bluuebunny/crossref_metadata_2025 huggingface dataset:
FTY720, a New Immunosuppressant, Promotes Long-Term Graft Survival and Inhibits the Progression of Graft Coronary Artery Disease in a Murine Model of Cardiac Transplantation
Authors: Hwang Myung-Woo , Matsumori Akira , Furukawa Yutaka , Ono Koh , Okada Masaharu , Iwasaki Atsushi , Hara Masatake , Sasayama Shigetake
Published: June 2012

Background
—Effective immunosuppression is a critical determinant of organ and patient survival in cardiac transplantation. The present study was designed to determine the potency of FTY720, a new synthesized immunosuppressant, and examine its clinical potential as an immunosuppressant.

Methods and Results
—Hearts of DBA/2 mice were transplanted heterotopically in C57BL/6 mice. Recipients were treated with oral FTY720 in doses of 0.3, 1, 3, or 10 mg · kg
−1
· d
−1
or with 40 mg · kg
−1
· d
−1
of cyclosporin A (CsA) as a comparative treatment. The median graft survival time (MST) was significantly prolonged by treatment with FTY720 10 mg · kg
−1
· d
−1
. MST was not prolonged by FTY720 1 mg · kg
−1
· d
−1
or CsA. However, FTY720 1 mg · kg
−1
· d
−1
combined with CsA 40 mg · kg
−1
· d
−1
resulted in a significant prolongation of MST. Histopathological studies performed 5 days after transplantation demonstrated remarkable suppression of inflammatory response by treatment with FTY720 10 mg · kg
−1
· d
−1
. Interleukin (IL)-2 and interferon (IFN)-γ production was not suppressed; however, cytotoxic T lymphocyte activity was strongly suppressed in vitro. In addition, IL-2–stimulated T-cell proliferation and class I and class II MHC antigen expression on IFN-γ–stimulated macrophages were strongly inhibited by FTY720. Histopathological studies 60 days after transplantation (DBA/2-B10.D2) demonstrated a beneficial effect on graft atherosclerosis.

Conclusions
—FTY720 promoted long-term cardiac graft survival and strongly inhibited the progression of graft atherosclerosis. These observations suggest that FTY720 has a promising clinical potential in cardiac transplantation.
Inhibition of NF-κB Activation by Pyrrolidine Dithiocarbamate Prevents In Vivo Expression of Proinflammatory Genes
Authors: Liu Shu Fang , Ye Xiaobing , Malik Asrar B.
Published: June 2012

Background
—The inability to inhibit multiple mediators of septic shock represents a major hurdle in the treatment of septic shock. In vivo inhibition of nuclear factor (NF)-κB activation, a transcription factor regulating expression of many proinflammatory genes, could provide a useful strategy for the treatment of septic shock.

Methods and Results
—In rats challenged with lipopolysaccharide (LPS) 8 mg/kg IV, we determined the time course of NF-κB activation and expression of multiple inflammatory signals: tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1 (ICAM)-1. We studied the effects of in vivo inhibition of NF-κB activation using pyrrolidine dithiocarbamate (PDTC) on the expression of these mediators. NF-κB activation preceded the induction of TNF-α, COX-2, CINC, and ICAM-1 mRNAs. PDTC prevented the LPS-induced NF-κB activation but did not inhibit activation of the transcription factors AP-1, Sp-1, and CREB. PDTC inhibited the LPS-induced expression of TNF-α, COX-2, CINC, and ICAM-1 mRNA and proteins and reduced the LPS-induced increases in plasma TNF-α, 6-keto-prostaglandin F
1α
, and CINC concentrations. Inhibition of expression of these mediators prevented the increases in myeloperoxidase activity (a measure of neutrophil sequestration) in the heart, lungs, and liver.

Conclusions
—NF-κB activation correlates with LPS-induced expression of TNF-α, COX-2, CINC, and ICAM-1 genes in vivo. PDTC inhibits NF-κB activation and expression of these proinflammatory genes and their products. Thus, blocking NF-κB activation may be an effective strategy in the treatment of septic shock.
Chlamydia pneumoniae
Infection of Vascular Smooth Muscle and Endothelial Cells Activates NF-κB and Induces Tissue Factor and PAI-1 Expression
Authors: Dechend Ralf , Maass M. , Gieffers J. , Dietz R. , Scheidereit C. , Leutz A. , Gulba D. C.
Published: June 2012

Background
—Recent reports link
C. pneumoniae
infection of arteriosclerotic lesions to the precipitation of acute coronary syndromes, which also feature tissue factor and plasminogen activator inhibitor 1 (PAI-1) overexpression. We investigated whether or not
C. pneumoniae
can induce thrombogenicity by upregulation of procoagulant proteins.

Methods and Results
—Human vascular endothelial and smooth muscle cells were infected with a strain of
C. pneumoniae
isolated from an arteriosclerotic coronary artery. Tissue factor, PAI-1, and interleukin-6 expression was increased in infected cells. Concomitantly, NF-κB was activated and IκBα degraded. p50/p65 heterodimers were identified as the components responsible for the NF-κB activity.

Conclusions
—These data provide evidence that
C. pneumoniae
infection can induce procoagulant protein and proinflammatory cytokine expression. This cellular response is accompanied by activation of NF-κB. Our results demonstrate how
C. pneumoniae
infection may initiate acute coronary syndromes.
Expression of NADH/NADPH Oxidase p22
phox
in Human Coronary Arteries
Authors: Azumi Hiroshi , Inoue Nobutaka , Takeshita Saori , Rikitake Yoshiyuki , Kawashima Seinosuke , Hayashi Yoshitake , Itoh Hiroshi , Yokoyama Mitsuhiro
Published: June 2012

Background
—NADH/NADPH oxidase is an important source of superoxide in the vasculature. Recently, we found that polymorphism of the gene p22
phox
, a critical component of this oxidase, is associated with a risk of coronary artery disease. The aim of this study was to investigate the localization of p22
phox
in human coronary arteries and to examine its difference in expression between nonatherosclerotic and atherosclerotic coronary arteries.

