bluuebunny/crossref_metadata_2025 huggingface dataset:
Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties
Authors: Kontush Anatol , de Faria Eliana Cotta , Chantepie Sandrine , Chapman M. John
Published: January 2004

Objective—

Hyperalphalipoproteinemia (HALP) is characterized by elevated plasma levels of high-density lipoprotein (HDL) particles with altered composition, metabolism, and function. The impact of such modification on antioxidative activities of HDL subfractions is indeterminate.

Methods and Results—

Gradient fractionation revealed that buoyant HDL2b and 2a and small dense HDL3b and 3c levels were elevated up to 2.0-fold in HALP subjects (n=9; mean plasma HDL cholesterol, 79 mg/dL) with low hepatic lipase activity. HDL2a, 3a, 3b, and 3c displayed lower specific antioxidative activity (sAA) during low-density lipoprotein (LDL) oxidation (−15% to −86%, on a unit particle mass basis) than their normolipidemic counterparts (n=13). LDL oxidation was delayed by control HDL3a, 3b, and 3c (up to −79%) but specifically by HDL3c (−54%) in HALP. Paraoxonase activity was deficient in all HALP HDL subfractions. Paraoxonase, PAF-AH, and LCAT activities together accounted for ≈50% of variation in sAA. Abnormal chemical composition of HDL3b and 3c (cholesterol-deficient, triglyceride-enriched) in HALP was associated with impaired sAA. Systemic oxidative stress (as plasma 8-isoprostanes) tended to be elevated (1.5-fold) in HALP and negatively correlated with sAA (as TBARS).

Conclusions—

Intrinsic antioxidative activity of HDL subspecies is impaired in HALP, reflecting altered enzymatic and physicochemical properties.
Inverse Association Between Birth Weight and C-Reactive Protein Concentrations in the MIDSPAN Family Study
Authors: Sattar Naveed , McConnachie Alex , O’Reilly Denis , Upton Mark N. , Greer Ian A. , Smith George Davey , Watt Graham
Published: January 2004

Objective—

Inflammation markers and low birth weight each predict elevated risk of cardiovascular events and type 2 diabetes. However, potential associations between the low-grade inflammatory response as represented by C-reactive protein (CRP) concentrations and low birth weight have been sparsely examined.

Methods and results—

In the MIDSPAN Family Study, 1663 individuals had birth weight data and CRP concentrations measured as adults (age 30 to 59). The relationship between these parameters was examined after adjusting for factors known to influence CRP concentrations inclusive of age, body mass index, smoking, socio-economic deprivation, and hormone use in women. After adjusting for potential confounders, there was a negative association between birth weight and CRP, whereby a 1-kg increase in birth weight is associated with a 10.7% decrease in CRP (95% CI: 3.0% to 17.8% decrease). There was no strong evidence that the effects differed in men and women (
P
=0.32).

Conclusion—

Low birth weight contributes to elevated CRP concentration in adult life. Future studies are required to determine to what extent this association reflects catch-up centile crossing, in utero programming, or genetic factors.
Raising High-Density Lipoprotein in Humans Through Inhibition of Cholesteryl Ester Transfer Protein
Authors: Clark Ronald W. , Sutfin Tamara A. , Ruggeri Roger B. , Willauer Ann T. , Sugarman Eliot D. , Magnus-Aryitey George , Cosgrove Patricia G. , Sand Thomas M. , Wester Ronald T. , Williams John A. , Perlman Michael E. , Bamberger Mark J.
Published: January 2004

Objective—

The ability of the potent cholesteryl ester transfer protein (CETP) inhibitor torcetrapib (CP-529,414) to raise high-density lipoprotein cholesterol (HDL-C) levels in healthy young subjects was tested in this initial phase 1 multidose study.

Methods and Results—

Five groups of 8 subjects each were randomized to placebo (n=2) or torcetrapib (n=6) at 10, 30, 60, and 120 mg daily and 120 mg twice daily for 14 days. Torcetrapib was well tolerated, with all treated subjects completing the study. The correlation of plasma drug levels with inhibition (EC50=43 nM) was as expected based on in vitro potency (IC50 ≈50 nM), and increases in CETP mass were consistent with the proposed mechanism of inhibition. CETP inhibition increased with escalating dose, leading to elevations of HDL-C of 16% to 91%. Total plasma cholesterol did not change significantly because of a reduction in nonHDL-C, including a 21% to 42% lowering of low-density lipoprotein cholesterol at the higher doses. Apolipoprotein A-I and E were elevated 27% and 66%, respectively, and apoB was reduced 26% with 120 mg twice daily. Cholesteryl ester content decreased and triglyceride increased in the nonHDL plasma fraction, with contrasting changes occurring in HDL.

Conclusions—

These effects of CETP inhibition resemble those observed in partial CETP deficiency. This work serves as a prelude to further studies in subjects with low HDL, or combinations of dyslipidemia, in assessing the role of CETP in atherosclerosis.
Vascular Heme Oxygenase-1 Induction Suppresses Microvascular Thrombus Formation In Vivo
Authors: Lindenblatt N. , Bordel R. , Schareck W. , Menger M.D. , Vollmar B.
Published: January 2004

Objective—

By heme degradation, heme oxygenase-1 (HO-1) provides endogenous carbon monoxide and bilirubin, both of which play major roles in vascular biology. The current study aimed to examine whether induction of HO-1 and its byproducts modulate the process of microvascular thrombus formation in vivo.

