bluuebunny/crossref_metadata_2025 huggingface dataset:
NO Attenuates Insulin Signaling and Motility in Aortic Smooth Muscle Cells via Protein Tyrosine Phosphatase 1B–Mediated Mechanism
Authors: Sreejayan Nair , Lin Yi , Hassid Aviv
Published: July 2002

Objective

—

Hyperinsulinemia is a significant risk factor for the pathogenesis of vascular disease. Protein tyrosine phosphatase 1B (PTP1B) has been recognized as a modulator of insulin signaling in nonvascular cells, and we have recently reported that NO increases the activity of PTP1B in rat vascular smooth muscle cells. In the present study, we tested the hypothesis that NO attenuates insulin-stimulated cell motility via a PTP1B-mediated mechanism involving downregulation of insulin signal transduction.

Methods and Results

—

Treatment of primary aortic smooth muscle cells from newborn rats with the NO donor
S
-nitroso-
N
-acetylpenicillamine reduced cell motility, tyrosine phosphorylation levels of insulin receptor β subunit and insulin receptor substrate-1, and extracellular signal–regulated kinase activity. Overexpression of wild-type PTP1B via an adenoviral vector blocked the capacity of insulin to stimulate cell motility and insulin receptor phosphorylation, whereas expression of a dominant-negative mutant of PTP1B attenuated the capacity of NO to decrease cell motility.

Conclusions

—

Our findings indicate that activation of PTP1B is necessary and sufficient to account for the capacity of NO to decrease insulin-stimulated signal transduction and cell motility in cultured aortic smooth muscle cells. The results could explain the capacity of NO to oppose neointima formation in states of hyperinsulinemia.
Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Induced Upon Monocyte Differentiation and Is Expressed in Human Atheroma
Authors: Major Terry C. , Liang Liang , Lu Xiaokang , Rosebury Wendy , Bocan Thomas M.A.
Published: July 2002

Objective—Because extracellular matrix metalloproteinase inducer (EMMPRIN), a tumor cell–derived protein, induces matrix metalloproteinases (MMPs) in fibroblasts and because MMPs are important in atheroma formation, we investigated if EMMPRIN was expressed in granulocyte/macrophage-colony stimulating factor (GM-CSF)–differentiated human peripheral blood monocytes (HPBM) and macrophage foam cells. In addition, EMMPRIN was studied for its expression in human atheroma.

Methods and Results—After 10 days of GM-CSF–induced monocyte differentiation, EMMPRIN mRNA increased 5- to 8-fold relative to undifferentiated monocytes. GM-CSF treatment of HPBM revealed that both EMMPRIN mRNA and protein were upregulated by day 2 over undifferentiated monocytes. GM-CSF–differentiated HPBM showed characteristic macrophage phenotype by showing increases in pancake-like morphology and increases in biochemical markers such as apolipoprotein E, MMP-9, and cholesterol ester (CE). While acetylated LDL treatment of the 10-day GM-CSF–differentiated HPBM increased CE mass 13- to 321-fold, EMMPRIN expression was unchanged relative to nonlipid-loaded macrophages. In human coronary atherosclerotic samples, EMMPRIN was observed in CD68(+) macrophage-rich areas as well as areas of MMP-9 expressions.

Conclusions—Based on these data, we conclude that monocyte differentiation induces EMMPRIN expression, CE enrichment of foam cells has no further effect on EMMPRIN expression, and EMMPRIN is present in human atheroma. Therefore, EMMPRIN may play a role in atherosclerosis development.
Prospective Study of Effect of Androgens on Serum Inflammatory Markers in Men
Authors: Ng Martin K.C. , Liu Peter Y. , Williams Andrew J. , Nakhla Shirley , Ly Lam P. , Handelsman David J. , Celermajer David S.
Published: July 2002

Objective

—

Because male sex is an independent risk factor for the severity of atherosclerosis, it is possible that androgens may be proatherogenic. There is evidence that sex hormones, particularly estrogens, regulate (or modulate) inflammation, a process integral to atherogenesis. Because levels of serum inflammatory markers predict cardiovascular outcomes, we prospectively assessed the effects of androgen therapy on these markers in older men.

Methods and Results

—

Levels of high-sensitivity C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured from sera collected at baseline and at the end of 2 randomized double-blind placebo-controlled trials evaluating the effects of 3 months of androgen treatment with either dihydrotestosterone (DHT) or recombinant human chorionic gonadotropin (rhCG) in healthy men aged >60 years with partial androgen deficiency (serum testosterone levels <15 nmol/L). For the DHT study (70 mg transdermally daily), 33 men completed 3 months of treatment (16 men were treated with DHT, and there were 17 controls). For the rhCG (250 μg twice weekly) study, 20 men were treated with rhCG, and there were 20 controls. In both studies, groups were well matched for age and vascular risk factors. Androgen levels (DHT and testosterone) were consistently maintained at eugonadal levels throughout the trials, with estradiol markedly increased by rhCG but not DHT. Baseline CRP levels were 0.74 to 1.49 mg/L, sVCAM-1 levels were 847 to 950 ng/mL, and sICAM-1 levels were 256 to 292 ng/mL in all groups. Neither DHT nor rhCG resulted in significant changes in CRP, sVCAM-1, or sICAM-1 compared with placebo (
P
>0.3 in both studies).

