
—

Few studies have quantified the relation between carotid plaques and stroke in asymptomatic patients, and limited data exist on the importance of location of plaques or the association with subtypes of cerebral infarction. We investigated the relationship between carotid plaques, measured at different locations, and risk of stroke and subtypes of cerebral infarction in a population-based study.

Methods and Results
—

The study was based on the Rotterdam Study and included 4217 neurologically asymptomatic subjects aged 55 years or older. Presence of carotid plaques at 6 locations in the carotid arteries was assessed at baseline. Severity was categorized according to the number of affected sites. After a mean follow-up of 5.2 years, 160 strokes had occurred. Data were analyzed using Cox proportional hazards regression. Plaques increased the risk of stroke and cerebral infarction ≈1.5-fold, irrespective of plaque location. Severe carotid plaques increased the risk of nonlacunar infarction in anterior (RR 3.2 [95% CI, 1.1 to 9.7]) but not in posterior circulation (RR 0.6 [95% CI, 0.1 to 4.9]). A >10-fold increased risk of lacunar infarction was found in subjects with severe plaques (RR 10.8 [95% CI, 1.7 to 69.7]). No clear difference in risk estimates was seen between ipsilateral and contralateral infarction.

Conclusions
—

Carotid plaques increase the risk of stroke and cerebral infarction, irrespective of their location. Plaques increase the risk of infarctions in the anterior but not in the posterior circulation. It is likely that carotid plaques in neurologically asymptomatic subjects are both markers of generalized atherosclerosis and sources of thromboemboli.
Meta-Analysis of Wine and Beer Consumption in Relation to Vascular Risk
Authors: Di Castelnuovo Augusto , Rotondo Serenella , Iacoviello Licia , Donati Maria Benedetta , de Gaetano Giovanni
Published: July 2002

Background
—

Many epidemiological studies have evaluated whether different alcoholic beverages protect against cardiovascular disease. We performed a meta-analysis of 26 studies on the relationship between wine or beer consumption and vascular risk.

Methods and Results
—

General variance-based method and fitting models were applied to pooled data derived from 26 studies that gave a quantitative estimation of the vascular risk associated with either beverage consumption. From 13 studies involving 209 418 persons, the relative risk of vascular disease associated with wine intake was 0.68 (95% confidence interval, 0.59 to 0.77) relative to nondrinkers. There was strong evidence from 10 studies involving 176 042 persons to support a J-shaped relationship between different amounts of wine intake and vascular risk. A statistically significant inverse association was found up to a daily intake of 150 mL of wine. The overall relative risk of moderate beer consumption, which was measured in 15 studies involving 208 036 persons, was 0.78 (95% confidence interval, 0.70 to 0.86). However, no significant relationship between different amounts of beer intake and vascular risk was found after meta-analyzing 7 studies involving 136 382 persons.

Conclusions
—

These findings show evidence of a significant inverse association between light-to-moderate wine consumption and vascular risk. A similar, although smaller association was also apparent in beer consumption studies. The latter finding, however, is difficult to interpret because no meaningful relationship could be found between different amounts of beer intake and vascular risk.
Cardiopulmonary Bypass Induces Release of Soluble CD40 Ligand
Authors: Nannizzi-Alaimo Lisa , Rubenstein Mark H. , Alves Veronica L. , Leong Gil Y. , Phillips David R. , Gold Herman K.
Published: July 2002

Background
—

Cardiopulmonary bypass (CPB) is known to induce platelet activation, thrombosis, thrombocytopenia, and a systemic inflammatory response. It is known that CD40 ligand (CD40L) exists in platelets, that a soluble form of this protein (sCD40L) is released on platelet activation, that platelets are the primary source of sCD40L in blood, and that sCD40L is involved in thrombosis and inflammation. The present study was designed to determine whether sCD40L is released during CPB.

Methods and Results
—

Blood was obtained from patients undergoing CPB-requiring surgery and analyzed for sCD40L, interleukin-6, and platelet factor 4 and β-thromboglobulin (markers of platelet activation). Platelets were also isolated and analyzed for their levels of CD40L. Plasma levels of sCD40L increased >1.7-fold (from 0.29 to 0.51 ng/mL,
P
=0.001) within 1 hour on CPB and increased further to 3.7-fold (to 1.08 ng/mL,
P
=0.03) 2 hours after the procedure. Half of the released sCD40L was cleared in 2 hours, which allowed the sCD40L to return to approximately baseline levels 8 hours after the procedure. The platelet content of CD40L was decreased by 40% (2.675 to 1.64 ng/10
8
platelets,
P
=0.001) 1 hour after initiation of CPB and was similar to that observed for platelet factor 4 and β-thromboglobulin. Interleukin-6, a marker of inflammation, also increased during CPB.