Methods and Results—

In individual microvessels of mouse cremaster muscle preparations, ferric chloride-induced thrombus formation was analyzed using intravital fluorescence microscopy. When mice were pretreated with an intraperitoneal injection of hemin, a HO-1 inducer, immunohistochemistry and Western blot protein analysis of cremaster muscle tissue displayed a marked induction of HO-1. In these animals, superfusion with ferric chloride solution induced arteriolar and venular thrombus formation, which, however, was significantly delayed when compared with thrombus formation in animals without HO-1 induction. The delay in thrombus formation in hemin-treated mice was completely blunted by tin protoporphyrin-IX, a HO-1 inhibitor, but not by copper protoporphyrin-IX, which does not inhibit the enzyme. Coadministration of the vitamin E analogue Trolox in HO-1–blocked animals almost completely restored the delay in thrombus formation, implying that, besides CO, the antioxidant HO pathway metabolite bilirubin mainly contributes to the antithrombotic property of HO-1. This was further supported by the fact that bilirubin was found as effective as hemin in delay of ferric chloride-induced thrombus formation. Animals with HO-1 induction revealed reduced P-selectin protein expression in cremaster muscle tissue, which most probably presented the molecular basis for delayed thrombus growth.

Conclusion—

Local induction of HO-1 activity may be of preventive and therapeutic value for clinical disorders with increased risk of thrombotic events.
Inhibition of Plasmin Activity by Tranexamic Acid Does Not Influence Inflammatory Pathways During Human Endotoxemia
Authors: Renckens Rosemarijn , Weijer Sebastiaan , de Vos Alex F. , Pater Jennie M. , Meijers Joost C. , Hack C. Erik , Levi Marcel , van der Poll Tom
Published: January 2004

Objective—Plasmin activates several proinflammatory pathways at the cellular level in vitro. Lipopolysaccharide (LPS) administration to healthy humans results in a rapid generation of plasmin activity, accompanied by activation of a number of inflammatory systems.

Methods and Results—To determine the role of early plasmin activity in LPS-induced inflammation in vivo, 16 healthy males received an intravenous bolus injection with LPS (fromEscherichia coli, 4 ng/kg) directly preceded by a 30-minute intravenous infusion of tranexamic acid (2 g, n=8), a plasmin activation inhibitor, or placebo (n=8). LPS injection induced marked increases in the plasma levels of D-dimer and plasmin-α2-antiplasmin complexes, indicative of plasmin activation and generation, respectively, which were strongly attenuated by tranexamic acid (bothP<0.01 versus placebo). However, tranexamic acid did not influence LPS-induced coagulation activation, granulocytosis, neutrophil activation (expression of CD11b, CD66b, and L-selectin) or degranulation (plasma concentrations of elastase-α1-antitrypsin and bactericidal permeability-increasing protein), endothelial cell activation (plasma levels of von Willebrand factor and soluble E-selectin), or cytokine release.

Conclusion—These data argue against a role of early plasmin generation in the subsequent activation of other inflammatory pathways during human endotoxemia.
Hydroxymethyl-Glutaryl Coenzyme A Reductase Inhibition Limits Cytomegalovirus Infection in Human Endothelial Cells
Authors: Potena Luciano , Frascaroli Giada , Grigioni Francesco , Lazzarotto Tiziana , Magnani Gaia , Tomasi Luciana , Coccolo Fabio , Gabrielli Liliana , Magelli Carlo , Landini Maria P. , Branzi Angelo
Published: January 2004

Background—

Statins exert anti-inflammatory effects independently of cholesterol-lowering properties. Cytomegalovirus (CMV) infection appears to be implicated in the pathophysiology of atherosclerosis by inducing inflammatory modifications in endothelial cells, especially in immunosuppressed patients. We investigated whether the activity of statins can inhibit replication of CMV in human endothelial cells.

Methods and Results—

Human umbilical vein endothelial cells (HUVECs) were infected with CMV and coincubated with fluvastatin at 0.1 and 0.2 μmol/L. Fluvastatin inhibited (
P
<0.001) CMV antigen expression, and this effect was dose related (
P
<0.001). Quantitative polymerase chain reaction showed that CMV DNA concentration was consistently lower in supernatants from fluvastatin-treated cells than in infected controls, and viral particle concentration was up to 30 times lower in 0.2 μmol/L fluvastatin-treated cells than in infected controls (10.5±0.9 versus 0.34±0.03 per 10
3
pfu/mL,
P
<0.001). Addition of mevalonate to treated cultures almost completely abolished fluvastatin inhibition of viral growth. Electrophoretic mobility shift assay showed that fluvastatin reduced nuclear factor-κB binding activity in CMV-infected cells.

Conclusions—

HMG-CoA inhibition by fluvastatin restrains CMV replication in HUVECs by inhibiting viral antigen expression, DNA synthesis, and viral particle production, conceivably by involving a reduction of nuclear factor-κB binding activity.
Determinants and Prognostic Impact of Heart Failure Complicating Acute Coronary Syndromes
Authors: Steg Philippe Gabriel , Dabbous Omar H. , Feldman Laurent J. , Cohen-Solal Alain , Aumont Marie-Claude , López-Sendón José , Budaj Andrzej , Goldberg Robert J. , Klein Werner , Anderson Frederick A.
Published: January 2004

Background—

Few data are available on the impact of heart failure (HF) across all types of acute coronary syndromes (ACS).