Conclusions

—

Exogenous androgen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men; this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women. These data provide a measure of reassurance concerning potential adverse cardiovascular effects of androgen therapy in older men.
Aspirin InhibitsChlamydia pneumoniae–Induced Nuclear Factor-κB Activation, Cytokine Expression, and Bacterial Development in Human Endothelial Cells
Authors: Tiran Andreas , Gruber Hans-Jürgen , Graier Wolfgang F. , Wagner Andreas H. , van Leeuwen Ellen B.M. , Tiran Beate
Published: July 2002

Objective—Chlamydia pneumoniaehas been associated with atherosclerosis. Infection of vascular endothelial cells withC pneumoniaeincreases the expression of proatherogenic cytokines mediated by nuclear factor (NF)-κB, a transcription factor. The present study was designed to test the effect of aspirin onC pneumoniae–induced NF-κB activation, interleukin expression, and bacterial development in cultured human endothelial cells.

Methods and Results—Aspirin, its metabolite salicylic acid, and 2 other unrelated NF-κB inhibitors showed a strong concentration-dependent inhibitory effect on chlamydial growth, indicated by the reduction of bacterial inclusions and the titer of infectious progeny. Involvement of the transcription factor NF-κB was confirmed by electrophoretic mobility shift assay and by transfection experiments with appropriate decoy oligodeoxynucleotides. Attenuation of theC pneumoniae–induced activation of NF-κB by aspirin also reduced the secretion of interleukin-6 and interleukin-8, indicating efficient inhibition of NF-κB gene expression. Reduction of chlamydial growth was not caused by apoptosis of the host cell, as determined by monitoring characteristic chromatin condensation.

Conclusions—These data provide evidence that NF-κB–mediated gene activation represents a crucial step in the developmental cycle ofC pneumoniae. Aspirin exerts an anti-chlamydial effect that is due to the inhibition ofC pneumoniae–induced NF-κB activation, which might account for some of the cardioprotective activity of aspirin.
Flow-Dependent Remodeling in the Carotid Artery of Fibroblast Growth Factor-2 Knockout Mice
Authors: Sullivan Chris J. , Hoying James B.
Published: July 2002

Objective

—

Fibroblast growth factor-2 (FGF2) has been implicated as a mediator in the structural remodeling of arteries. Chronic changes in blood flow are known to cause reorganization of the vessel wall, resulting in permanent changes in artery size (flow-dependent remodeling). Using FGF2 knockout (
Fgf2
−/−
) mice, we tested the hypothesis that FGF2 is required during flow-dependent remodeling of the carotid arteries.

Methods and Results

—

All branches originating from the left common carotid artery (LCCA), except for the left thyroid artery, were ligated to reduce flow in the LCCA and increase flow in the contralateral right common carotid artery (RCCA). Age- and sex-matched control animals did not undergo ligation of the LCCA branches. Morphometric analysis showed that by day 7, vessel diameter was significantly greater in the high-flow RCCA of FGF2 wild-type (
Fgf2

+/+

) and
Fgf2
−/−
mice versus the respective control RCCA, demonstrating outward remodeling. In contrast, vessel diameter was decreased by day 7 in the low-flow LCCA of both genotypes compared with the control LCCA, showing inward remodeling. No differences were observed between
Fgf2

+/+

and
Fgf2
−/−
mice in either high-flow or low-flow remodeling.

Conclusions

—

Given these results, we demonstrate that FGF2 is not essential for flow-dependent remodeling of the carotid arteries.
Baroreflex Buffering and Susceptibility to Vasoactive Drugs
Authors: Jordan Jens , Tank Jens , Shannon John R. , Diedrich Andre , Lipp Axel , Schröder Christoph , Arnold Guy , Sharma Arya M. , Biaggioni Italo , Robertson David , Luft Friedrich C.
Published: July 2002

Background—

The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known.

Methods and Results—

We characterized baroreflex function and responses to vasoactive drugs in patients with idiopathic orthostatic intolerance, patients with essential hypertension, patients with monogenic hypertension and brachydactyly, patients with multiple system atrophy, and control subjects. We used phenylephrine sensitivity during ganglionic blockade as a measure of baroreflex buffering. Phenylephrine (25 μg) increased systolic blood pressure 6±1.6 mm Hg in control subjects, 6±1.1 mm Hg in orthostatic intolerance patients, 18±3.9 mm Hg in patients with essential hypertension, 31±3.4 mm Hg in patients with monogenic hypertension, and 25±3.4 mm Hg in patients with multiple system atrophy. Similar differences in sensitivities between groups were observed with nitroprusside. The sensitivity to vasoactive drugs was highly correlated with baroreflex buffering function and to a lesser degree with baroreflex control of heart rate. In control subjects, sensitivities to nitroprusside and phenylephrine infusions were correlated with baroreflex heart rate control and sympathetic nerve traffic.