Conclusions
—

The present study demonstrates that CPB causes an increase in the concentration of plasma sCD40L. The corresponding decrease in platelet CD40L suggests that this prothrombotic and proinflammatory protein was derived primarily from platelets and may contribute to the thrombotic and inflammatory complications associated with CPB.
Electrical Connections Between Pulmonary Veins
Authors: Takahashi Atsushi , Iesaka Yoshito , Takahashi Yoshihide , Takahashi Ryoko , Kobayashi Kenzaburo , Takagi Katsumasa , Kuboyama Osamu , Nishimori Takeo , Takei Hidenobu , Amemiya Hiroshi , Fujiwara Hideomi , Hiraoka Masayasu
Published: July 2002

Background

—

Electrical disconnection of the myocardial extensions into arrhythmogenic pulmonary veins (PVs) is recognized as a curative technique for paroxysmal atrial fibrillation (AF). However, the presence of electrical connections between the PVs, which may make achievement of PV disconnection difficult, has not been systematically evaluated.

Methods and Results

—

Forty-nine consecutive patients with drug-resistant AF underwent ostial radiofrequency (RF) catheter ablation of arrhythmogenic PVs with foci triggering AF. Pacing from inside the targeted PV was performed after each RF delivery to identify the left atrial exit site of the residual venoatrial conduction. Successful PV disconnection was defined as achieving elimination of the PV potentials during sinus rhythm or left atrial pacing, and the loss of left atrial conduction during intra-PV pacing. A total of 112 arrhythmogenic PVs were identified. PV disconnection was achieved with 10±6.1 minutes of RF delivery to the ostia of 101 targeted PVs. In 7 left superior (LS) PVs from 7 patients (14%), the earliest atrial activity was recorded from the left inferior (LI) PV ostium during intra-LSPV pacing after 11±4.7 minutes of RF delivery to the LSPV ostium. Disconnection of these LSPVs was achieved by LIPV disconnection. In the remaining 4 PVs from 4 patients, PV disconnection could not be achieved.

Conclusions

—

Fourteen percent of the patients had electrical connections between contiguous PVs. In these patients, ostial ablation of an untargeted PV was required for successful targeted PV disconnection.
Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase
Authors: Takemoto Masao , Sun Jianxin , Hiroki Junko , Shimokawa Hiroaki , Liao James K.
Published: July 2002

Background

—

Hypoxia-induced pulmonary hypertension is a major cause of morbidity and mortality. Hypoxia induces pulmonary vasoconstriction, in part, by decreasing endothelial nitric oxide synthase (eNOS) expression. The mechanism by which hypoxia decreases eNOS expression is not known but may involve Rho-kinase–induced actin cytoskeletal changes in vascular endothelial cells.

Methods and Results

—

To determine whether hypoxia regulates eNOS expression through Rho-kinase, we exposed human saphenous and pulmonary artery endothelial cells to hypoxia (3% O
2
) with and without a Rho-kinase inhibitor, hydroxyfasudil (0.1 to 100 μmol/L), for various durations (0 to 48 hours). Hypoxia increased Rho-kinase expression and activity by 50% and 74%, decreased eNOS mRNA and protein expression by 66±3% and 57±5%, and inhibited eNOS activity by 48±9%. All of these effects of hypoxia on eNOS were reversed by cotreatment with hydroxyfasudil. Furthermore, inhibition of Rho by
Clostridium botulinum
C3 transferase or Rho-kinase by overexpression of dominant-negative Rho-kinase reversed hypoxia-induced decrease in eNOS expression. Indeed, disruption of the actin cytoskeleton, the downstream target of Rho-kinase, by cytochalasin D also upregulated eNOS expression. Hypoxia reduced eNOS mRNA half-life from 22±2 to 13±2 hours, which was reversed by cotreatment with hydroxyfasudil. However, neither hypoxia nor hydroxyfasudil had any effects on eNOS gene transcription.

Conclusions

—

These results indicate that hypoxia-induced decrease in eNOS expression is mediated by Rho-kinase and suggest that Rho-kinase inhibitors may have therapeutic benefits in patients with hypoxia-induced pulmonary hypertension.
Efficacy Assessment of Meloxicam, a Preferential Cyclooxygenase-2 Inhibitor, in Acute Coronary Syndromes Without ST-Segment Elevation
Authors: Altman Raul , Luciardi Hector L. , Muntaner Juan , Del Rio Fatima , Berman Sofia G. , Lopez Ruben , Gonzalez Claudio
Published: July 2002

Background

—

Despite the use of heparin, aspirin, and other antiplatelet agents, acute coronary syndrome patients without ST-segment elevation remain at risk of cardiovascular thrombotic events. Given the role of inflammation in the pathogenesis of arterial thrombosis, we tested the hypothesis that the combination of meloxicam, a preferential COX-2 inhibitor, and heparin and aspirin would be superior to heparin and aspirin alone.