Methods and Results—

The Global Registry of Acute Coronary Events (GRACE) is a prospective study of patients hospitalized with ACS. Data from 16 166 patients were analyzed: 13 707 patients without prior HF or cardiogenic shock at presentation were identified. Of these, 1778 (13%) had an admission diagnosis of HF (Killip class II or III). HF on admission was associated with a marked increase in mortality rates during hospitalization (12.0% versus 2.9% [with versus without HF],
P
<0.0001) and at 6 months after discharge (8.5% versus 2.8%,
P
<0.0001). Of note, HF increased mortality rates in patients with unstable angina (defined as ACS with normal biochemical markers of necrosis; mortality rates: 6.7% with versus 1.6% without HF at admission,
P
<0.0001). By logistic regression analysis, admission HF was an independent predictor of hospital death (odds ratio, 2.2;
P
<0.0001). Admission HF was associated with longer hospital stay and higher readmission rates. Patients with HF had lower rates of catheterization and percutaneous cardiac intervention, and fewer received β-blockers and statins. Hospital development of HF (versus HF on presentation) was associated with an even higher in-hospital mortality rate (17.8% versus 12.0%,
P
<0.0001). In patients with HF, in-hospital revascularization was associated with lower 6-month death rates (14.0% versus 23.7%,
P
<0.0001; adjusted hazard ratio, 0.5; 95% CI, 0.37 to 0.68,
P
<0.0001).

Conclusions—

In this observational registry, heart failure was associated with reduced hospital and 6-month survival across all ACS subsets, including patients with normal markers of necrosis. More aggressive treatment of these patients may be warranted to improve prognosis.
Inhibition of Restenosis With a Paclitaxel-Eluting, Polymer-Free Coronary Stent
Authors: Gershlick Anthony , De Scheerder Ivan , Chevalier Bernard , Stephens-Lloyd Amanda , Camenzind Edoardo , Vrints Christian , Reifart Nicolaus , Missault Luc , Goy Jean-Jacques , Brinker Jeffrey A. , Raizner Albert E. , Urban Philip , Heldman Alan W.
Published: January 2004

Background—

The use of a stent to deliver a drug may reduce in-stent restenosis. Paclitaxel interrupts the smooth muscle cell cycle by stabilizing microtubules, thereby arresting mitosis.

Methods and Results—

On the basis of prior animal studies, the European evaLUation of the pacliTaxel Eluting Stent (ELUTES) pilot clinical trial (n=190) investigated the safety and efficacy of V-Flex Plus coronary stents (Cook Inc) coated with escalating doses of paclitaxel (0.2, 0.7, 1.4, and 2.7 μg/mm
2
stent surface area) applied directly to the abluminal surface of the stent in de novo lesions compared with bare stent alone. The primary efficacy end point was angiographic percent diameter stenosis at 6 months. At angiographic follow-up, percent diameter stenosis was 33.9±26.7% in controls (n=34) and 14.2±16.6% in the 2.7-μg/mm
2
group (n=31;
P
=0.006). Late loss decreased from 0.73±0.73 to 0.11±0.50 mm (
P
=0.002). Binary restenosis (≥50% at follow-up) decreased from 20.6% to 3.2% (
P
=0.056), with no significant benefit from intermediate paclitaxel doses. Freedom from major adverse cardiac events in the highest (effective) dose group was 92%, 89%, and 86% at 1, 6, and 12 months, respectively (
P
=NS versus control). No late stent thromboses were seen in any treated group despite clopidogrel treatment for 3 months only.

Conclusions—

Paclitaxel applied directly to the abluminal surface of a bare metal coronary stent, at a dose density of 2.7 μg/mm
2
, reduced angiographic indicators of in-stent restenosis without short- or medium-term side effects.
High Plasma Heparin Cofactor II Activity Is Associated With Reduced Incidence of In-Stent Restenosis After Percutaneous Coronary Intervention
Authors: Takamori Nobuyuki , Azuma Hiroyuki , Kato Midori , Hashizume Shunji , Aihara Ken-ichi , Akaike Masashi , Tamura Katsuya , Matsumoto Toshio
Published: January 2004

Background—

Thrombin plays an important role in the development of atherosclerosis and restenosis after percutaneous coronary intervention. Because heparin cofactor II (HCII) inhibits thrombin action in the presence of dermatan sulfate, which is abundantly present in arterial wall, HCII may affect vascular remodeling by modulating thrombin action. We hypothesized that patients with high plasma HCII activity may show a reduced incidence of in-stent restenosis (ISR).

Methods and Results—

Sequential coronary arteries (n=166) with NIR stent (Boston Scientific Corp) implantation in 134 patients were evaluated before, immediately after, and at 6 months after percutaneous coronary intervention. Patients were divided into the following groups: high HCII (≥110%, 45 lesions in 36 patients), normal HCII (≥80% and <110%, 81 lesions in 66 patients), and low HCII (<80%, 40 lesions in 32 patients). Percent diameter stenosis at follow-up in the high-HCII group (18.7%) was significantly lower (
P
=0.046) than that in the normal-HCII group (30.3%) or the low-HCII group (29.0%). The ISR rate in the high-HCII group (6.7%) was significantly lower than that in the low-HCII group (30.0%) (
P
=0.0039). Furthermore, multivariate analysis demonstrated that high plasma HCII activity is an independent factor in reducing the incidence of angiographic restenosis (odds ratio, 0.953/1% increase of HCII; 95% CI, 0.911 to 0.998).

Conclusions—

The results demonstrate that HCII may have a hitherto unrecognized effect in inhibiting ISR. The effect of HCII may be mediated by inactivating thrombin in injured arteries, thereby inhibiting vascular smooth muscle cell migration and proliferation.
Vascular Oxidant Stress Enhances Progression and Angiogenesis of Experimental Atheroma
Authors: Khatri Jaikirshan J. , Johnson Chad , Magid Richard , Lessner Susan M. , Laude Karine M. , Dikalov Sergey I. , Harrison David G. , Sung Hak-Joon , Rong Yuan , Galis Zorina S.
Published: January 2004

Background—

Although multiple pathological processes have been associated with oxidative stress, the causative relation between oxidative stress and arterial lesion progression remains unclear.