Conclusions—

Our findings are consistent with an important effect of baroreflex blood pressure buffering on the sensitivity to vasoactive drugs. They suggest that even moderate changes in baroreflex function may have a substantial effect on the sensitivity to vasoactive medications.
Which Patients Benefit From Percutaneous Mitral Balloon Valvuloplasty?
Authors: Palacios Igor F. , Sanchez Pedro L. , Harrell Lari C. , Weyman Arthur E. , Block Peter C.
Published: July 2002

Background

—

Percutaneous mitral balloon valvuloplasty (PMV) results in good immediate results, particularly in patients with echocardiographic scores (Echo-Sc) ≤8. However, which variables relate to long-term outcome is unclear.

Methods and Results

—

We report the immediate and long-term clinical follow-up (mean, 4.2±3.7 years; range, 0.5 to 15) of 879 patients who underwent 939 PMV procedures. Patients were divided into 2 groups, Echo-Sc ≤8 (n=601) and Echo-Sc >8 (n=278). PMV resulted in an increase in mitral valve area from 1.0±0.3 to 2.0±0.6 cm
2
in patients with Echo-Sc ≤8 and from 0.8±0.3 to 1.6±0.6 cm
2
in patients with Echo-Sc >8 (
P
<0.0001). Although adverse events (death, mitral valve surgery, and redo PMV) were low within the first 5 years of follow-up, a progressive number of events occurred beyond this period. Nevertheless, survival (82% versus 57%) and event-free survival (38% versus 22%) at 12-year follow-up was greater in patients with Echo-Sc ≤8 (
P
<0.0001). Cox regression analysis identified post-PMV mitral regurgitation ≥3+, Echo-Sc >8, age, prior surgical commissurotomy, NYHA functional class IV, pre-PMV mitral regurgitation ≥2+, and higher post-PMV pulmonary artery pressure as independent predictors of combined events at long-term follow-up.

Conclusions

—

The immediate and long-term outcome of patients undergoing PMV is multifactorial. The use of the Echo-Sc in conjunction with other clinical and morphological predictors of PMV outcome allows identification of patients who will obtain the best outcome from PMV.
Coronary Flow Velocity Reserve After Percutaneous Interventions Is Predictive of Periprocedural Outcome
Authors: Albertal M. , Voskuil M. , Piek J.J. , de Bruyne B. , Van Langenhove G. , Kay P.I. , Costa M.A. , Boersma E. , Beijsterveldt T. , Sousa J.E. , Belardi J.A. , Serruys P.W.
Published: July 2002

Background

—

Because heterogeneous results have been reported, we assessed coronary flow velocity changes in individuals who underwent percutaneous transluminal coronary angioplasty (PTCA) and examined their impact on clinical outcome.

Methods and Results

—

As part of the Doppler Endpoints Balloon Angioplasty Trial Europe (DEBATE) II study, 379 patients underwent Doppler flow–guided angioplasty. All patients were evaluated according to their coronary flow velocity reserve (CFVR) results (≥2.5 or <2.5) at the end of the procedure. A CFVR <2.5 after angioplasty was associated with an elevated baseline blood flow velocity in both the target artery and reference artery. CFVR before PTCA and CFVR in the reference artery were independent predictors of an optimal CFVR after balloon angioplasty (CFVR before PTCA: odds ratio [OR], 2.26; 95% confidence interval [CI], 1.57 to 3.24; CFVR in reference artery: OR, 1.90; 95% CI, 1.21 to 2.98; both
P
<0.001) and stent implantation (before PTCA: OR, 2.54; 95% CI, 1.47 to 4.36; reference artery: OR, 1.97; 95% CI, 1.07 to 3.87; both
P
<0.05). A low CFVR at the end of the procedure was an independent predictor of major adverse cardiac events (MACE) at 30 days (OR, 4.71; 95% CI, 1.14 to 25.92;
P
=0.034) and at 1 year (OR, 2.06; 95% CI, 1.16 to 3.66;
P
=0.014). After excluding MACE at 30 days, no difference in MACE at 1 year was observed between the patients with and without a CFVR <2.5 at the end of the procedure.

Conclusions

—

A low postprocedural CFVR was associated with a worse periprocedural outcome (which was related to microcirculatory disturbances), but there was no significant difference at late follow-up.
Effect of 3 Months of Antimicrobial Treatment With Clarithromycin in Acute Non–Q-Wave Coronary Syndrome
Authors: Sinisalo Juha , Mattila Kimmo , Valtonen Ville , Anttonen Olli , Juvonen Jukka , Melin John , Vuorinen-Markkola Helena , Nieminen Markku S.
Published: July 2002

Background

—

Coronary artery disease, an inflammatory disease, may be caused by infection. We investigated whether the antibiotic clarithromycin would reduce morbidity and mortality in patients with acute non–Q-wave coronary syndrome.

Methods and Results

—

Altogether, 148 patients with acute non–Q-wave infarction or unstable angina were randomly assigned to receive double-blind treatment with either clarithromycin or placebo for 3 months. The primary end point was a composite of death, myocardial infarction, or unstable angina during treatment; the secondary end point was occurrence of any cardiovascular event during the entire follow-up period (average 555 days, range 138 to 924 days). There was a trend toward fewer patients meeting primary end-point criteria in the clarithromycin group than in the placebo group (11 versus 19 patients, respectively; risk ratio 0.54, 95% CI 0.25 to 1.14;
P
=0.10). By the end of the entire follow-up, 16 patients in the clarithromycin group and 27 in the placebo group had experienced a cardiovascular event (risk ratio 0.49, 95% CI 0.26 to 0.92;
P
=0.03).