Methods and Results

—

In an open-label, randomized, prospective, single-blind pilot study, patients with acute coronary syndromes without ST-segment elevation were randomized to aspirin and heparin treatment (n=60) or aspirin, heparin, and meloxicam (n=60) during coronary care unit stay. Patients then received aspirin or aspirin plus meloxicam for 30 days. During the coronary care unit stay, the primary outcomes variable of recurrent angina, myocardial infarction, or death was significantly lower in the patients receiving meloxicam (15.0% versus 38.3%,
P
=0.007). The second composite variable (coronary revascularization procedures, myocardial infarction, and death) was also significantly lower in meloxicam-treated patients (10.0% versus 26.7%,
P
=0.034). At 90 days, the primary end point remained significantly lower in the meloxicam group (21.7% versus 48.3%,
P
=0.004), as did the secondary end point (13.3% versus 33.3%,
P
=0.015) and the need for revascularization alone (11.7% versus 30.0%,
P
=0.025). No adverse complications associated with the meloxicam treatment were observed.

Conclusions

—

Meloxicam with heparin and aspirin was associated with significant reductions in adverse outcomes in acute coronary syndrome patients without ST-segment elevation. Additional larger trials are required to confirm the findings of this pilot study.
Effect of Implantable Defibrillators on Arrhythmic Events and Mortality in the Multicenter Unsustained Tachycardia Trial
Authors: Lee Kerry L. , Hafley Gail , Fisher John D. , Gold Michael R. , Prystowsky Eric N. , Talajic Mario , Josephson Mark E. , Packer Douglas L. , Buxton Alfred E.
Published: July 2002

Background

—

The Multicenter Unsustained Tachycardia Trial (MUSTT) was designed to evaluate an antiarrhythmic treatment strategy, including drugs and implantable defibrillators (ICDs), guided by electrophysiological (EP) testing. We performed several statistical analyses to assess the contribution of defibrillators to the observed treatment benefit.

Methods and Results

—

First, the effects of defibrillators were indirectly examined by comparing the randomized treatment arms (EP-guided therapy versus no antiarrhythmic therapy) within subgroups that varied according to ICD usage. Use of ICDs increased during the trial; hence, the randomized treatments were compared according to date of enrollment. There were also site-specific differences in ICD use; hence, the randomized arms were compared within groups of sites defined by level of ICD use. There was a distinct “dose response” in relation to ICD use. Where ICD use was high, EP-guided therapy produced significant reductions in arrhythmic death or cardiac arrest (
P
<0.004). Where ICD use was low, there was no benefit of EP-guided therapy. Finally, outcomes of EP-guided therapy patients who received an ICD were directly compared with outcomes of other patients using the Cox proportional hazards model with receipt of an ICD as a time-dependent covariate. Adjusted for other prognostic factors, patients who received an ICD had risk reductions of >70% in arrhythmic death or cardiac arrest and >50% in total mortality (
P
<0.001 for both end points).

Conclusions

—

The benefit of EP-guided antiarrhythmic therapy observed in MUSTT was due to improved outcomes among patients who received an ICD but not among patients who received antiarrhythmic drugs.
Effects of Ventricular Premature Stimulus Coupling Interval on Blood Pressure and Heart Rate Turbulence
Authors: Watanabe Mari A. , Marine Joseph E. , Sheldon Robert , Josephson Mark E.
Published: July 2002

Background

—

Heart rate turbulence (HRT) is a promising noninvasive risk stratifier for mortality after myocardial infarction. On the basis of a study of ventricular premature complex coupling interval and sympathetic nerve burst amplitude, we hypothesized that measures of HRT would increase with increased prematurity of the coupling interval.

Methods and Results

—

Twenty-eight patients undergoing programmed electrical stimulation were studied (12 with prior myocardial infarction, aged 60±18 years). An extrastimulus was delivered from the right ventricular apex after 20 sinus beats with a V-S
2
coupling interval decremented by 20 to 30 ms until refractoriness was reached. Turbulence slope (TS), turbulence timing (TT), and turbulence onset were calculated for each extrastimulus, and the linear regressions of these parameters on coupling interval and compensatory pause were calculated. Arterial blood pressure was measured with arterial catheter or a noninvasive continuous blood pressure transducer (Buffington cuff). TS and turbulence onset were abnormal in 4 and 13 patients, respectively. HRT parameters were significantly correlated with coupling interval or compensatory pause in only 2 or 3 patients for a given regression analysis. This absence of correlation was found likely to be due to lack of correlation between compensatory pause and systolic blood pressure after the compensatory pause. Heart rate and TS were correlated: Patients with high heart rate had low TS and late TT (TS=−2.7+0.01×sinus cycle length,
P
=0.018; TT=8.8 to 0.005×sinus cycle length,
P
=0.013).

Conclusions

—

HRT can be induced by programmed stimulation. In this setting, heart rate affects HRT but not ventricular premature complex prematurity. Induced HRT seems to be a valid method for measuring HRT parameters in patients with few ventricular premature complexes.
Role of Transcoronary Ablation of Septal Hypertrophy in Patients With Hypertrophic Cardiomyopathy, New York Heart Association Functional Class III or IV, and Outflow Obstruction Only Under Provocable Conditions
Authors: Gietzen Frank H. , Leuner Christian J. , Obergassel Ludger , Strunk-Mueller Claudia , Kuhn Horst
Published: July 2002

Background

—

Transcoronary ablation of septal hypertrophy (TASH) for hypertrophic cardiomyopathy seems to be an effective alternative to surgical myectomy. It remains a point of debate whether an outflow obstruction at rest is a necessary criterion for interventional therapy.