Methods and Results
—Using coronary artery sections from autopsied cases (n=11), the expression of p22
phox
was examined by immunohistochemistry and Western blotting. In nonatherosclerotic coronary arteries, p22
phox
was weakly expressed, mainly in the adventitia. In atherosclerotic coronary arteries, intensive immunoreactivity was detected in neointimal and medial smooth muscle cells and infiltrating macrophages in hypercellular regions and at the shoulder region. Semiquantitative analysis and Western blotting showed that the expression of p22
phox
in atherosclerotic coronary arteries was more pronounced than that in nonatherosclerotic arteries. Double staining revealed p22
phox
expression in adventitial fibroblasts, smooth muscle cells, macrophages in the neointima and media, and endothelial cells.

Conclusions
—As atherosclerosis progressed, the expression of p22
phox
increased through the vessel wall. p22
phox
might participate in the pathogenesis and pathophysiology of atherosclerotic coronary disease.
Angiographic Findings in Patients With Refractory Unstable Angina According to Troponin T Status
Authors: Heeschen Christopher , van den Brand Marcel J. , Hamm Christian W. , Simoons Maarten L.
Published: June 2012

Background
—The CAPTURE (C7E3 fab AntiPlatelet Therapy in Unstable REfactory angina) trial enrolled patients with refractory unstable angina and documented a therapeutic benefit for abciximab, a platelet glycoprotein IIb/IIIa receptor antagonist, that was particularly evident in patients with elevated troponin T (TnT) levels. In the current study, we related the angiographic data to the TnT status of the CAPTURE patients.

Methods and Results
—In 853 patients, angiographic data at baseline and 18 to 24 hours after treatment were available and assessed by an Angiographic Committee with respect to TIMI flow, lesion severity, and visibility of thrombus. TnT levels >0.1 μg/L were found in 30.9% of the patients. Before randomization, thrombus was visible in 14.6% of TnT-positive patients (TnT levels >0.1 μg/L) and 4.2% of TnT-negative patients (
P
=0.004). Complex lesion characteristics B2+/C (72.0% versus 53.9%;
P
<0.001) and TIMI flow <2 (15.6% versus 5.1%;
P
<0.001) were more frequent in TnT-positive patients. Abciximab was effective with respect to reduction of visible thrombus, increase of TIMI flow, and reduction of cardiac events in TnT-positive patients only. Multivariate analysis identified TnT status, but not angiographic findings, as an independent predictor for both outcome and efficacy of treatment with abciximab.

Conclusions
—Complex lesion characteristics and visible thrombus formation at baseline were significantly linked to TnT elevation. However, TnT status was a more powerful predictor of increased cardiac risk and efficacy of treatment with abciximab than either. Relative to the angiogram, TnT can thus be considered a more sensitive marker for the underlying pathology, identifying patients with unstable angina who will particularly benefit from antiplatelet treatment.
Generation of Anti-Hirudin Antibodies in Heparin-Induced Thrombocytopenic Patients Treated With R-Hirudin
Authors: Song Xuehong , Huhle Günter , Wang Lianchun , Hoffmann Ursula , Harenberg Job
Published: June 2012

Background
—Hirudin is a small protein with strong thrombin inhibition that may be antigenic. The generation and disappearance of anti-hirudin antibodies were investigated in patients with heparin-induced thrombocytopenia who were treated with recombinant hirudin (r-hirudin) for ≥5 days.

Methods and Results
—The IgA, IgE, IgG, and IgM isotypes of anti-hirudin antibodies were determined by ELISA before and after the start of r-hirudin therapy. A total of 56% of patients (13 of 23) developed ≥1 antibody isotype during therapy. No IgE antibodies were generated. IgA, IgG, and IgM antibodies were detected in 30% (7 of 23), 52% (12 of 23), and 17% (4 of 23) of patients, respectively. Four patients generated only IgG, 2 patients developed either IgM or IgG and IgM, 5 patients IgG and IgA, and 2 patients IgG, IgM, and IgA antibodies. IgM antibodies disappeared within 8 days of the cessation of r-hirudin. IgA and IgG antibodies disappeared within 1 year in all but 1 patient. Binding of purified IgG to r-hirudin in IgG antibody–positive patients (n=7) was demonstrated by competitive ELISA for r-hirudin. Of the 7 IgG antibody samples, 1 each neutralized or enhanced the anticoagulant activity of r-hirudin.

Conclusions
—R-hirudin may be antigenic in patients with heparin-induced thrombocytopenia. More comprehensive investigations will be required to determine the biological relevance of this and to establish the antibody-generation pattern in other diseases.
Intracoronary Thrombus and Platelet Glycoprotein IIb/IIIa Receptor Blockade With Tirofiban in Unstable Angina or Non–Q-Wave Myocardial Infarction
Authors: Zhao Xue-Qiao , Théroux Pierre , Snapinn Steven M. , Sax Frederic L.
Published: June 2012

Background
—The present study describes the effects of tirofiban, a nonpeptide platelet glycoprotein (GP) IIb/IIIa receptor blocker, on the characteristics of culprit lesions in patients with unstable angina (UA) or non–Q-wave myocardial infarction (NQWMI).

Methods and Results
—Of 1915 patients enrolled in PRISM-PLUS, 1491 had a readable film obtained a median of 65 hours after randomization. A core laboratory examined the culprit lesions for intracoronary thrombus burden (primary end point) and for TIMI flow grade distribution and severity of the obstruction and of underlying coronary artery disease (secondary end points). The combination of tirofiban plus heparin compared with heparin alone significantly reduced the intracoronary thrombus burden of the culprit lesions (OR=0.77,
P
=0.022), improved the perfusion grade (OR=0.65,
P
=0.002), and decreased the severity of the obstruction (
P
=0.037), but it did not influence the severity of the underlying plaque. Persistence of a thrombus in 45% of patients was associated with a 2.4-fold increase in the odds of death at 30 days (
P
=0.005) and a 2-fold increase in the odds of myocardial infarction (
P
=0.002).