Conclusions

—

Clarithromycin appears to reduce the risk of ischemic cardiovascular events in patients presenting with acute non–Q-wave infarction or unstable angina. No signs of this effect diminishing were observed during follow-up.
Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction
Authors: Antman Elliott M. , Louwerenburg Hans W. , Baars Hubert F. , Wesdorp Jan C.L. , Hamer Bas , Bassand Jean-Pierre , Bigonzi Frederique , Pisapia Ghislaine , Gibson C. Michael , Heidbuchel Hein , Braunwald Eugene , Van de Werf Frans
Published: July 2002

Background

—

ENTIRE-TIMI 23 evaluated enoxaparin with full-dose tenecteplase (TNK) and half-dose TNK plus abciximab.

Methods and Results

—

Patients (n=483) with ST-elevation MI presenting <6 hours from symptom onset were randomized to full-dose TNK and either unfractionated heparin (UFH) (bolus 60 U/kg; infusion 12 U/kg per hour) or enoxaparin (1.0 mg/kg subcutaneously every 12 hours±initial 30 mg intravenous bolus), or half-dose TNK plus abciximab and either UFH (bolus 40 U/kg; infusion 7 U/kg per hour) or enoxaparin (0.3 to 0.75 mg/kg subcutaneously every 12 hours±initial intravenous bolus of 30 mg). With full-dose TNK and UFH, the rate of TIMI 3 flow at 60 minutes was 52% and was 48% to 51% with enoxaparin. Using combination therapy, the rate of TIMI 3 flow was 48% with UFH and 47% to 58% with enoxaparin. The rate of TIMI 3 flow among all UFH patients was 50% and was 51% among enoxaparin patients. Through 30 days, death/recurrent MI occurred in the full-dose TNK group in 15.9% of patients with UFH and 4.4% with enoxaparin (
P
=0.005). In the combination therapy group, the rates were 6.5% with UFH and 5.5% with enoxaparin. The rate of major hemorrhage with full-dose TNK was 2.4% with UFH and 1.9% with enoxaparin; with combination therapy, it was 5.2% using UFH and 8.5% with enoxaparin.

Conclusions

—

Enoxaparin is associated with similar TIMI 3 flow rates as UFH at an early time point while exhibiting advantages over UFH with respect to ischemic events through 30 days. These findings with enoxaparin are achieved with a similar risk of major hemorrhage.
Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events
Authors: Eikelboom John W. , Hirsh Jack , Weitz Jeffrey I. , Johnston Marilyn , Yi Qilong , Yusuf Salim
Published: July 2002

Background

—

We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population.

Methods and Results

—

Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B
2
levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B
2
, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7;
P
=0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4;
P
=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4;
P
<0.001) than those in the lower quartile.

Conclusions

—

In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B
2
predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B
2
levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.
Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production
Authors: Wassmann Sven , Laufs Ulrich , Stamenkovic Djordje , Linz Wolfgang , Stasch Johannes-Peter , Ahlbory Katja , Rösen Renate , Böhm Michael , Nickenig Georg
Published: July 2002

Background

—

It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens.

Methods and Results

—

To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg · kg
−1
· d
−1
) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced the activity and expression of vascular membrane-bound rac1, a GTPase required for the activation of the NAD(P)H oxidase. Finally, blood pressure levels were significantly decreased in spontaneously hypertensive rats treated with raloxifene. All SERM effects were also detected in healthy age-matched Wistar rats. In cultured rat aortic vascular smooth muscle cells, raloxifene inhibited angiotensin II-induced reactive oxygen species production dependent on estrogen receptor activation.

Conclusions

—

Raloxifene treatment improves hypertension-induced endothelial dysfunction by increased bioavailability of NO. This is achieved by an increased activity of endothelial NO synthase and by an estrogen receptor-dependent reduction in release of reactive oxygen species from vascular cells. These vascular effects cause a profound blood pressure reduction and lead to decreased vascular damage in male spontaneously hypertensive rats.
Cyclooxygenase-2 Promotes Early Atherosclerotic Lesion Formation in LDL Receptor–Deficient Mice
Authors: Burleigh Michael E. , Babaev Vladimir R. , Oates John A. , Harris Raymond C. , Gautam Shiva , Riendeau Denis , Marnett Lawrence J. , Morrow Jason D. , Fazio Sergio , Linton MacRae F.
Published: July 2002

Background
—

Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor–deficient (LDLR
−/−
) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR
−/−
mice.

Methods and Results
—

Treatment of male LDLR
−/−
mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1–mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF
1α
. Fetal liver cell transplantation was used to generate LDLR
−/−
mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2
−/−
→LDLR
−/−
mice developed significantly less (33% to 39%) atherosclerosis than control COX-2
+/+
→LDLR
−/−
mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups.