Methods and Results

—

TASH was compared in 45 consecutive patients with no resting gradient and a provocable gradient of ≥30 mm Hg (group I) and in 84 consecutive patients with a resting gradient of ≥30 mm Hg (80±33 mm Hg) (group II). At baseline, all patients were in NYHA functional class (FC) III or IV, unresponsive to medical treatment. Patients in group I were older (63±12 versus 55±17 years,
P
=0.005) and had a lower postextrasystolic gradient (110±44 versus 171±40 mm Hg,
P
<0.001). The groups were similar with respect to NYHA FC (3.1±0.3 versus 3.1±0.3), basal septal thickness (22±4 versus 23±3 mm), maximal oxygen consumption (13.1±4.6 versus 14.5±5.0 mL/kg per minute), and pulmonary artery mean pressure at workload (42±9 versus 42±10 mm Hg) (
P
>0.05). Median follow-up was 7 months after TASH. The 2 groups showed a significant and similar improvement in provocable obstruction (to 24±24 and 56±51 mm Hg, respectively), basal septal thickness (to 12±3 and 12±4 mm, respectively), NYHA FC (to 1.7±0.6 and 1.5±0.6, respectively), maximal oxygen consumption (to 16.0±5.3 and 16.6±6.0 mL/kg per minute, respectively), and pulmonary artery mean pressure at workload (to 36±9 and 34±9 mm Hg, respectively) (
P
>0.05).

Conclusions

—

TASH seems to have beneficial clinical and hemodynamic effects in patients with either provocable or resting outflow obstruction.
Magnetic Resonance–Guided Placement of Atrial Septal Closure Device in Animal Model of Patent Foramen Ovale
Authors: Buecker Arno , Spuentrup Elmar , Grabitz Ralph , Freudenthal Franz , Muehler Eberhard G. , Schaeffter Tobias , van Vaals Joop J. , Günther Rolf W.
Published: July 2002

Background

—

Percutaneous closure of the patent foramen ovale (PFO) is usually performed under x-ray in combination with ultrasound guidance. We tested the feasibility of applying magnetic resonance (MR) guidance for percutaneous closure of PFO in an animal model, thus avoiding the disadvantage of ionizing radiation.

Methods and Results

—

Real-time MRI with radial or spiral k-space filling (15 frames per second) on an interventional 1.5-T high-field whole-body system was exploited to examine the feasibility of MR-guided closure of the PFO in 7 piglets weighing ≈14 kg. A specially designed prototype nonmagnetic closure device was introduced via the femoral vein. The short bore of the magnet and in-room monitors allowed for visualization and steering of the catheter with the loaded occluder. Catheterization of the left atrium and, finally, correct placement of the device was possible in all animals. Deployment of the device was depicted by real-time MR, and initial misplacement, which occurred in 2 animals, was easily detected and corrected.

Conclusions

—

Real-time MR guidance of PFO closure, without the use of ionizing radiation, is feasible in an animal model.
Cross-Reactivity of Anti-CagA Antibodies With Vascular Wall Antigens
Authors: Franceschi Francesco , Sepulveda Antonia R. , Gasbarrini Antonio , Pola Paolo , Silveri Nicolò Gentiloni , Gasbarrini Giovanni , Graham David Y. , Genta Robert M.
Published: July 2002

Background

—

Helicobacter pylori
-CagA positive strains have been shown to be associated with atherosclerosis. However, the pathogenesis is still undetermined. The aim of this study was to determine whether anti-CagA antibodies cross-react with antigens of normal and atherosclerotic arteries.

Methods and Results

—

Eight umbilical cord sections, 14 atherosclerotic artery sections, and 10 gastrointestinal tract sections were examined by immunohistochemistry using polyclonal anti-CagA antibodies. Five atherosclerotic and 3 normal artery samples were also lysed in ice-cold lysis buffer containing protease inhibitors and were immunoprecipitated using the same antibodies. Anti-CagA antibodies reacted with cytoplasm and nuclei of smooth muscle cells in umbilical cord and atherosclerotic vessel sections, cytoplasm of fibroblasts-like cells in intimal atherosclerotic plaques, and the cell membranes of endothelial cells. Anti-CagA antibodies also specifically immunoprecipitated 2 high molecular weight antigens of 160 and 180 kDa from both normal and atherosclerotic artery lysates.

Conclusions

—

Anti-CagA antibodies cross-react with antigens of both normal and atherosclerotic blood vessels. We speculate that the binding of anti-CagA antibodies to those antigens in injured arteries could influence the progression of atherosclerosis in CagA-positive
H pylori
-infected patients.
B-Type Natriuretic Peptide and Clinical Judgment in Emergency Diagnosis of Heart Failure
Authors: McCullough Peter A. , Nowak Richard M. , McCord James , Hollander Judd E. , Herrmann Howard C. , Steg Philippe G. , Duc Philippe , Westheim Arne , Omland Torbjørn , Knudsen Cathrine Wold , Storrow Alan B. , Abraham William T. , Lamba Sumant , Wu Alan H.B. , Perez Alberto , Clopton Paul , Krishnaswamy Padma , Kazanegra Radmila , Maisel Alan S.
Published: July 2002

Background

—

We sought to determine the degree to which B-type natriuretic peptide (BNP) adds to clinical judgment in the diagnosis of congestive heart failure (CHF).