Methods and Results—

To test the effect of creating arterial wall oxidative stress, we compared progression of mouse carotid lesions induced by flow cessation in the wild-type (WT) versus transgenic mice (Tg

p22vsmc

), in which overexpression of p22phox, a critical component of NAD(P)H oxidase was targeted to smooth muscle cell (SMC). Compared with WT mice, arterial lesions grew significantly larger in Tg

p22vsmc

(
P
<0.001) and demonstrated elevated hydrogen peroxide (H
2
O
2
) and vascular endothelial growth factor (VEGF) levels at all time points examined (
P
<0.001, n=4 animals per time point), probably related to increased expression of hypoxia inducible factor (HIF)-1α via SMC oxidative stress in the Tg

p22vsmc

arteries, both basally (203±12% versus WT,
P
<0.001, n=3) and after lesion formation. Interestingly, Tg

p22vsmc

lesions were complicated by extensive neointimal angiogenesis. In vitro experiments confirmed SMCs isolated from Tg

p22vsmc

to be the source for increased H
2
O
2
, VEGF, and HIF-1α and their capacity to induce angiogenic cord-like structures when cocultured with endothelial cells. The antioxidant ebselen inhibited SMC activities in vitro and intralesion angiogenesis and lesion progression in vivo.

Conclusions—

We have demonstrated a novel pathway by which oxidative stress can trigger in vivo an angiogenic switch associated with experimental plaque progression and angiogenesis. This pathway may be related to human atheroma progression and destabilization through intraplaque hemorrhage.
Plasticity of Human Adipose Lineage Cells Toward Endothelial Cells
Authors: Planat-Benard Valérie , Silvestre Jean-Sébastien , Cousin Béatrice , André Mireille , Nibbelink Maryse , Tamarat Radia , Clergue Michel , Manneville Carole , Saillan-Barreau Corinne , Duriez Micheline , Tedgui Alain , Levy Bernard , Pénicaud Luc , Casteilla Louis
Published: January 2004

Background—

Adipose tissue development and remodeling are closely associated with the growth of vascular network. We hypothesized that adipose tissue may contain progenitor cells with angiogenic potential and that therapy based on adipose tissue-derived progenitor cells administration may constitute a promising cell therapy in patients with ischemic disease.

Methods and Results—

In mice, cultured stromal-vascular fraction (SVF) cells from adipose tissue have a great proangiogenic potential, comparable to that of bone marrow mononuclear cells in the mouse ischemic hindlimb model. Similarly, cultured human SVF cells differentiate into endothelial cells, incorporate into vessels, and promote both postischemic neovascularization in nude mice and vessel-like structure formation in Matrigel plug. In vitro, these cells represent a homogeneous population of CD34- and CD13-positive cells, which can spontaneously express the endothelial cell markers CD31 and von Willebrand factor when cultured in semisolid medium. Interestingly, dedifferentiated mature human adipocytes have the potential to rapidly acquire the endothelial phenotype in vitro and to promote neovascularization in ischemic tissue and vessel-like structure formation in Matrigel plug, suggesting that cells of endothelial and adipocyte phenotypes may have a common precursor.

Conclusions—

This study demonstrates, for the first time, that adipocytes and endothelial cells have a common progenitor. Such adipose lineage cells participate in vascular-like structure formation in Matrigel plug and enhance the neovascularization reaction in ischemic tissue. These results also highlight the concept that adipose lineage cells represent a suitable new cell source for therapeutic angiogenesis in ischemic disease.
Randomized, Controlled Dose-Ranging Study of the Selective Adenosine A
2A
Receptor Agonist Binodenoson for Pharmacological Stress as an Adjunct to Myocardial Perfusion Imaging
Authors: Udelson James E. , Heller Gary V. , Wackers Frans J.Th. , Chai Andrew , Hinchman David , Coleman Patrick S. , Dilsizian Vasken , DiCarli Marcello , Hachamovitch Rory , Johnson James R. , Barrett Richard J. , Gibbons Raymond J.
Published: January 2004

Background—

Dipyridamole and adenosine cause frequent side effects as a result of nonspecific adenosine receptor stimulation. Selective agonism of the adenosine A
2A
receptor should result in a similar degree of coronary vasodilation (and thus similar perfusion images) with fewer side effects.

Methods and Results—

In a multicenter, randomized, single-blind, 2-arm crossover trial, 240 patients underwent 2 single photon emission computed tomographic (SPECT) imaging studies in random order, first after pharmacological stress with adenosine and a second study with the selective adenosine A
2A
receptor agonist binodenoson, using 1 of 4 dosing regimens. Safety, tolerability, and SPECT image concordance between the 2 agents were examined. Exact categorical agreement in the extent and severity of reversible perfusion defects ranged from 79% to 87%, with kappa values from 0.69 to 0.85, indicating very good to excellent agreement between binodenoson and adenosine. The risk of any safety event/side effect was significantly lower with any dose of binodenoson than with adenosine (
P
≤0.01) because of a dose-related reduction in subjective side effects, as objective events were infrequent. There was a reduction in the severity of chest pain, dyspnea, and flushing in all binodenoson doses compared with adenosine (
P
<0.01), and the magnitude of severity reduction was dose-related.

Conclusions—

The selective adenosine A
2A
receptor agonist binodenoson results in an extent and severity of reversible perfusion defects on SPECT imaging similar to nonselective adenosine receptor stimulation, accompanied by a dose-related reduction in the incidence and severity of side effects.
C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Paul Antoni , Ko Kerry W.S. , Li Lan , Yechoor Vijay , McCrory Mark A. , Szalai Alexander J. , Chan Lawrence
Published: January 2004

Background—

Plasma C-reactive protein (CRP) concentration is a strong predictor of atherosclerosis. However, to date, there is no in vivo evidence that CRP is proatherogenic.