Conclusions
—

The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR
−/−
mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis.
(Circulation. 2002;105:1816-1823.)
Patterns of Myocardial Endothelin-1 Expression and Outcome After Cardiac Transplantation
Authors: Ferri Claudio , Properzi Giuliana , Tomassoni Gianluca , Santucci Anna , Desideri Giovambattista , Giuliani Anna Elisa , Starling Randall C. , Ratliff Norman B. , Cook Daniel J. , McCarthy Patrick , Young James B. , Yamani Mohamad H.
Published: July 2002

Background
—

Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy.

Methods and Results
—

Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection (
P
=0.02). Compared with patients with negative interstitial ET-1 expression (n=22), patients with positive interstitial ET-1 expression (n=25) had higher incidence of post-transplantation ischemic injury (52% versus 9%,
P
=0.002), lower mean episodes of acute rejection (≥ grade 2) during the first 3 months of transplant (1.09±0.66 versus 1.86±1.6,
P
=0.048), and more common vasculopathy at 2 years (50% versus 15%,
P
=0.02), and they tended to have worse survival (83.2% versus 100%,
P
=0.058).

Conclusions
—

Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.
Effects of Pinacidil on Electrophysiological Properties of Epicardial Border Zone of Healing Canine Infarcts
Authors: Coromilas James , Costeas Constantinos , Deruyter Bernard , Dillon Stephen M. , Peters Nicholas S. , Wit Andrew L.
Published: July 2002

Background

—

K
ATP
channels, activated by ischemia, participate in the arrhythmogenic response to acute coronary occlusion. The function of these channels in border zones of healing infarcts, where arrhythmias also arise, has not been investigated. Do these channels remain maximally activated during infarct healing, or do they downregulate after a period of time? Both might preclude further activation.

Methods and Results

—

Myocardial infarction was produced in dogs by ligation of the left anterior descending coronary artery. Impulse propagation in the epicardial border zone (EBZ) of 4-day-old healing infarcts was mapped during administration of pinacidil, a K
ATP
channel activator, directly into the EBZ coronary blood supply. Pinacidil restored conduction and excitability when the EBZ was initially inexcitable and had large regions of block (6 of 8 experiments). This allowed reentrant circuits to form in the EBZ, causing tachycardia (4 of 8 experiments
)
. In hearts with an initially excitable EBZ, pinacidil shortened the effective refractory period and abolished conduction block at short cycle lengths (7 experiments). This effect prevented initiation of reentry (1 of 2 experiments).

Conclusions

—

The response to pinacidil indicates that K
ATP
channels in the EBZ remain functional and can be activated to influence electrophysiological properties and arrhythmogenesis.
Statin Therapy Accelerates Reendothelialization
Authors: Walter Dirk H. , Rittig Kilian , Bahlmann Ferdinand H. , Kirchmair Rudolf , Silver Marcy , Murayama Toshinori , Nishimura Hiromi , Losordo Douglas W. , Asahara Takayuki , Isner Jeffrey M.
Published: July 2002

Background

—

Primary and secondary prevention trials suggest that statins possess favorable effects independent of cholesterol reduction. We investigated whether statin therapy may also accelerate reendothelialization after carotid balloon injury.

Methods and Results

—

Simvastatin treatment in 34 male Sprague-Dawley rats accelerated reendothelialization of the balloon-injured arterial segments (reendothelialized area at 2 weeks, 12.3±1.8 versus 5.4±1.1 mm
2
,
P
< 0.01) and resulted in a dose-dependent (0.2 or 1 mg/kg IP) significant reduction in neointimal thickening at 2, 3, and 4 weeks compared with saline-injected controls (n=18). To elucidate the mechanism, we investigated the contribution of bone marrow–derived endothelial progenitor cells (EPCs) by bone marrow transplantation from Tie2/lacZ mice to background mice or nude rats. X-gal staining of mouse carotid artery specimens revealed a 2.9-fold increase in the number of β-gal–positive cells per square millimeter appearing on the carotid artery luminal surface at 2 weeks, and double-fluorescence immunohistochemistry disclosed a significant 5-fold increase in the number of double-positive cells (β-gal, isolectin B4) on the luminal surface in carotid arteries of statin-treated nude rats (20±3 versus 4±1 cells/mm surface length,
P
<0.005). Statins increased circulating rat EPCs (2.4-fold at 2 weeks and 2.5-fold at 4 weeks,
P
<0.001) and induced adhesiveness of cultured human EPCs by upregulation of the integrin subunits α
5
, β
1
, α
v
, and β
5
of human EPCs as shown by reverse transcription–polymerase chain reaction and fluorescence-activated cell sorting.

Conclusions

—

These findings establish additional mechanisms by which statins may specifically preempt disordered vascular wall pathology and constitute physiological evidence that EPC mobilization represents a functionally relevant consequence of statin therapy.
Cardiac Nitric Oxide Synthase 1 Regulates Basal and β-Adrenergic Contractility in Murine Ventricular Myocytes
Authors: Ashley Euan A. , Sears Claire E. , Bryant Simon M. , Watkins Hugh C. , Casadei Barbara
Published: July 2002

Background

—

Evidence indicates that myocardial NO production can modulate contractility, but the source of NO remains uncertain. Here, we investigated the role of a type 1 NO synthase isoform (NOS1), which has been recently localized to the cardiac sarcoplasmic reticulum, in the regulation of basal and β-adrenergic myocardial contraction.