Methods and Results

—

The Breathing Not Properly Multinational Study was a prospective diagnostic test evaluation study conducted in 7 centers. Of 1586 participants who presented with acute dyspnea, 1538 (97%) had clinical certainty of CHF determined by the attending physician in the emergency department. Participants underwent routine care and had BNP measured in a blinded fashion. The reference standard for CHF was adjudicated by 2 independent cardiologists, also blinded to BNP results. The final diagnosis was CHF in 722 (47%) participants. At an 80% cutoff level of certainty of CHF, clinical judgment had a sensitivity of 49% and specificity of 96%. At 100 pg/mL, BNP had a sensitivity of 90% and specificity of 73%. In determining the correct diagnosis (CHF versus no CHF), adding BNP to clinical judgment would have enhanced diagnostic accuracy from 74% to 81%. In those participants with an intermediate (21% to 79%) probability of CHF, BNP at a cutoff of 100 pg/mL correctly classified 74% of the cases. The areas under the receiver operating characteristic curve were 0.86 (95% CI 0.84 to 0.88), 0.90 (95% CI 0.88 to 0.91), and 0.93 (95% CI 0.92 to 0.94) for clinical judgment, for BNP at a cutoff of 100 pg/mL, and for the 2 in combination, respectively (
P
<0.0001 for all pairwise comparisons).

Conclusions

—

The evaluation of acute dyspnea would be improved with the addition of BNP testing to clinical judgment in the emergency department.
Familial Aggregation of Low-Renin Hypertension
Authors: Fisher Naomi D.L. , Hurwitz Shelley , Jeunemaitre Xavier , Hopkins Paul N. , Hollenberg Norman K. , Williams Gordon H.
Published: July 2002

Low-renin hypertension, representing roughly one quarter of all essential hypertension, is widely recognized by distinct physiological features, including salt-sensitivity, diuretic- responsiveness, and a favorable natural history. Although certain demographic features including age, ethnicity, and diabetes mellitus predispose to low-renin hypertension, these factors account for only a minority of cases. We examined familial concordance for renin status in 119 families with 257 hypertensive members. Low-renin was defined rigorously by plasma renin activity ≤0.69 ng angiotensin I/L per second, drawn when subjects had achieved balance after 5 to 7 days on a 10 mmol sodium diet and had stood upright for at least 1 hour. Given the prevalence of low-renin hypertension in our general population, low-renin hypertension was significantly more concordant among siblings than expected by chance (
P
=0.01). There were twice as many low-renin families as expected (10.9% versus 5.5%), in sharp contrast to the normal-renin state, in which the observed and expected were similar (61.0% versus 58.6%). These results were independent of age, race, and gender. Variance in renin status attributable to family membership was 35%. Association studies were performed on 8 polymorphisms in 5 candidate genes, and significant association was confirmed with the G460W polymorphism of the adducin gene. Familial determinants, which are probably but not definitely genetic, contribute to the low-renin hypertension state.
Effects of Celecoxib on Ambulatory Blood Pressure in Hypertensive Patients on ACE Inhibitors
Authors: White William B. , Kent Jeffrey , Taylor Addison , Verburg Kenneth M. , Lefkowith James B. , Whelton Andrew
Published: July 2002

Nonselective nonsteroidal anti-inflammatory agents have been shown to attenuate the antihypertensive efficacy of ACE inhibitors with average increases in systolic blood pressure (BP) of 5 to 10 mm Hg. Less is known about the specific cyclooxygenase-2 (COX-2) inhibitors now widely used for the treatment of arthritis. The objective of this study was to determine the effects of celecoxib compared with placebo on 24-hour BP levels in ACE inhibitor-treated patients with hypertension. This was a randomized, double-blind, placebo-controlled, parallel-group clinical trial involving 178 men and women (mean age, 53 years) with essential hypertension who were treated and controlled with lisinopril monotherapy (10 to 40 mg daily). Baseline BP values were obtained using 24-hour ambulatory recordings. Patients received either celecoxib, 200 mg twice daily (twice the recommended dose for osteoarthritis) (n=91), or placebo (n=87) for 4 weeks, and changes in the 24-hour BP, body weight, and clinical laboratory parameters were assessed. Mean changes from baseline in the 24-hour systolic and diastolic BP were 2.6/1.5±0.9/0.6 mm Hg on celecoxib versus 1.0/0.3±1/0.6 mm Hg on placebo (
P
=0.34 for systolic BP;
P
=0.45 for diastolic BP). The proportion of patients whose 24-hour BP increased by at least 5, 10, 15, or 20 mm Hg were also similar on celecoxib and placebo. No changes in body weight, serum creatinine, or potassium occurred in either group. Thus, these data demonstrate that high doses of celecoxib have no significant effect on the antihypertensive effect of the ACE inhibitor lisinopril. The placebo-subtracted changes observed in 24-hour BP (1.6/1.2 mm Hg) are less than what has been reported for nonselective nonsteroidal anti-inflammatory agents in ACE inhibitor-treated patients.
Blood Pressure–Independent Attenuation of Cardiac Hypertrophy by AT
1
R-AS Gene Therapy
Authors: Pachori Alok S. , Numan Mohammed T. , Ferrario Carlos M. , Diz Debra M. , Raizada Mohan K. , Katovich Michael J.
Published: July 2002