Methods and Results—

We studied the effect of human CRP transgene (tg) expression, under basal and turpentine-stimulated conditions, on atherosclerosis in apolipoprotein (apo) E
−/−
mice. Aortic atherosclerotic lesions in 29-week-old male mice were 48% larger (
P
<0.02) in turpentine-treated mice and 34% larger (
P
<0.05) in untreated CRPtg
+/0
/apoE
−/−
mice. Turpentine treatment per se did not affect the extent of atherosclerosis in CRP transgenic or nontransgenic apoE
−/−
mice. Transgenic mice exhibited lower plasma complement C3 but increased deposition of CRP and C3 in the lesions, which suggests that CRP stimulated activation of complement within the lesion. There was more intense and widespread vascular cell adhesion molecule-1 and collagen staining in the lesions of CRPtg
+/0
/apoE
−/−
mice than in CRPtg
0/0
/apoE
−/−
littermates. Lesions of CRPtg
+/0
/apoE
−/−
mice contained increased angiotensin type 1 receptor (AT1-R) transcripts and displayed increased AT1-R immunostaining compared with those of CRPtg
0/0
/apoE
−/−
mice. There was no difference in blood pressure in the 2 types of mice, which indicates that the proatherogenic effect of CRP-associated AT1-R overexpression is local and not mediated by its hypertensive properties.

Conclusions—

Human CRP transgene expression causes accelerated aortic atherosclerosis in apoE
−/−
mice. CRP was detected in the lesion, which was associated with increased C3 deposition and increased AT1-R, vascular cell adhesion molecule-1, and collagen expression. These data document a proatherogenic role for CRP in vivo.
Biological Pacemaker Implanted in Canine Left Bundle Branch Provides Ventricular Escape Rhythms That Have Physiologically Acceptable Rates
Authors: Plotnikov Alexei N. , Sosunov Eugene A. , Qu Jihong , Shlapakova Iryna N. , Anyukhovsky Evgeny P. , Liu Lili , Janse Michiel J. , Brink Peter R. , Cohen Ira S. , Robinson Richard B. , Danilo Peter , Rosen Michael R.
Published: January 2004

Background—

We hypothesized that administration of the HCN2 gene to the left bundle-branch (LBB) system of intact dogs would provide pacemaker function in the physiological range of heart rates.

Methods and Results—

An adenoviral construct incorporating HCN2 and green fluorescent protein (GFP) as a marker was injected via catheter under fluoroscopic control into the posterior division of the LBB. Controls were injected with an adenoviral construct of GFP alone or saline. Animals were monitored electrocardiographically for up to 7 days after surgery, at which time they were anesthetized and subjected to vagal stimulation to permit emergence of escape pacemakers. Hearts were then removed and injection sites visually identified and removed for microelectrode study of action potentials, patch clamp studies of pacemaker current, and/or immunohistochemical studies of HCN2. For 48 hours postoperatively, 7 of 7 animals subjected to 24-hour ECG monitoring showed multiple ventricular premature depolarizations and/or ventricular tachycardia attributable to injection-induced injury. Thereafter, sinus rhythm prevailed. During vagal stimulation, HCN2-injected dogs showed rhythms originating from the left ventricle, the rate of which was significantly more rapid than in the controls. Excised posterior divisions of the LBB from HCN2-injected animals manifested automatic rates significantly greater than the controls. Isolated tissues showed immunohistochemical and biophysical evidence of overexpressed HCN2.

Conclusions—

A gene-therapy approach for induction of biological pacemaker activity within the LBB system provides ventricular escape rhythms that have physiologically acceptable rates. Long-term stability and feasibility of the approach remain to be tested.
Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Authors: Virmani Renu , Guagliumi Giulio , Farb Andrew , Musumeci Giuseppe , Grieco Niccolo , Motta Teresio , Mihalcsik Laurian , Tespili Maurizio , Valsecchi Orazio , Kolodgie Frank D.
Published: January 2004

Background—

The US Food and Drug Administration recently issued a warning of subacute thrombosis and hypersensitivity reactions to sirolimus-eluting stents (Cypher). The cause and incidence of these events have not been determined.

Methods and Results—

We present findings of a 58-year-old man who died of late stent thrombosis 18 months after receiving 2 Cypher stents for unstable angina. Although angiographic and intravascular ultrasound results at 8 months demonstrated the absence of neointimal formation, vessel enlargement was present. An autopsy showed aneurysmal dilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils.

Conclusions—

The known pharmacokinetic elution profile of Cypher stents and the presence of polymer fragments surrounded by giant cells and eosinophils suggest that a reaction to the polymer may have caused late stent thrombosis. Careful long-term follow-up of patients with vessel enlargement after Cypher stent placement is recommended.
Effects of COX Inhibition on Blood Pressure and Kidney Function in ACE Inhibitor-Treated Blacks and Hispanics
Authors: Izhar Munavvar , Alausa Tunji , Folker Amy , Hung Elena , Bakris George L.
Published: January 2004