Methods and Results

—

Contraction was assessed in left ventricular myocytes isolated from mice with NOS1 gene disruption (NOS1
−/−
mice) and their littermate controls (NOS1
+/+
mice) at 3 stimulation frequencies (1, 3, and 6 Hz) in basal conditions and during β-adrenergic stimulation with isoproterenol (2 nmol/L). In addition, we examined the effects of acute specific inhibition of NOS1 with vinyl-
l
-
N
-5-(1-imino-3-butenyl)-
l
-ornithine (L-VNIO, 500 μmol/L). NOS1

−/−

myocytes exhibited greater contraction at all frequencies (percent cell shortening at 6 Hz, 10.7±0.92% in NOS1
−/−
myocytes versus 7.21±0.8% in NOS1
+/+
myocytes;
P
<0.05) with a flat frequency-contraction relationship. Time to 50% relaxation was increased in NOS1
−/−
myocytes at all frequencies (at 6 Hz, 26.53±1.4 ms in NOS1
−/−
myocytes versus 21.27±1.3 ms in NOS1
+/+
myocytes;
P
<0.05). L-VNIO prolonged time to 50% relaxation at all frequencies (at 6 Hz, 21.28±1.7 ms in NOS1
+/+
myocytes versus 26.45±1.4 ms in NOS1
+/+
+L-VNIO myocytes;
P
<0.05) but did not significantly increase basal contraction. However, both NOS1
−/−
myocytes and NOS1
+/+
myocytes treated with L-VNIO showed a greatly enhanced contraction in response to β-adrenergic stimulation (percent increase in contraction at 6 Hz, 25.2±10.8 in NOS1
+/+
myocytes, 68.2±11.2 in NOS1
−/−
myocytes, and 65.1±13.2 in NOS1
+/+
+L-VNIO myocytes;
P
<0.05).

Conclusions

—

NOS1 disruption enhances basal contraction and the inotropic response to β-adrenergic stimulation in murine ventricular myocytes. These findings indicate that cardiac NOS1-derived NO plays a significant role in the autocrine regulation of myocardial contractility.
Coronary Pressure Measurement After Stenting Predicts Adverse Events at Follow-Up
Authors: Pijls Nico H.J. , Klauss Volker , Siebert Uwe , Powers Eric , Takazawa Kenji , Fearon William F. , Escaned Javier , Tsurumi Yukio , Akasaka Takashi , Samady Habib , De Bruyne Bernard
Published: July 2002

Background

—

Coronary stenting is associated with a restenosis rate of 15% to 20% at 6-month follow-up, despite optimum angiographic stent implantation. In this multicenter registry, we investigated the relation between optimum physiological stent implantation as assessed by poststent fractional flow reserve (FFR) and outcome at 6 months.

Methods and Results

—

In 750 patients, coronary pressure measurement at maximum hyperemia was performed after angiographically apparently satisfactory stent implantation. Poststenting FFR was calculated and related to major adverse events (including need for repeat target vessel revascularization) at 6 months. In 76 patients (10.2%), at least 1 adverse event occurred. Five patients died, 19 experienced myocardial infarction, and 52 underwent at least 1 repeat target vessel revascularization. By multivariate analysis, FFR immediately after stenting was the most significant independent variable related to all types of events. In 36% of the patients, FFR normalized (>0.95), and event rate was 4.9% in that group. In 32% of the patients, poststent FFR was between 0.90 and 0.95, and event rate was 6.2%. In 32% of patients, poststent FFR was <0.90, and event rate was 20.3%. In 6% of the patients, FFR was <0.80, and event rate was 29.5% (
P
<0.001).

Conclusions

—

FFR after stenting is a strong independent predictor of outcome at 6 months.
Mental Stress Induces Prolonged Endothelial Dysfunction via Endothelin-A Receptors
Authors: Spieker Lukas E. , Hürlimann David , Ruschitzka Frank , Corti Roberto , Enseleit Frank , Shaw Sidney , Hayoz Daniel , Deanfield John E. , Lüscher Thomas F. , Noll Georg
Published: July 2002

Background
—

Mental stress is a risk factor for atherosclerosis and may precipitate myocardial ischemia and infarction. Because endothelial dysfunction is an early manifestation of atherosclerosis, we investigated the impact of mental stress on endothelial function.

Methods and Results
—

The effects of a 3-minute mental stress task on endothelium-dependent vasodilation were studied in healthy subjects without cardiovascular risk factors. Flow-mediated (FMD) and nitroglycerin (0.4 mg sublingual)-induced vasodilation were studied before and after mental stress by high-resolution ultrasound of the radial artery. Additionally, FMD was assessed before and 10 to 45 minutes after mental stress during intraarterial infusion of a selective endothelin A receptor antagonist (BQ-123, 1 nmol/min) or saline, respectively. Endothelium-dependent vasodilation was reduced by half for about 45 minutes (8.0±1.1% versus 4.1±1.0%;
P
<0.002), whereas endothelium-independent vasodilation to nitroglycerin remained unaffected (15.6±1.6 versus 14.3±1.3%; NS). Intraarterial infusion of BQ-123, a selective endothelin-A receptor antagonist, but not saline prevented the impairment of endothelium-dependent vasodilation (8.6±1.2 versus 9.4±1.3%; NS). In contrast, intraarterial infusion of norepinephrine of similar duration as mental stress did not inhibit FMD.