Our studies have established that a single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense gene causes prolonged antihypertensive actions in the spontaneously hypertensive rat. These results suggest that antisense gene therapy is a conceptually valid strategy for the control of hypertension at the genetic level. To evaluate whether attenuation of the pathophysiological aspects of hypertension are dependent on the blood pressure lowering actions of antisense gene therapy, we chose the renin transgenic rat as a hypertensive animal model and cardiac hypertrophy as the hypertension-associated pathophysiology. A single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense in the neonatal rat resulted in long-term expression of the antisense transgene in various cardiovascular-relevant tissues, including the heart. This expression was associated with a significant attenuation of cardiac hypertrophy despite its failure to normalize high blood pressure. Developmental studies indicated that cardiac hypertrophy was evident as early as 16 days of age in viral vector–treated control transgenic rats, despite these animals exhibiting normal blood pressure. These observations demonstrate that, in the renin-transgenic rat, the onset of cardiac hypertrophy occurs during development and is prevented without normalization of high blood pressure. Collectively, these results provide further proof of the concept and indicate that antisense gene therapy could successfully target the local tissues’ renin-angiotensin system to produce beneficial cardiovascular outcomes.
Insulin Sensitivity and Blood Pressure in Black and White Children
Authors: Cruz Martha L. , Huang Terry T-K. , Johnson Maria S. , Gower Barbara A. , Goran Michael I.
Published: July 2002

Although insulin sensitivity is correlated with high blood pressure in adults, it is unclear whether such a relationship exists in children across ethnic groups. Therefore, the aims of the study were to establish (1) if body composition and insulin sensitivity were related to blood pressure in children, and (2) if any differences in blood pressure between white and black children were explained by body composition and/or insulin sensitivity. Insulin sensitivity and the acute insulin response were established by the minimal model and body composition by dual-energy X-ray absorptiometry. Blood pressure was recorded in the supine position. Body composition, fasting insulin (
P
<0.01), and the acute insulin response (
P
<0.05) were positively related to systolic blood pressure but not to diastolic blood pressure, and insulin sensitivity (
P
<0.001) was negatively related to systolic blood pressure but not to diastolic blood pressure. Insulin sensitivity was negatively associated with systolic and diastolic blood pressure after adjustment for body composition (
P
<0.01). Black children had higher systolic (110±9.2 versus 105±8.5 mm Hg,
P
=0.01) and diastolic (59±7.0 versus 54±8.0 mm Hg,
P
<0.01) blood pressure than did white children. The ethnic difference in blood pressure was not explained by body composition, fasting insulin, acute insulin response, or insulin sensitivity. In conclusion, the relationship between insulin sensitivity and systolic blood pressure is evident early in life. Black ethnicity and low insulin sensitivity contribute independently to higher blood pressure in children.
Cardiovascular Phenotypes of Kinin B
2
Receptor– and Tissue Kallikrein–Deficient Mice
Authors: Trabold Fabien , Pons Sandrine , Hagege Albert A. , Bloch-Faure May , Alhenc-Gelas François , Giudicelli Jean-François , Richer-Giudicelli Christine , Meneton Pierre
Published: July 2002

To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, the systemic and regional hemodynamics of kinin B
2
receptor–deficient (B
2
−/−
) and tissue kallikrein–deficient (TK
−/−
) mice were compared with their wild-type (WT) littermates on a pure C57BL/6 genetic background. B
2
−/−
, TK
−/−
, and WT adult mice were normotensive and displayed normal hemodynamic (left ventricular [LV] pressure, cardiac output, total peripheral resistance, dP/dt
max
) and echocardiographic (septum and LV posterior wall thickness, LV diameter, LV mass, and LV fractional shortening) parameters. However, heart rate was lower in B
2
−/−
mice compared with TK
−/−
and WT mice. In addition, B
2
−/−
mice, but not TK
−/−
mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did WT mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilatation capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B
2
−/−
mice were significantly more sensitive than were TK
−/−
mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Finally, renin mRNA levels were significantly greater in B
2
−/−
mice and smaller in TK
−/−
mice compared with WT mice. Taken together, these results indicate that under basal conditions, the kinin B
2
receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the coronaries and the kidneys. The phenotypic differences observed between TK
−/−
and B
2
−/−
mice could be underlain by tissue kallikrein kinin–independent effect and/or kinin B
1
receptor activation.
Enhanced Endothelin Activity Prevents Vasodilation to Insulin in Insulin Resistance
Authors: Miller Allison W. , Tulbert Christina , Puskar Michelle , Busija David W.
Published: July 2002

Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin’s effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-
l
-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.
Long-Term Adrenomedullin Infusion Improves Survival in Malignant Hypertensive Rats
Authors: Mori Yosuke , Nishikimi Toshio , Kobayashi Naohiko , Ono Hidehiko , Kangawa Kenji , Matsuoka Hiroaki
Published: July 2002

Previous studies have demonstrated that adrenomedullin has inhibitory effects on the proliferation and DNA synthesis of mesangial cells and vascular smooth muscle cells in vitro and that plasma adrenomedullin levels are markedly elevated in malignant hypertension. This study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in malignant hypertensive rats. We studied the following 3 groups: control Wistar Kyoto rats, deoxycorticosterone acetate–salt spontaneously hypertensive rats, and adrenomedullin-treated deoxycorticosterone acetate–salt spontaneously hypertensive rats. Chronic adrenomedullin infusion using an osmotic minipump was started simultaneously with deoxycorticosterone acetate–salt treatment. After 3 weeks of the treatment, malignant hypertensive rats were characterized by higher blood pressure, kidney weight, urinary protein excretion, glomerular injury score, plasma renin concentration, aldosterone level, endogenous rat plasma adrenomedullin level, renal cortical tissue angiotensin II level, angiotensin-converting enzyme mRNA level, and transforming growth factor-β1 mRNA level in the renal cortex, and by lower creatinine clearance, compared with the control rats. Chronic adrenomedullin infusion significantly improved these parameters (kidney weight −6.5%, urinary protein excretion −63.8%, glomerular injury score −38.3%, plasma renin concentration −52.4%, aldosterone −23.2%, rat adrenomedullin −28.6%, renal angiotensin II −28.1%, renal angiotensin-converting enzyme mRNA −38.3%, renal transforming growth factor-β1 mRNA −56.2%, and creatinine clearance +20.5%) without significant reduction of mean arterial pressure (−4%). Kaplan-Meier survival analysis showed that adrenomedullin infusion significantly prolonged survival time. These results suggest that subdepressor dose of chronic adrenomedullin infusion has renoprotective effects in this malignant hypertension model, at least in part, via inhibition of the circulating and intrarenal renin-angiotensin system.
Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning
Authors: Shinmura Ken , Xuan Yu-Ting , Tang Xian-Liang , Kodani Eitaro , Han Hui , Zhu Yanqing , Bolli Roberto
Published: July 2002

Cyclooxygenase-2 (COX-2) is known to mediate the cardioprotective effects of the late phase of ischemic preconditioning (PC); however, the signaling pathways involved in COX-2 induction following ischemic PC are unknown. In addition, although inducible nitric oxide synthase (iNOS) has been identified as a co-mediator of late PC together with COX-2, the interaction between iNOS and COX-2 in the heart is unknown. Using conscious rabbits, we found that the induction of COX-2 expression 24 hours after ischemic PC was blocked by pretreatment with inhibitors of protein kinase C (PKC), Src protein tyrosine kinases (PTKs), and nuclear factor-κB (NF-κB) but not by inhibitors of NOS or scavengers of reactive oxygen species (ROS). The selective iNOS inhibitors SMT and 1400W, given 24 hours after PC, abrogated the increase in myocardial prostaglandin E
2
(PGE
2
) and 6-keto-PGF
1α
, whereas the selective soluble guanylate cyclase inhibitor ODQ had no effect. COX-2 selective inhibitors (celecoxib and NS-398) did not affect iNOS activity. These results demonstrate that (i) ischemic PC upregulates cardiac COX-2 via PKC-, Src PTK-, and NF-κB–dependent signaling pathways, whereas generation of NO and ROS is not necessary, and (ii) the activity of newly synthesized COX-2 following PC requires iNOS-derived NO whereas iNOS activity is independent of COX-2–derived prostanoids, indicating that COX-2 is located downstream of iNOS in the protective pathway of late PC. The data also indicate that iNOS modulates COX-2 activity via cGMP-independent mechanisms. To our knowledge, this is the first demonstration that iNOS-derived NO drives prostanoid synthesis by COX-2 in the heart. NO-mediated activation of COX-2 may be a heretofore unrecognized mechanism by which NO exerts its salubrious effects in the late phase of PC.
Reduction of
I
to
Causes Hypertrophy in Neonatal Rat Ventricular Myocytes
Authors: Kassiri Zamaneh , Zobel Carsten , Nguyen The-Tin T. , Molkentin Jeffery D. , Backx Peter H.
Published: July 2002