Cyclo-oxygenase (COX) inhibitors attenuate the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors and reduce kidney function. The study tests the hypothesis that these two classes of drugs have similar effects on glomerular filtration rate (GFR) and 24-hour blood pressure. The primary endpoint was change in 24-hour systolic blood pressure. Using a randomized crossover design, 25 black and Hispanic hypertensive participants (mean age 58±3 years) with osteoarthritis were studied. All participants received an ACE inhibitor at baseline. Once systolic blood pressure was <140 mm Hg, either celecoxib 200 mg/d or diclofenac 75 mg twice daily for 4 weeks was started. After measurements were obtained, all participants underwent a 2-week washout period and crossed over to the other drug for 4 weeks. A significant difference in mean 24-hour systolic blood pressure was noted between groups at 4 weeks (+4.1±1.1 mm Hg diclofenac versus +0.6±0.6 mm Hg celecoxib;
P
=0.01). However, because celecoxib has duration of action shorter than 24 hours, we compared ambulatory values at celecoxib trough and peak activities. At peak, no difference in systolic blood pressure was noted between agents (+3.6±0.04 mm Hg diclofenac versus +4.2±1.9 mm Hg celecoxib;
P
=0.67). GFR was also differentially affected at 24 hours (−9.9±2.4 mL/min diclofenac versus −0.4±1.2 mL/min celecoxib;
P
=0.01). We conclude that diclofenac and celecoxib increase systolic blood pressure at peak levels; however, these agents differ in their 24-hour effects. Differences observed in blood pressure response between COX inhibitors may not be related in their sensitivity but rather their dosing frequency.
Childhood Blood Pressure as a Predictor of Arterial Stiffness in Young Adults
Authors: Li Shengxu , Chen Wei , Srinivasan Sathanur R. , Berenson Gerald S.
Published: January 2004

Increased arterial stiffness is an independent predictor of cardiovascular disease and mortality in middle-aged and older adults. However, limited data are available regarding the relationship of arterial stiffness in young adults with risk factors measured in childhood, adulthood, or as a cumulative burden from childhood to adulthood. This aspect was examined in a sample of 835 black and white young adults (72% whites, 44% men) aged 24 to 44 years who had at least 4 measurements of traditional risk factors over an average follow-up period of 26.5 years since childhood. Brachial-ankle pulse wave velocity (baPWV) measured by a simple automatic oscillometric technique was used as an index of arterial stiffness. The cumulative burden of risk factors since childhood was measured as area under the curve divided by follow-up years. In young adults, the baPWV was higher in males versus females (
P
<0.001) and blacks versus whites (
P
<0.001). In multiple regression analyses, independent predictors of baPWV in young adults were systolic blood pressure in childhood; systolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and smoking in adulthood; and cumulative burden of systolic blood pressure and triglycerides and duration of smoking years from childhood. Thus, systolic blood pressure beginning in childhood is a consistent predictor of arterial stiffness in free-living, asymptomatic young adults. These findings underscore the importance of childhood blood pressure in the evolution of arterial stiffness and the need for beginning preventive cardiology early in life.
l
-Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species
Authors: Noris Marina , Todeschini Marta , Cassis Paola , Pasta Fabio , Cappellini Anna , Bonazzola Samantha , Macconi Daniela , Maucci Raffaella , Porrati Francesca , Benigni Ariela , Picciolo Claudio , Remuzzi Giuseppe
Published: January 2004

Less nitric oxide (NO)-dependent vasodilation and excess formation of reactive oxygen species could explain poor placenta perfusion in preeclampsia, but the pathways involved are unknown. We tested the hypothesis that reduced NO activity and increased oxidative stress in preeclamptic placenta is related to a low bioavailability of
l
-arginine. Placental endothelial NO synthase (ecNOS) expression (by immunoperoxidase) and activity (by diaphorase and [
3
H]L-citrulline formation) were comparable in normotensive pregnancy and in preeclampsia, whereas nitrotyrosine staining, a marker of peroxynitrite, was stronger in preeclamptic villi, confirming previously reported data. Oxidative tissue damage was documented in preeclamptic villi by strong 4-hydroxynonenal-lysine staining (by immunoperoxidase), which closely colocalized with nitrotyrosine. Concentration of the NO precursor
l
-arginine (by HPLC) in umbilical blood and in villous tissue was lower in preeclampsia than in normotensive pregnancy. This was not caused by a defective
l
-arginine transport, because gene expression of the CAT-1, 4F2hc, and LAT-1 cationic amino acid transporters (by real-time reverse-transcription polymerase chain reaction [RT-PCR]) was normal. Instead, gene expression (by real-time RT-PCR) and protein tissue content (by immunoperoxidase and Western blot) of arginase II—the enzyme that degrades arginine to ornithine—were higher in preeclamptic villi than in normotensive pregnancy. These results provide a biochemical explanation for defective NO activity and increased oxidative stress in preeclamptic placenta. In normal placenta, adequate concentration of
l
-arginine orients ecNOS toward NO. In preeclampsia, a lower than normal
l
-arginine concentration caused by arginase II overexpression redirects ecNOS toward peroxynitrite.
Sympathetic Responses to Stress and Rilmenidine in 2K1C Rabbits
Authors: Head Geoffrey A. , Burke Sandra L.
Published: January 2004

We determined whether the sympathetic excitatory responses to environmental stressors and the sympathoinhibitory responses to rilmenidine are altered by renovascular hypertension. Rabbits were made hypertensive with a clip on the right renal artery, and a left renal nerve recording electrode was implanted. After 3 or 6 weeks, the animals were given air-jet stress and loud noise stress before and after intravenous rilmenidine. Three and 6 weeks after renal clipping, mean arterial pressure was 28% and 36% greater than preclip values. Air-jet stress elicited a marked increase in renal sympathetic nerve activity, mean arterial pressure, and heart rate. Renal sympathetic nerve activity responses were much greater in hypertensive rabbits, but the pressor responses were similar to those observed in normotensive animals. Acute administration of rilmenidine decreased blood pressure more in hypertensive animals but with a much lesser inhibition of sympathetic activity. Rilmenidine markedly reduced increased sympathetic activity during air-jet stress in 3-week clipped rabbits but to a lesser extent in the other groups. These studies show that while sympathetic responses to stress were markedly enhanced in renal clip hypertensive rabbits, they did not result in greater pressor responses, thus suggesting that vascular neuroeffector mechanisms were not altered. By contrast, the increased effects of rilmenidine suggest a much greater contribution to the hypertension by the sympathetic nervous system, but one that is caused by an enhanced “nonvascular” neuroeffector mechanism. As such, sympathoinhibitory agents such as rilmenidine are very suitable and very effective agents for the treatment of renovascular hypertension.
Factors Associated With Hypertension Awareness, Treatment, and Control in a Representative Sample of the Chinese Population
Authors: Muntner Paul , Gu Dongfeng , Wu Xiqui , Duan Xiufang , Wenqi Gan , Whelton Paul K. , He Jiang
Published: January 2004