Conclusions
—

Mental stress induces prolonged endothelial dysfunction, which is prevented by selective endothelin-A receptor antagonism. This represents a novel and important link between mental stress and atherosclerotic vascular disease.
Simvastatin Reduces Neointimal Thickening in Low-Density Lipoprotein Receptor–Deficient Mice After Experimental Angioplasty Without Changing Plasma Lipids
Authors: Chen Zhiping , Fukutomi Tatsuya , Zago Alexandre C. , Ehlers Raila , Detmers Patricia A. , Wright Samuel D. , Rogers Campbell , Simon Daniel I.
Published: July 2002

Background

—

Statins exert antiinflammatory and antiproliferative actions independent of cholesterol lowering. To determine whether these actions might affect neointimal formation, we investigated the effect of simvastatin on the response to experimental angioplasty in LDL receptor–deficient (LDLR
−/−
) mice, a model of hypercholesterolemia in which changes in plasma lipids are not observed in response to simvastatin.

Methods and Results

—

Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDLR
−/−
mice treated with low-dose (2 mg/kg) or high-dose (20 mg/kg) simvastatin or vehicle subcutaneously 72 hours before and then daily after injury. After 7 and 28 days, intimal and medial sizes were measured and the intima to media area ratio (I:M) was calculated. Total plasma cholesterol and triglyceride levels were similar in simvastatin- and vehicle-treated mice. Intimal thickening and I:M were reduced significantly by low- and high-dose simvastatin compared with vehicle alone. Simvastatin treatment was associated with reduced cellular proliferation (BrdU), leukocyte accumulation (CD45), and platelet-derived growth factor–induced phosphorylation of the survival factor Akt and increased apoptosis after injury.

Conclusions

—

Simvastatin modulates vascular repair after injury in the absence of lipid-lowering effects. Although the mechanisms are not yet established, additional research may lead to new understanding of the actions of statins and novel therapeutic interventions for preventing restenosis.
Catechol-O-Methyltransferase and Blood Pressure in Humans
Authors: Jordan Jens , Lipp Axel , Tank Jens , Schröder Christoph , Stoffels Mandy , Franke Gabriele , Diedrich Andre , Arnold Guy , Goldstein David S. , Sharma Arya M. , Luft Friedrich C.
Published: July 2002

Background

—

Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown.

Methods and Results

—

We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was ≈3.5 times greater than the maximal response to entacapone.

Conclusions

—

COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.
Radioactive 133-Xenon Gas-Filled Balloon to Prevent Restenosis
Authors: Apple Marc , Waksman Ron , Chan Rosanna C. , Vodovotz Yoram , Fournadjiev Jana , Bass Bill G.
Published: July 2002

Background—

Ionizing radiation administered intraluminally via catheter-based systems using solid β and γ sources or liquid-filled balloons has shown reduction in the neointima formation after injury in the porcine model. We propose a novel system that uses a 133-Xenon (
133
Xe) radioactive gas-filled balloon catheter system.

Methods and Results—

Overstretch balloon injury was performed in the coronary arteries of 33 domestic pigs. A novel
133
Xe radioactive gas–filled balloon (3.5/45 mm) was positioned to overlap the injured segment with margins. After vacuum was obtained in the balloon catheter, ≈2.5 cc of
133
Xe gas was injected to fill the balloon. Doses of 0, 7.5, 15, and 30 Gy were delivered to a distance of 0.25 mm from the balloon surface. The dwell time ranged from 1.0 to 4.0 minutes, depending on the dose. Localization of
133
Xe in the balloon was verified by a γ camera. The average activity in a 3.5/45-mm balloon was measured at 67.7±12.1 mCi, and the total diffusion loss of the injected dose was 0.26% per minute of the injected dose. Bedside radiation exposure measured between 2 and 6 mR/h, and the shallow dose equivalent was calculated as 0.037 mrem per treatment. Histomorphometric analysis at 2 weeks showed inhibition of the intimal area (intimal area corrected for medial fracture length [IA/FL]) in the irradiated segments of 0.26±0.08 with 30 Gy, 0.07±0.24 with 15 Gy, and 0.12±0.89 with 7.5 Gy versus 0.76±0.08 with control
P
<0.001.

Conclusions—

133
Xe gas–filled balloon is feasible and effective in the reduction of neointima formation in the porcine model and safe for use in coronary arteries.
Regulation of Kv4.3 Current by KChIP2 Splice Variants
Authors: Deschênes Isabelle , DiSilvestre Deborah , Juang George J. , Wu Richard C. , An W. Frank , Tomaselli Gordon F.
Published: July 2002

Background

—

The transient outward potassium current (
I
to
) encoded by the Kv4 family of potassium channels is important in the repolarization of cardiac myocytes. KChIPs are a recently identified group of Ca
2+
-binding accessory subunits that modulate Kv4-encoded currents. KChIP2 is the only family member expressed in the heart.