Conclusions
—The addition of tirofiban to heparin reduced the thrombus burden of the culprit lesion and improved distal perfusion in patients with UA or NQWMI, which supports the clinical benefit observed with the combination treatment.
Ticlopidine and Clopidogrel
Authors: Quinn Martin J. , Fitzgerald Desmond J.
Published: June 2012

Abstract

—The thienopyridines ticlopidine and clopidogrel are inhibitors of platelet function in vivo. Their mode of action has not been defined, but it appears that they require conversion to as yet unidentified metabolites that are noncompetitive antagonists of the platelet ADP receptor. Inhibition of platelet aggregation with these compounds is delayed until 24 to 48 hours after administration. Maximum inhibition occurs after 3 to 5 days, and recovery is slow after drug withdrawal. Ticlopidine is effective in preventing cardiovascular events in cerebrovascular, cardiovascular, and peripheral vascular disease, with an efficacy that is similar to aspirin. However, its use is associated with significant and sometimes fatal adverse reactions, specifically neutropenia and bone marrow aplasia. Gastrointestinal side effects and skin rashes are common and result in discontinuation of therapy in up to 10% of patients. Clopidogrel is at least as effective as aspirin in preventing cardiovascular events in patients with a history of vascular disease. It appears to be safer than ticlopidine, although its efficacy in acute coronary syndromes or post–coronary-stent insertion has not been reported. Important outstanding issues are whether clopidogrel adds to the benefit of aspirin and whether the combination of these agents is safe. If so, this combination may become the standard for antithrombotic therapy in cardiovascular disease.
β-Particle–Emitting Radioactive Stent Implantation
Authors: Wardeh A. J. , Kay I. P. , Sabaté M. , Coen V. L. M. A. , Gijzel A. L. , Ligthart J. M. R. , den Boer A. , Levendag P. C. , van der Giessen W. J. , Serruys P. W.
Published: June 2012

Background
—This study represents the Heart Center Rotterdam’s contribution to the Isostents for Restenosis Intervention Study, a nonrandomized multicenter trial evaluating the safety and feasibility of the radioactive Isostent in patients with single coronary artery disease. Restenosis after stent implantation is primarily caused by neointimal hyperplasia. In animal studies, β-particle–emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation.

Methods and Results
—The radioisotope
32
P, a β-particle emitter with a half-life of 14.3 days, was directly embedded into the Isostent. The calculated range of radioactivity was 0.75 to 1.5 μCi. Quantitative coronary angiography measurements were performed before and after the procedure and at 6-month follow-up. A total of 31 radioactive stents were used in 26 patients; 30 (97%) were successfully implanted, and 1 was embolized. Treated lesions were in the left anterior descending coronary artery (n=12), the right coronary artery (n=8), or the left circumflex coronary artery (n=6). Five patients received additional, nonradioactive stents. Treated lesion lengths were 13±4 mm, with a reference diameter of 2.93±0.47 mm. Minimum lumen diameter increased from 0.87±0.28 mm preprocedure to 2.84±0.35 mm postprocedure. No in-hospital adverse cardiac events occurred. All patients received aspirin indefinitely and ticlopidine for 4 weeks. Twenty-three patients (88%) returned for 6-month angiographic follow-up; 17% of them had in-stent restenosis, and 13% had repeat revascularization. No restenosis was observed at the stent edges. Minimum lumen diameter at follow-up averaged 1.85±0.69 mm, which resulted in a late loss of 0.99±0.59 mm and a late loss index of 0.53±0.35. No other major cardiac events occurred during the 6-month follow-up.

Conclusions
—The use of radioactive stents with an activity of 0.75 to 1.5 μCi is safe and feasible.
Effects of Testosterone on Coronary Vasomotor Regulation in Men With Coronary Heart Disease
Authors: Webb Carolyn M. , McNeill John G. , Hayward Christopher S. , de Zeigler Dominique , Collins Peter
Published: June 2012

Background
—The increased incidence of coronary artery disease in men compared with premenopausal women suggests a detrimental role of male hormones on the cardiovascular system. However, testosterone has direct relaxing effects on coronary arteries in animals, as shown both in vitro and in vivo. The effect of testosterone on the human coronary circulation remains unknown.

Methods and Results
—We studied 13 men (aged 61±11 years) with coronary artery disease. They underwent measurement of coronary artery diameter and blood flow after a 3-minute intracoronary infusion of vehicle control (ethanol) followed by 2-minute intracoronary infusions of acetylcholine (10
−7
to 10
−5
mol/L) until peak velocity response. A dose-response curve to 3-minute infusions of testosterone (10
−10
to 10
−7
mol/L) was then determined, and the acetylcholine infusions were repeated. Finally, an intracoronary bolus of isosorbide dinitrate (1000 μg) was given. Coronary blood flow was calculated from measurements of blood flow velocity using intracoronary Doppler and coronary artery diameter using quantitative coronary angiography. Testosterone significantly increased coronary artery diameter compared with baseline (2.78±0.74 mm versus 2.86±0.72 mm [
P
=0.05], 2.87±0.71 mm [
P
=0.038], and 2.90±0.75 mm [
P
=0.005] for baseline versus testosterone 10
−9
to 10
−7
mol/L, respectively). A significant increase in coronary blood flow occurred at all concentrations of testosterone compared with baseline (geometric mean [95% CI]: 32 [25, 42] versus 36.3 [27, 48] {
P
=0.006}, 35.3 [26, 47] {
P
=0.029}, 36.8 [28, 49] {
P
=0.002}, and 37 [28, 48] {
P
=0.002} mL/min for baseline versus testosterone 10
−10
to 10
−7
mol/L, respectively). No differences existed in coronary diameter or blood flow responses to acetylcholine before versus after testosterone.