We studied factors associated with awareness, treatment, and control of hypertension (systolic/diastolic blood pressure measurements ≥140/90 mm Hg, respectively, and/or current drug treatment for hypertension) in a representative sample of the Chinese population (n=15 838). Awareness, treatment, and control were defined by self-report of a hypertension diagnosis, self-report of current antihypertensive medication use, and a systolic and diastolic blood pressure <140/90 mm Hg, respectively. Higher awareness (OR; 95% CI) was noted for persons who were married (1.43; 1.09, 1.88) and had their blood pressure measured in 1 year (47.4; 31.7, 70.4) or 1 to 5 years (11.4; 7.09, 18.2) preceding their study visit; lower awareness was found among men (0.62; 0.52, 0.74) and current smokers (0.79; 0.63, 0.99). Among those aware of their hypertension, treatment was more common (OR; 95% CI) at higher income (1.24 [0.87, 1.75], 1.46 [1.01, 2.12] and 1.58 [1.06, 2.37] for increasing versus the lowest quartile of income) and for participants who had their blood pressure measured during the preceding year (3.87; 1.89, 7.93) and was less common among men (0.76; 0.59, 0.98). Controlled hypertension was more common (OR; 95% CI) among persons whose blood pressure had been measured 1 year (4.93; 1.51, 16.1) and 1 to 5 years (14.8; 3.63, 60.5) prior to their study visit and, among persons aware of their hypertension diagnosis, those who undertook lifestyle modification (1.59; 1.11, 2.27). These data identify potential methods for improving blood pressure control in China through the identification, follow-up, and lifestyle modification of persons with high blood pressure.
PPARγ Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice
Authors: Ryan Michael J. , Didion Sean P. , Mathur Satya , Faraci Frank M. , Sigmund Curt D.
Published: January 2004

The peroxisome proliferator activated receptor (PPARγ) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R
+
A
+
). Rosiglitazone decreased systolic (138±5 versus 128±5 mm Hg) and mean blood pressure (145±5 versus 126±7 mm Hg) of R
+
A
+
mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R
+
A
+
mice when compared with littermate controls (RA
−
). There were no effects of rosiglitazone on RA
−
mice; however, relaxation to acetylcholine (49±10 versus 82±9% at 100 μmol/L) and nitric oxide (51±11 versus 72±6% at 10 μmol/L) was significantly improved in treated R
+
A
+
mice. Rosiglitazone treatment of R
+
A
+
mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R
+
A
+
and RA
−
mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPARγ-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester (200 μmol/L) or the PPARγ antagonist bisphenol A diglycidyl ether; 4,4′-isopropylidenediphenol diglycidyl ether (100 μmol/L). These data suggest that in addition to potential genomic regulation caused by PPARγ activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.
Normative Values for Circadian and Ultradian Cardiovascular Rhythms in Childhood
Authors: Hadtstein Charlotte , Wühl Elke , Soergel Marianne , Witte Klaus , Schaefer Franz
Published: January 2004

To assess the prevalence and characteristics of physiological circadian (24-hour) and ultradian (12-, 8-, and 6-hour) rhythms of mean arterial blood pressure (BP) and heart rate (HR), we analyzed 24-hour ambulatory BP profiles from 938 healthy school children aged 5 to 18 years. Cosine harmonics were fitted by Fourier analysis, and an amplitude and acrophase (time of peak) were calculated for each rhythm. Ninety percent of children displayed circadian rhythmicity of BP, independent of age, whereas circadian HR rhythmicity decreased with puberty from 96% to 87% (
P
<0.0001). Puberty had marked effects on the prevalence of ultradian rhythmicity: 12- and 6-hour rhythms increased for BP (27% to 47%,
P
<0.0001; 18% to 25%,
P
=0.01) and HR (36% to 47%, 17% to 31%, both
P
=0.001), whereas 8-hour BP rhythms decreased (34% to 23%,
P
=0.002). Median amplitudes were 10.1, 5.9, 5.6, and 5.2 mm Hg for the 24-, 12-, 8-, and 6-hour BP rhythms, respectively, and 13.4, 7.7, 6.8, and 6.4 bpm for HR. The acrophase occurred at approximately 14:00 hours, 8:00 hours, 5:30 hours, and 2:00 hours (military time) for the four BP rhythms, and at 13:30 hours, 08:30 hours, 01:50 hours, and 02:00 hours for HR. For the combined curve, the peak–trough difference was 25.9 mm Hg and 35 bpm for BP and HR, respectively, with the peaks occurring at 13:50 hours and 13:10 hours. There was marked association between BP and HR rhythms, both for prevalence (
P
<0.0001 for coupling of BP and HR rhythms of the same period length) and timing, with a median time lag of BP after HR acrophase of only 21, 16, 13, and 5 minutes for the four rhythms, respectively.
Genome-Wide Scan Identifies Novel QTLs for Cholesterol and LDL Levels in F2[Dahl R×S]-Intercross Rats
Authors: Herrera Victoria L.M. , Didishvili Tamara , Lopez Lyle V. , Myers Richard H. , Ruiz-Opazo Nelson
Published: January 2004