Prolonged action potential duration (APD) and decreased transient outward K
+
current (
I
to
) as a result of decreased expression of K
v4.2
and K
v4.3
genes are commonly observed in heart disease. We found that treatment of cultured neonatal rat ventricular myocytes with Heteropoda Toxin
3
, a blocker of cardiac
I
to
, induced hypertrophy as measured using cell membrane capacitance and
3
H-leucine uptake. To dissect the role of specific
I
to
-encoding genes in hypertrophy,
I
to
was selectively reduced by overexpressing mutant dominant-negative (DN) transgenes.
I
to
amplitude was reduced equally (by about 50%) by overexpression of DN K
v1.4
(K
v1.4
N) or DN K
v4.2
(either K
v4.2
N or K
v4.2
W362F), but only DN K
v4.2
prolonged APD duration (at 1 Hz) and induced myocyte hypertrophy. This hypertrophy was prevented by coexpressing wild-type K
v4.2
channels (K
v4.2
F) with the DN K
v4.2
genes, suggesting the hypertrophy is due to
I
to
reduction and not nonspecific effects of transgene overexpression. The hypertrophy caused by reductions of K
v4.x
-based
I
to
was associated with increased activity of the calcium-dependent phosphatase, calcineurin, and could be prevented by coinfection with Ad-CAIN, a specific calcineurin inhibitor. The hypertrophy and calcineurin activation induced by K
v4.2
N infection were prevented by blocking Ca
2+
entry and excitability with verapamil or high [K
+
]
o
. Our studies suggest that reductions of K
v4.2/3
-based
I
to
play a role in hypertrophy signaling by activation of calcineurin.
Characterization of the Mouse Aortic Carboxypeptidase-Like Protein Promoter Reveals Activity in Differentiated and Dedifferentiated Vascular Smooth Muscle Cells
Authors: Layne Matthew D. , Yet Shaw-Fang , Maemura Koji , Hsieh Chung-Ming , Liu Xiaoli , Ith Bonna , Lee Mu-En , Perrella Mark A.
Published: July 2002

The dedifferentiation and proliferation of vascular smooth muscle cells (VSMCs) contribute to the formation of vascular lesions. In this study, the regulation of aortic carboxypeptidase-like protein (ACLP) expression in VSMCs was investigated. After mouse carotid injury, the expression of ACLP increases in the dedifferentiated VSMCs of the neointima in a pattern that differs from that of smooth muscle α-actin. To better understand the regulation of ACLP in VSMCs, we characterized the 21-exon mouse
ACLP
gene and 5′-flanking region and examined its promoter activity. In transient transfection assays, 2.5 kb of the
ACLP
5′-flanking sequence directed high levels of luciferase reporter activity in primary cultured rat aortic smooth muscle cells, and this activity was not dependent on serum response factor. We identified a positive element between base pairs −156 and −122 by analysis of 5′ deletion and mutant constructs. By use of electrophoretic mobility shift assays with rat aortic smooth muscle cell nuclear extracts, Sp1 and Sp3 transcription factors bound to this region, and transfection assays in D.Mel.2 cells revealed that both Sp1 and Sp3 transactivated the
ACLP
promoter. Transgenic mice harboring the −2.5-kb
ACLP
promoter upstream from a nuclear-targeted LacZ gene were generated, and expression was detected in the VSMCs of large blood vessels, arterioles, and veins. Interestingly,
ACLP
promoter–LacZ reporter activity increased within the neointimal VSMCs of injured carotid vessels, consistent with the expression of the endogenous ACLP protein. The
ACLP
promoter may provide a novel tool to target gene expression to dedifferentiated VSMCs.
Leptin Induces Endothelin-1 in Endothelial Cells In Vitro
Authors: Quehenberger Peter , Exner Markus , Sunder-Plassmann Raute , Ruzicka Katharina , Bieglmayer Christian , Endler Georg , Muellner Claudia , Speiser Wolfgang , Wagner Oswald
Published: July 2002

Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual’s body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, were also observed in obese subjects. The pathomechanisms underlying this ET-1 increase in obesity are poorly understood. In the present study, we investigated the influence of the
ob
gene product leptin on the expression of ET-1 in human umbilical vein endothelial cells (HUVECs). Binding studies using
125
I-radiolabeled leptin revealed high- and low-affinity leptin binding sites on HUVECs (Kd1=13.1±3.1 nmol/L and Kd2=1390±198 nmol/L, respectively), mediating a time- and dose-dependent increase of ET-1 mRNA expression and protein secretion after incubation of HUVECs with leptin. This leptin-induced ET-1 expression was inhibited by preincubation of HUVECs with 0.75 μmol/L antisense phosphorothioate oligonucleotides directed against the leptin receptor Ob-Rb. Furthermore, after incubation with leptin, increased nuclear staining of c-fos and c-jun, the major components of the transcription factor AP-1, and increased AP-1 DNA binding were observed. Transient transfection studies with ET-1 promoter constructs showed that leptin-induced promoter activity was abolished in the absence of AP-1 binding sites or by cotransfection with a plasmid overexpressing a mutated jun, which is able to bind c-fos but not DNA. Thus, leptin upregulates ET-1 production in HUVECs via a mechanism potentially involving jun binding members of the bZIP family.