Conclusions
—Short-term intracoronary administration of testosterone, at physiological concentrations, induces coronary artery dilatation and increases coronary blood flow in men with established coronary artery disease.
The Direct Antiatherogenic Effect of Estrogen Is Present, Absent, or Reversed, Depending on the State of the Arterial Endothelium
Authors: Holm Pernille , Andersen Heidi L. , Andersen Malene R. , Erhardtsen Elisabeth , Stender Steen
Published: June 2012

Background
—This study further investigated the relationship between estrogen, arterial endothelium, and nitric oxide (NO) in cholesterol-clamped rabbits.

Methods and Results
—Rabbits were ovariectomized, balloon-injured in the thoracic aorta, and grouped to receive cholesterol-enriched chow together with either 17β-estradiol or vehicle for 1, 2, 4, or 8 weeks. In the undamaged aorta, cholesterol accumulation of the placebo rabbits was significantly increased from week 4 to 8 (
P
<0.001). This increase was almost completely inhibited by estrogen (
P
<0.001). In the balloon-injured aorta, the estrogen and placebo rabbits accumulated similar amounts of cholesterol in the reendothelialized areas. In the deendothelialized areas, the estrogen group surprisingly accumulated significantly more cholesterol than the placebo group. This difference was apparent from week 2 and became significant at week 8 (
P
<0.01). Circulating nitrite/nitrate were significantly increased by estrogen at weeks 1, 2, and 4 but not at week 8. Similarly, in additional experiments, basal NO release was significantly higher in estrogen-treated than in placebo-treated rabbits after 4 (
P
<0.05) but not after 8 weeks. Stimulated NO release and endothelial NO synthase activity did not differ between groups. Mononuclear-endothelial cell binding was reduced by 50% by estrogen after 4 weeks (
P
<0.05). This difference, however, was abolished by coadministration of N
G
-nitro-
l
-arginine methyl ester, an inhibitor of NO production.

Conclusions
—The direct antiatherogenic effect of estrogen was present, absent, or reversed, depending on the state of the arterial endothelium, and preceded by a transient increase in NO production followed by a reduced mononuclear-endothelial cell binding.
Results of a Multicenter Randomized Clinical Trial of Exercise and Long-Term Survival in Myocardial Infarction Patients
Authors: Dorn Joan , Naughton John , Imamura Dai , Trevisan Maurizio
Published: June 2012

Background
—This study examined whether a supervised exercise program improved 19-year survival in 30- to 64-year-old male myocardial infarction patients.

Methods and Results
—The men (n=651) were participants in the National Exercise and Heart Disease Project, a 3-year multicenter randomized clinical trial conducted in the United States (1976–1979). The treatment group (n=315) exercised for 8 weeks in a laboratory. Thereafter, they jogged, cycled, or swam in a gymnasium/pool setting guided by an individualized target heart rate. Participants in the control group (n=319) were to maintain normal routines but not participate in any regular exercise program. Participants were followed up until their death or December 31, 1995. Cox proportional hazards analysis revealed the all-cause mortality risk estimates (95% CIs) in the exercise group compared with controls to be 0.69 (0.39 to 1.25) after an average follow-up of 3 years, 0.84 (0.55 to 1.28) after 5 years, 0.95 (0.71 to 1.29) after 10 years, 1.02 (0.79 to 1.32) after 15 years, and 1.09 (0.87 to 1.36) after 19 years. Cardiovascular disease (CVD) mortality risk estimates (95% CI) for the same follow-up periods were 0.73 (0.37 to 1.43), 0.98 (0.60 to 1.61), 1.21 (0.79 to 1.60), 1.14 (0.84 to 1.54), and 1.16 (0.88 to 1.52). However, each 1-MET increase in work capacity from baseline to the end of the original trial resulted in consistent reductions in all-cause and CVD mortality risk at each follow-up period, regardless of initial work-capacity level.

Conclusions
—These findings indicate exercise-program participation resulted in nonsignificantly reduced mortality risks early in the follow-up period. Benefits diminished as time since participation increased, which suggests that the protective mechanisms associated with the program may be short term. Contamination between groups over time could also explain the diminished effects, because increased work capacity provided survival benefits up to 19 years.
Usefulness of a Tilt Training Program for the Prevention of Refractory Neurocardiogenic Syncope in Adolescents
Authors: Di Girolamo Enrico , Di Iorio Cesare , Leonzio Luigi , Sabatini Panfilo , Barsotti Antonio
Published: June 2012

Background
—Recurrent syncope represents a debilitating disorder and quality of life deteriorates as a function of recurrence of symptoms. Although the administration of β-blockers, vasoconstrictors, fludrocortisone, and serotonin reuptake inhibitors may be helpful in preventing episodes, many patients are intolerant of or respond poorly to these agents. Orthostatic training has been reported to be effective in preventing refractory syncope. Thus, to determine whether a tilt training program could prevent symptoms in adolescents, the following controlled study was undertaken.

Methods and Results
—Forty-seven consecutive adolescents (18 male and 29 female, mean age 16.0±2.2 years) with recurrent syncope and positive head-up tilt test refractory to previous traditional therapies were distributed between 2 groups, depending on their consent (24 patients) or refusal (controls, 23 patients) to enter the program. Orthostatic training was started, in the presence of a family member, with a series of 5 in-hospital sessions. The 24 patients and their relatives were then instructed to perform the tilt training at home by standing against a wall twice a day for a planned duration of up to 40 minutes, depending on the in-hospital orthostatic tolerance. Head-up tilt response was reevaluated after 1 month, and the clinical effect was noted over a mean follow-up of 18.2±5.3 months (range 15 to 23); 26.1% of patients in the control group and 95.8% of patients in the training group became tilt-negative (
P
<0.0001). Spontaneous syncope was observed in 56.5% versus 0% in the control and training group, respectively (
P
<0.0001).