Methods and Results

—

We previously cloned 2 novel splice variants of KChIP2 from human heart, named KChIP2S and KChIP2T. The transmural distribution of KChIP2 mRNA and protein in human and canine left ventricle was examined using kinetic RT-PCR and Western blots in the same tissues. A steep gradient of mRNA with greater KChIP2 expression in the epicardium was observed. However, no gradient of immunoreactive protein was observed. Immunocytochemistry reveals KChIP2 expression in the t-tubules and the nucleus. The predominant effects of all 3 KChIP2 splice variants on hKv4.3-encoded current are to increase the density, slow the current decay in a Ca
2+
-dependent manner, and hasten recovery from inactivation in a splice variant–specific fashion.

Conclusions

—

A family of KChIP2 proteins is expressed in human hearts that exhibits differential modulation of hKv4.3 current in a Ca
2+
-dependent fashion. The effect of KChIP2 on the biophysical properties of expressed Kv4.3 current and the absence of a gradient of protein across the ventricular wall suggest that KChIP2 is either not a requisite component of human or canine ventricular
I
to
or that its functional effect is being affected or additionally modified by other factors present in myocardial cells.
Downregulation of Myocardial Myocyte Enhancer Factor 2C and Myocyte Enhancer Factor 2C–Regulated Gene Expression in Diabetic Patients With Nonischemic Heart Failure
Authors: Razeghi Peter , Young Martin E. , Cockrill Tonya C. , Frazier O. Howard , Taegtmeyer Heinrich
Published: July 2002

Background

—

In animal studies, diabetes has been shown to induce changes in gene expression of key regulators in cardiac energy metabolism and calcium homeostasis. In the present study, we tested the hypothesis that metabolic gene expression in nonischemic failing hearts of diabetic patients differs from that in nonischemic failing hearts of nondiabetic patients.

Methods and Results

—

Left ventricular tissue was obtained from nonfailing hearts (n=6) and from nonischemic failing hearts of patients with or without type 2 diabetes. Myocardial transcript levels of key regulators in energy substrate metabolism (glucose transporter 1, glucose transporter 4, pyruvate dehydrogenase kinase 4, peroxisome proliferator–activated receptor α, muscle carnitine palmitoyl transferase-1, medium-chain acyl-CoA dehydrogenase, and uncoupling protein 3), calcium homeostasis (sarcoplasmic reticulum Ca
2+
-ATPase [SERCA2a], phospholamban, and cardiac ryanodine receptor), and contractile function (myosin heavy chain α) were measured using real-time quantitative reverse transcription–polymerase chain reaction. In addition, we measured myocyte enhancer factor 2C (MEF2C) and SERCA2a protein levels. Only MEF2C regulated transcripts (glucose transporter 4, SERCA2a, and myosin heavy chain α) were lower in the diabetic group compared with the nondiabetic group. MEF2C protein content was also decreased.

Conclusion

—

MEF2C and MEF2C-regulated genes are decreased in the failing hearts of diabetic patients. This transcriptional mechanism may contribute to the contractile dysfunction in heart failure patients with diabetes.
Aldosterone Is Produced From Ventricles in Patients With Essential Hypertension
Authors: Yamamoto Nobuyasu , Yasue Hirofumi , Mizuno Yuji , Yoshimura Michihiro , Fujii Hiromi , Nakayama Masafumi , Harada Eisaku , Nakamura Shota , Ito Teruhiko , Ogawa Hisao
Published: July 2002

This study was designed to examine whether aldosterone is produced from the hearts of patients with essential hypertension without left ventricular systolic dysfunction (LVSD). The study population consisted of 20 patients with essential hypertension without LVSD and 22 control subjects. Plasma levels of aldosterone, serum ACE activity, and B-type natriuretic peptide levels were measured in the anterior interventricular vein (AIV), coronary sinus, and aortic root during cardiac catheterization. The plasma aldosterone levels were significantly higher in AIV and coronary sinus than in aortic root (99±11 versus 88±10 pg/mL,
P
<0.01, and 100±12 versus 88±10 pg/mL,
P
<0.01, respectively) in the hypertension group. On the other hand, there were no significant differences in aldosterone levels for these sites in the control group. There were no significant differences in ACE activity levels between aortic root, AIV, and coronary sinus in either the hypertension or control group. The levels of B-type natriuretic peptide were significantly higher in AIV than in aortic root in both groups. The difference in aldosterone levels between AIV and aortic root (Δ Aldo[AIV−Ao]) had a significant positive correlation with the difference in ACE activity between AIV and aortic root (ΔACE[AIV−Ao]) (
r
=0.501,
P
<0.05) in the hypertension group. Both Δ Aldo[AIV−Ao] and ΔACE[AIV−Ao] had a significant positive correlation with diastolic blood pressure (
r
=0.498,
P
<0.05;
r
=0.577,
P
<0.01, respectively) in the hypertension group. We conclude that production of aldosterone is activated in the left ventricles in patients with essential hypertension without LVSD in proportion to the severity of hypertension.