Hypercholesterolemia is a significant risk factor for coronary artery disease development. Genes influencing nonmonogenic hypercholesterolemia susceptibility in humans remain to be identified. Animal models are key investigative systems because major confounding variables such as diet, activity, and genetic background can be controlled. We performed a 121-marker, total genome-analysis of an F2[Dahl R×S]-intercross selected for contrasting parental strain susceptibilities for hyperlipidemia on regular rat diets at 6 months of age. Quantitative traits studied were plasma total cholesterol, triglyceride, HDL, and LDL levels adjusted for obesity. Genome-wide analysis of 200 F2-intercross male rats detects two QTLs with highly significant linkage for total cholesterol (TC) on chromosome (chr) 5−133.3 Mbp (LOD 5.8), and chr5−54.2 Mbp (LOD 4.8), and two QTLs with significant linkage for TC: on chromosome 8, chr8−60.4 Mbp (LOD 3.8), and chromosome 2, chr2−243.5 Mbp (LOD 3.4). A QTL for LDL with significant linkage is detected on chromosome 5, chr5−104 Mbp (LOD 3.7). These QTLs contribute from 7% to 12% of total trait variance, respectively, with Dahl-S allele effects resulting in increased TC and LDL levels consistent with hyperlipidemia susceptibility in the parental Dahl-S rat strain. Predicted QTL-peaks do not coincide with previous genome scans. Human homologues of two TC-QTLs span genes listed in a LocusLink profile for cholesterol. Only suggestive loci were detected for HDL and total triglyceride levels. Altogether, the data demonstrates the contribution of multiple QTLs to hypercholesterolemia making a multipathway pathogenic framework imperative. QTL-peak candidate genes delineated are syntenic between rat and human genomes, increasing clinical relevance and mandating further study.
Muscarinic M2 Receptor Stimulation of Cav1.2b Requires Phosphatidylinositol 3-Kinase, Protein Kinase C, and c-Src
Authors: Callaghan B. , Koh S.D. , Keef K.D.
Published: January 2004

This study investigated regulation of L-type calcium channels (Cav1.2b) by acetylcholine (ACh) in rabbit portal vein myocytes. Whole-cell currents were recorded using 5 mmol/L barium as charge carrier. ACh (10 μmol/L) increased peak currents by 40%. This effect was not reversed by the selective muscarinic M3 receptor antagonist 4-DAMP (100 nmol/L) but was blocked by the M2 receptor antagonist methoctramine (5 μmol/L). The classical and novel protein kinase C (PKC) antagonist calphostin C (50 nmol/L) abolished ACh responses, whereas the classical PKC antagonist Gö6976 (200 nmol/L) had no effect. ACh responses were also abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (20 μmol/L), by the c-Src inhibitor PP2 (10 μmol/L) (but not the inactive analogue PP3), and by dialyzing cells with an antibody to the G-protein subunit Gβγ. Cells dialyzed with c-Src had significantly greater currents than control cells. Current enhancement persisted in the presence of LY294002, suggesting that c-Src is downstream of PI3K. Phorbol 12,13-dibutyrate (PDBu, 0.1 μmol/L) increased currents by 74%. This effect was abolished by calphostin C and reduced by Gö6976. The PDBu response was also reduced by PP2, and the PP2-insensitive component was blocked by Gö6976. In summary, these data suggest that ACh enhances Cav1.2b currents via M2 receptors that couple sequentially to Gβγ, PI3K, a novel PKC, and c-Src. PDBu stimulates the novel PKC/c-Src pathway along with a second pathway that is independent of c-Src and involves a classical PKC.
MCIP1 Overexpression Suppresses Left Ventricular Remodeling and Sustains Cardiac Function After Myocardial Infarction
Authors: van Rooij Eva , Doevendans Pieter A. , Crijns Harry J.G.M. , Heeneman Sylvia , Lips Daniel J. , van Bilsen Marc , Williams R. Sanders , Olson Eric N. , Bassel-Duby Rhonda , Rothermel Beverly A. , De Windt Leon J.
Published: January 2004

Pathological remodeling of the left ventricle (LV) after myocardial infarction (MI) is a major cause of heart failure. Although cardiac hypertrophy after increased loading conditions has been recognized as a clinical risk factor for human heart failure, it is unknown whether post-MI hypertrophic remodeling of the myocardium is beneficial for cardiac function over time, nor which regulatory pathways play a crucial role in this process. To address these questions, transgenic (TG) mice engineered to overexpress modulatory calcineurin-interacting protein-1 (MCIP1) in the myocardium were used to achieve cardiac-specific inhibition of calcineurin activation. MCIP1-TG mice and their wild-type (WT) littermates, were subjected to MI and analyzed 4 weeks later. At 4 weeks after MI, calcineurin was activated in the LV of WT mice, which was significantly reduced in MCIP1-TG mice. WT mice displayed a 78% increase in LV mass after MI, which was reduced by 38% in MCIP1-TG mice. Echocardiography indicated marked LV dilation and loss of systolic function in WT-MI mice, whereas TG-MI mice displayed a remarkable preservation of LV geometry and contractility, a pronounced reduction in myofiber hypertrophy, collagen deposition, and β-MHC expression compared with WT-MI mice. Together, these results reveal a protective role for MCIP1 in the post-MI heart and suggest that calcineurin is a crucial regulator of postinfarction-induced pathological LV remodeling. The improvement in functional, structural, and molecular abnormalities in MCIP1-TG mice challenges the adaptive value of post-MI hypertrophy of the remote myocardium. The full text of this article is available online at http://circres.ahajournals.org.