Conclusions
—Orthostatic training was found to significantly improve symptoms of adolescents with neurocardiogenic syncope unresponsive to or intolerant of traditional medications. Twice-a-day training sessions of 40 minutes were well accepted by patients.
Reduction in Vascular Lesion Formation by Hirudin Secreted From Retrovirus-Transduced Confluent Endothelial Cells on Vascular Grafts in Baboons
Authors: Lundell Anders , Kelly Andrew B. , Anderson Johanna , Marijianowski Monique , Rade Jeffrey J. , Hanson Stephen R. , Harker Laurence A.
Published: June 2012

Background
—The hypothesis that thrombin mediates the formation of neointimal vascular lesions at sites of mechanical vascular injury has been tested in baboons by measurement of the effects of hirudin delivered by retrovirus-transduced hirudin-secreting vascular endothelial cells (ECs) lining surgically implanted arterial vascular grafts (AVGs).

Methods and Results
—The antithrombotic efficacy of baboon ECs transduced with cDNA encoding hirudin was assessed in vitro and in vivo on thrombogenic segments in chronically exteriorized femoral arteriovenous (AV) shunts. Bilateral brachial AVGs lined with hirudin-transduced versus nonhirudin control ECs at confluent density were surgically implanted, and vascular lesion formations at distal graft-vessel anastomoses were compared after 30 days. Hirudin-transduced ECs secreted 20±6 ng · 10
6
cells
−1
· 24 h
−1
(range, 14 to 24 ng · 10
6
cells
−1
· 24 h
−1
) hirudin in supernatants of static cultures. Hirudin-secreting ECs on segments of collagen-coated graft interposed in chronic AV shunts decreased the accumulation of
111
In-labeled platelets to 0.52±0.34×10
9
platelets, compared with 0.82±0.49×10
9
platelets in controls (
P
=0.03) and reduced platelet deposition in propagated thrombotic tails extending downstream from segments of vascular graft from 1.38±0.41×10
9
platelets in controls to 0.59±0.22×10
9
platelets (
P
=0.04). ECs recovered from 30-day AVG implants generated 17±9 ng · 10
6
cells
−1
· 24 h
−1
(range, 9 to 25 ng · 10
6
cells
−1
· 24 h
−1
) hirudin. Hirudin-secreting ECs reduced neointimal lesion formation at distal graft-vessel anastomoses, ie, 1.02 mm
2
(range, 0.88 to 1.95 mm
2
) versus 1.82 mm
2
(range, 0.88 to 2.56 mm
2
) in contralateral AVGs bearing nonhirudin control ECs (
P
<0.01).

Conclusions
—Viral vector–directed secretion of hirudin from ECs lining implanted AVGs significantly reduces the formation of thrombus and neointimal vascular lesions.
Limb Blood Flow and Vascular Conductance Are Reduced With Age in Healthy Humans
Authors: Dinenno Frank A. , Jones Pamela P. , Seals Douglas R. , Tanaka Hirofumi
Published: June 2012

Background
—We tested the hypothesis that basal (resting) limb blood flow and vascular conductance are reduced with age in adult humans and that these changes are related to elevations in sympathetic vasoconstrictor nerve activity and reductions in limb oxygen demand.

Methods and Results
—Sixteen young (28±1 years; mean±SEM) and 15 older (63±1 years) healthy normotensive adult men were studied. Diastolic blood pressure and body fat were higher (
P
<0.005) in the older men, but there were no other age-related differences in subject characteristics. Femoral artery blood flow (Doppler ultrasound) was 26% lower in the older men (
P
<0.005), despite similar levels of cardiac output (systemic arterial blood flow) in the 2 groups. Femoral artery vascular conductance was 32% lower and femoral vascular resistance was 45% higher in the older men (
P
<0.005). Muscle sympathetic nerve activity (peroneal microneurography) was 74% higher in the older men (
P
<0.001) and correlated with femoral artery blood flow (
r
=−0.55,
P
<0.005), vascular conductance (
r
=−0.65,
P
<0.001), and vascular resistance (
r
=0.61,
P
<0.001). The age-related differences in femoral hemodynamics were no longer significant after correction for the influence of muscle sympathetic nerve activity. There were no significant age-group differences in leg tissue mass (by dual-energy x-ray absorptiometry), but estimated leg oxygen consumption was 15% lower in the older men (
P
<0.001). Femoral artery blood flow was directly related to estimated leg oxygen consumption (
r
=0.78,
P
<0.001). The age-group differences in femoral artery blood flow were no longer significant after correction for estimated leg oxygen consumption by ANCOVA.

Conclusions
—(1) Basal whole-leg arterial blood flow and vascular conductance are reduced with age in healthy adult men; (2) these changes are associated with elevations in sympathetic vasoconstrictor nerve activity; and (3) the lower whole-limb blood flow is related to a lower oxygen demand that is independent of tissue mass.
Simvastatin Preserves the Ischemic-Reperfused Myocardium in Normocholesterolemic Rat Hearts
Authors: Lefer Allan M. , Campbell Barry , Shin Yong-Kyoo , Scalia Rosario , Hayward Reid , Lefer David J.
Published: June 2012

Background
—Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as cardiomyocyte injury. These deleterious effects are due in large part to endothelial dysfunction leading to the upregulation of cell adhesion molecules and subsequent neutrophil-endothelium interaction. At clinically relevant doses, simvastatin, an HMG-CoA reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. We wanted to test the effects of simvastatin on neutrophil-mediated cardiac dysfunction in a controlled model of myocardial ischemia-reperfusion.

Methods and Results
—This study examines the effects of simvastatin in a neutrophil-dependent isolated perfused rat heart model of ischemia (I) (20 minutes) and reperfusion (R) (45 minutes) injury. Administration of simvastatin 25 μg/rat improved coronary flow and preserved left ventricular developed pressure (LVDP) and dP/dt
max
, indexes of cardiac contractile function. Final LVDP was 95±5 mm Hg in I/R hearts perfused with PMNs and simvastatin, compared with 49±4 mm Hg in PMN-perfused I/R hearts receiving only vehicle (
P
<0.001). In addition, simvastatin significantly reduced PMN accumulation in the ischemic myocardium (
P
<0.01). In PMN-perfused rat hearts after I/R, simvastatin also significantly attenuated P-selectin expression, CD18 upregulation in rat PMNs, and PMN adherence to rat vascular endothelium. Significant, although less potent, effects were obtained with pravastatin.

Conclusions
—These results provide evidence that HMG-CoA reductase inhibitors are potent and effective cardioprotective agents that inhibit leukocyte–endothelial cell interactions and preserve cardiac contractile function and coronary perfusion after myocardial ischemia and reperfusion. Moreover, these effects are unrelated to the cholesterol-lowering action of this agent and appear to be mediated by enhanced endothelial release of NO.
Platelet Glycoprotein IIb/IIIa Receptor Inhibition in Non–ST-Elevation Acute Coronary Syndromes
Authors: Boersma Eric , Akkerhuis K. Martijn , Théroux Pierre , Califf Robert M. , Topol Eric J. , Simoons Maarten L.
Published: June 2012

Background
—Glycoprotein (GP) IIb/IIIa receptor blockers prevent life-threatening cardiac complications in patients with acute coronary syndromes without ST-segment elevation and protect against thrombotic complications associated with percutaneous coronary interventions (PCIs). The question arises as to whether these 2 beneficial effects are independent and additive.

Methods and Results
—We analyzed data from the CAPTURE, PURSUIT, and PRISM-PLUS randomized trials, which studied the effects of the GP IIb/IIIa inhibitors abciximab, eptifibatide, and tirofiban, respectively, in acute coronary syndrome patients without persistent ST-segment elevation, with a period of study drug infusion before a possible PCI. During the period of pharmacological treatment, each trial demonstrated a significant reduction in the rate of death or nonfatal myocardial infarction in patients randomized to the GP IIb/IIIa inhibitor compared with placebo. The 3 trials combined showed a 2.5% event rate in this period in the GP IIb/IIIa inhibitor group (N=6125) versus 3.8% in placebo (N=6171), which implies a 34% relative reduction (
P
<0.001). During study medication, a PCI was performed in 1358 patients assigned GP IIb/IIIa inhibition and 1396 placebo patients. The event rate during the first 48 hours after PCI was also significantly lower in the GP IIb/IIIa inhibitor group (4.9% versus 8.0%; 41% reduction;
P
<0.001). No further benefit or rebound effect was observed beyond 48 hours after the PCI.

Conclusions
—There is conclusive evidence of an early benefit of GP IIb/IIIa inhibitors during medical treatment in patients with acute coronary syndromes without persistent ST-segment elevation. In addition, in patients subsequently undergoing PCI, GP IIb/IIIa inhibition protects against myocardial damage associated with the intervention.
Clinical Outcomes of Bivalirudin for Ischemic Heart Disease
Authors: Kong David F. , Topol Eric J. , Bittl John A. , White Harvey D. , Théroux Pierre , Hasselblad Vic , Califf Robert M.
Published: June 2012

Background
—Current treatment strategies for percutaneous coronary revascularization and acute coronary syndromes incorporate thrombin inhibition with either unfractionated or fractionated heparin. The peptide bivalirudin (Hirulog) is a direct thrombin inhibitor whose pharmacological properties differ from those of heparin. We conducted a systematic overview (meta-analysis) to assess the effect of bivalirudin on 4 end points: death, myocardial infarction, major hemorrhage, and the composite of death or infarction.

Methods and Results
—Six trials (5674 patients) represent the randomized, controlled bivalirudin experience, including 4603 patients undergoing elective percutaneous coronary revascularization and 1071 patients with acute coronary syndromes. ORs for the 4 clinical end points were calculated for each trial. Four trials (4973 patients) that compared bivalirudin with heparin were combined with the use of a random-effects model. In these trials, bivalirudin was associated with a significant reduction in the composite of death or infarction (OR 0.73, 95% CI 0.57 to 0.95;
P
=0.02) at 30 to 50 days, or 14 fewer events per 1000 patients so treated. There also was a significant reduction in major hemorrhage for the same trials (OR 0.41, 95% CI 0.32 to 0.52;
P
<0.001, or 58 fewer events per 1000 patients so treated). A similar analysis combined 2 dose-ranging trials (701 patients) that compared therapeutic (activated partial thromboplastin time more than twice the control time) with subtherapeutic bivalirudin anticoagulation (activated partial thromboplastin time less than twice the control time).

Conclusions
—Bivalirudin is at least as effective as heparin, with clearly superior safety. Thus, it provides an unprecedented net clinical benefit over heparin in patients with ischemic heart disease.
Cardiogenic Shock in Patients With Acute Ischemic Syndromes With and Without ST-Segment Elevation
Authors: Holmes David R. , Berger Peter B. , Hochman Judith S. , Granger Christopher B. , Thompson Trevor D. , Califf Robert M. , Vahanian Alec , Bates Eric R. , Topol Eric J.
Published: June 2012

Background
—Cardiogenic shock is usually considered a sequela of ST-segment elevation myocardial infarction. There are limited prospective data on the incidence and significance of shock in non−ST-segment elevation patients. This study assessed the incidence and outcomes of cardiogenic shock developing after enrollment among patients with and without ST-segment elevation in the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO)-IIb trial.

Methods and Results
—Among 12 084 patients in GUSTO-IIb who did not present with cardiogenic shock, 4092 (34%) had and 7991 (66%) did not have ST-segment elevation on the enrollment ECG. Cardiogenic shock developed in 4.2% of ST-segment elevation patients compared with 2.5% of patients without ST-segment elevation (odds ratio, 0.581; 95% CI, 0.472 to 0.715;
P
<0.001). Shock developed significantly later among patients without ST-segment elevation. There were significant differences in baseline characteristics between shock patients with and without ST-segment elevation: Patients without ST-segment elevation were older, more frequently had diabetes mellitus and 3-vessel disease, but had less TIMI grade 0 flow at angiography. Regardless of the initial ECG, mortality was high: 63% among patients with ST-segment elevation and 73% in those without ST-segment elevation.

Conclusions
—Cardiogenic shock occurs in the setting of acute ischemic syndromes regardless of whether ST-segment elevation is present. The incidence, patient characteristics, timing, clinical course, and angiographic findings differ between the 2 groups. Mortality from cardiogenic shock is similarly high among patients with and without ST-segment elevation.
Association of Heart Failure in Homozygous β-Thalassemia With the Major Histocompatibility Complex
Authors: Kremastinos Dimitrios T. , Flevari Panagiota , Spyropoulou Maria , Vrettou Helen , Tsiapras Dimitrios , Stavropoulos-Giokas Catherine G.
Published: June 2012

Background
—In β-thalassemia major, heart failure primarily affecting left ventricular systolic function is the most common complication and cause of death. Apart from iron deposition, it has been recently reported that myocarditis might be another contributing factor in the pathogenesis of acute or chronic heart failure, acting possibly through an autoimmune mechanism. In an attempt to assess the role of immunogenetic factors in the development of heart failure associated with β-thalassemia major, we studied the frequency of major histocompatibility antigens/alleles A, B, DR, and DQ in homozygous β-thalassemic patients with and without heart failure primarily affecting the left ventricle.

Methods and Results
—Forty-five consecutive unrelated Greek patients with homozygous β-thalassemia and left-sided chronic heart failure were studied. Fifty-eight unrelated Greek patients with homozygous β-thalassemia without heart failure and 130 unrelated Greek healthy controls were also studied. In all subjects, class I HLA-A and -B typing was performed by the complement-mediated lymphocytotoxicity assay, whereas class II HLA-DR and -DQ typing was performed by polymerase chain reaction. HLA-DRB1*1401 allele frequency was significantly increased in patients with β-thalassemia major without left-sided heart failure compared with those with heart failure (corrected
P
[
P
c
]=0.02, odds ratio 0.1) and healthy controls (
P
c
=0.001). HLA-DQA1*0501 allele frequency was increased in patients with heart failure compared with patients without heart failure (
P
c
=0.04, odds ratio 14) and healthy controls (
P
c
=0.004).

Conclusions
—Differences exist in the immunogenetic profile between homozygous β-thalassemic patients with and without left-sided heart failure, raising the possibility that genetically defined immune mechanisms may play an important role in the pathogenesis of heart failure in β-thalassemia.
MAPK Superfamily Plays an Important Role in Daunomycin-Induced Apoptosis of Cardiac Myocytes
Authors: Zhu Weidong , Zou Yunzeng , Aikawa Ryuichi , Harada Koichiro , Kudoh Sumiyo , Uozumi Hiroki , Hayashi Doubun , Gu Yaping , Yamazaki Tsutomu , Nagai Ryozo , Yazaki Yoshio , Komuro Issei
Published: June 2012

Background
—Although anthracyclines, such as daunomycin (DM) and adriamycin, are potent chemotherapeutic agents, they have serious adverse effects, including cardiac toxicity. In the present study, we investigated the molecular mechanisms of DM-induced cardiomyocyte impairment.

Methods and Results
—When cultured cardiac myocytes of neonatal rats were exposed to 1 μmol/L DM for 24 hours, many cells became positive for TUNEL staining, with morphological changes characteristic of apoptosis. Fragmentation of DNA into oligonucleosome-size fragments was recognized by agarose gel electrophoresis in DM-treated myocytes. DM activated 3 members of the mitogen-activated protein kinase (MAPK) family dose-dependently, such as extracellular signal-regulated protein kinases (ERKs), c-Jun NH
2
-terminal kinases, and p38 MAPK in cardiac myocytes. Oxyradical scavengers or Ca
2+
chelators inhibited DM-induced activation of ERKs and p38 MAPK. DM-induced activation of ERKs was also inhibited by overexpression of dominant negative mutants of Ras (D.N.Ras), and the p38 MAPK activation was attenuated by D.N.Rho. The number of DM-induced apoptotic cells was markedly increased when the ERK signaling pathway was selectively blocked by a specific MAPK/ERK kinase inhibitor, PD98059, whereas pretreatment with a specific inhibitor of p38 MAPK, SB203580, significantly reduced the amount of apoptosis.

Conclusions
—These results suggest that DM activates MAPKs through reactive oxygen species and Ca
2+
and that the MAPK family plays important roles in DM-induced apoptosis in cardiac myocytes. ERKs protect cardiomyocytes from apoptosis, whereas p38 MAPK is involved in the induction of cardiomyocyte apoptosis.
CPR Techniques That Combine Chest and Abdominal Compression and Decompression
Authors: Babbs Charles F.
Published: June 2012

Background
—This study was done to elucidate mechanisms by which newer cardiopulmonary resuscitation (CPR) techniques, including interposed abdominal compression (IAC), active compression-decompression (ACD), and Lifestick CPR, augment systemic perfusion pressure and forward flow and to compare the 3 techniques in the same test system.

Methods and Results
—Mathematical models describing hemodynamics of the adult human circulation during cardiac arrest and CPR were created and exercised by use of spreadsheet software. Assumptions of the models are limited to normal human anatomy and physiology, the definition of compliance (volume change/pressure change), and Ohm’s law (flow=pressure/resistance). Standard CPR generates 1.3 L/min forward and 25 mm Hg systemic perfusion pressure. In otherwise identical models, IAC-CPR generates 2.4 L/min and 45 mm Hg; ACD-CPR, 1.6 L/min and 30 mm Hg; and Lifestick CPR, which combines IAC and ACD, 3.1 L/min and 58 mm Hg. Augmented CPR techniques work by enhanced priming of either chest or abdominal pump mechanisms.

Conclusions
—Adjunctive maneuvers, combined with conventional chest compression, can produce substantial hemodynamic benefit in CPR by credible physiological mechanisms.
The T-Type Ca
2+
Channel Blocker Mibefradil Prevents the Development of a Substrate for Atrial Fibrillation by Tachycardia-Induced Atrial Remodeling in Dogs
Authors: Fareh Samir , Bénardeau Agnès , Thibault Bernard , Nattel Stanley
Published: June 2012

Background
—Ca
2+
overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca
2+
channel blockers attenuate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) inducibility. This study assessed the effects of the T-type Ca
2+
channel blocker mibefradil on tachycardia-induced atrial remodeling.

Methods and Results
—Dogs subjected to rapid atrial pacing (400 bpm) for 7 days were treated with mibefradil (100 mg/d, n=8) or matching placebo (n=10) in blinded fashion. Radiofrequency ablation of atrioventricular conduction and ventricular pacing were used to control ventricular rate. Placebo dogs showed significant decreases in atrial ERP (76±5 ms at a cycle length of 300 ms) and increases in ERP heterogeneity (27.7±2.4%), AF duration (414±232 seconds), and AF inducibility by single extrastimuli (41±10% of sites) compared with 10 unpaced control dogs (ERP 114±3 ms, ERP heterogeneity 13.8±0.9%, AF duration 7±3 seconds, AF inducibility 1.9±1.0% of sites). The changes caused by atrial tachycardia were strongly attenuated in mibefradil dogs, with ERPs averaging 102±7 ms, ERP heterogeneity 18.8±1.4%, AF duration 3±1 seconds, and AF inducibility 9.6±4.0% of sites. Among mibefradil-treated dogs, ERP, AF duration, and inducibility correlated with plasma drug concentration. Acute mibefradil administration did not alter ERP or AF.

Conclusions
—Mibefradil, a drug with strong T-type Ca
2+
channel blocking properties, prevents AF-promoting electrophysiological remodeling by atrial tachycardia. These findings have important potential implications for the mechanisms of tachycardia-induced atrial remodeling and demonstrate the feasibility of preventing electrical remodeling caused by several days of atrial tachycardia.
Opposing Effects of β
1
- and β
2
-Adrenergic Receptors on Cardiac Myocyte Apoptosis
Authors: Communal Catherine , Singh Krishna , Sawyer Douglas B. , Colucci Wilson S.
Published: June 2012

Background
—β-Adrenergic receptor (β-AR) stimulation increases apoptosis in adult rat cardiac (ventricular) myocytes (ARVMs) via activation of adenylyl cyclase. β
2
-ARs may couple to a G
i
-mediated signaling pathway that can oppose the actions of adenylyl cyclase.

Methods and Results
—In ARVMs, β-AR stimulation for 24 hours increased the number of apoptotic cells as measured by flow cytometry. β-AR–stimulated apoptosis was abolished by the β
1
-AR–selective antagonist CGP 20712A (
P
<0.05 versus β-AR stimulation alone) but was potentiated by the β
2
-AR–selective antagonist ICI 118,551 (
P
<0.05 versus β-AR stimulation alone). The muscarinic agonist carbachol also prevented β-AR–stimulated apoptosis (
P
<0.05 versus β-AR stimulation alone), whereas pertussis toxin potentiated the apoptotic action of β-AR stimulation (
P
<0.05 versus β-AR stimulation alone) and prevented the antiapoptotic action of carbachol.

Conclusions
—In ARVMs, stimulation of β
1
-ARs increases apoptosis via a cAMP-dependent mechanism, whereas stimulation of β
2
-ARs inhibits apoptosis via a G
i
-coupled pathway. These findings have implications for the pathophysiology and treatment of myocardial failure.
Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children
Authors: Bonnet Damien , Martin Delphine , Pascale de Lonlay  , Villain Elizabeth , Jouvet Philippe , Rabier Daniel , Brivet Michèle , Saudubray Jean-Marie
Published: June 2012

Background
—The clinical manifestations of inherited disorders of fatty acid oxidation vary according to the enzymatic defect. They may present as isolated cardiomyopathy, sudden death, progressive skeletal myopathy, or hepatic failure. Arrhythmia is an unusual presenting symptom of fatty acid oxidation deficiencies.

Methods and Results
—Over a period of 25 years, 107 patients were diagnosed with an inherited fatty acid oxidation disorder. Arrhythmia was the predominant presenting symptom in 24 cases. These 24 cases included 15 ventricular tachycardias, 4 atrial tachycardias, 4 sinus node dysfunctions with episodes of atrial tachycardia, 6 atrioventricular blocks, and 4 left bundle-branch blocks in newborn infants. Conduction disorders and atrial tachycardias were observed in patients with defects of long-chain fatty acid transport across the inner mitochondrial membrane (carnitine palmitoyl transferase type II deficiency and carnitine acylcarnitine translocase deficiency) and in patients with trifunctional protein deficiency. Ventricular tachycardias were observed in patients with any type of fatty acid oxidation deficiency. Arrhythmias were absent in patients with primary carnitine carrier, carnitine palmitoyl transferase I, and medium chain acyl coenzyme A dehydrogenase deficiencies.

Conclusions
—The accumulation of arrhythmogenic intermediary metabolites of fatty acids, such as long-chain acylcarnitines, may be responsible for arrhythmias. Inborn errors of fatty acid oxidation should be considered in unexplained sudden death or near-miss in infants and in infants with conduction defects or ventricular tachycardia. Diagnosis can be easily ascertained by an acylcarnitine profile from blood spots on filter paper.