bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuation of Rebound Ischemia After Discontinuation of Heparin Therapy by Glycoprotein IIb/IIIa Inhibition With Eptifibatide in Patients With Acute Coronary Syndromes
Authors: Lauer Michael A. , Houghtaling Penny L. , Peterson John G. , Granger Christopher B. , Bhatt Deepak L. , Sapp Shelly K. , Simoons Maarten L. , Harrington Robert A. , Topol Eric J. , Lincoff A. Michael
Published: September 2007

Background

A reactivation of ischemia after the discontinuation of intravenous heparin in acute coronary syndromes has been described. The effect of glycoprotein IIb/IIIa blockade on heparin rebound is unknown.

Methods and Results

Patients with acute coronary syndromes who received heparin therapy but not initial revascularization in the Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial were analyzed. Rates of death or myocardial (re)infarction while on heparin therapy and in 12-hour periods in the 2 days after heparin discontinuation were compared between eptifibatide and placebo. There was no difference between study groups in event rates during heparin infusion. In the 12 hours after heparin discontinuation, there was a 2.5-fold increase in all events, an 8-fold increase in death, and a 2-fold increase in myocardial infarction. However, in the 12 hours after heparin discontinuation, there was a significantly lower rate of events (1.68% versus 2.53%,
P
=0.03) and death (0.77% versus 0.21%,
P
=0.002) in the eptifibatide group compared with the placebo group. When only considering patients who were on study drug at the time of heparin discontinuation, the reduction in the combined end point was marginally significant, but the difference in the rate of death remained significant (0.68% versus 0.06%,
P
=0.004). In logistic regression analyses, the multivariate predictors of rebound events were the duration of heparin therapy, age, North American site, and lack of eptifibatide treatment.

Conclusions

An increase in death or myocardial infarction occurs in the 12 hours after heparin discontinuation in patients with acute coronary syndromes. This rebound is attenuated by glycoprotein IIb/IIIa inhibition with eptifibatide.
Staged Repair of Extensive Aortic Aneurysms
Authors: Safi Hazim J. , Miller Charles C. , Estrera Anthony L. , Huynh Tam T.T. , Rubenstein Forrest S. , Subramaniam Mahesh H. , Buja L. Maximilian
Published: September 2007

Background
—

Extensive aortic aneurysms (ascending aorta, aortic arch, and descending or thoracoabdominal aorta) require innovative surgical techniques. Some surgeons advocate a single procedure with long periods of profound hypothermia, whereas others use a staged approach. We adopted a two-staged procedure (elephant trunk technique) in 1991 for elective repair of extensive aortic aneurysms.

Methods and Results
—

Between February 1991 and May 2000, we performed a total of 1146 aortic aneurysm operations. Of these, 182 (15.9%) operations were first- or second-stage elephant trunk procedures, performed in a total of 117 patients. Stage 1 was completed in all 117 patients. Stage 2 was completed in 65 (55.6%) of 117 patients. Thirty-day mortality rate for the first stage was 5.1% (6 of 117). Mortality rate during the interval between operations was 3.6% (4 of 111), of which 75% (3of 4) were the result of aneurysm rupture. Thirty-day mortality rate for the second stage was 6.2% (4 of 65). A total of 43 patients did not return for second-stage repair. Among these patients, within an average period of 3.4 years (range, 1.5 months to 4.9 years), 13 of 43 (30.2%) died, 4 of 13 (30.8%) as the result of rupture. Two of 117 (1.7%) first-stage patients had postoperative stroke. No spinal cord dysfunction occurred in second-stage patients.

Conclusions
—

Extensive aortic aneurysms can be repaired with acceptable morbidity and mortality rates through the use of the elephant trunk technique. Death was most commonly the result of rupture, both in interval patients awaiting scheduled second-stage repair and in patients who did not return. After the first stage, prompt treatment of the remaining segment is crucial to the success of staged repair.
Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes
Authors: Ziolo Mark T. , Katoh Hideki , Bers Donald M.
Published: September 2007

Background—β-Adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca2+release channel (ryanodine receptor, RyR) during β-adrenergic stimulation.

Methods and Results—Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca2+spark frequency (CaSpF, reflecting resting RyR openings) and Ca2+transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 μmol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca2+transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca2+load).

Conclusions—iNOS/NO depresses β-adrenergic–stimulated RyR function through a cGMP-independent pathway (eg, NO- and/or peroxynitrite-dependent redox modification). This mechanism limits β-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.
Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Apoptosis in Cultured Neonatal Rat Cardiac Myocytes
Authors: Iwai-Kanai Eri , Hasegawa Koji , Sawamura Tatsuya , Fujita Masatoshi , Yanazume Tetsuhiko , Toyokuni Shinya , Adachi Souichi , Kihara Yasuki , Sasayama Shigetake
Published: September 2007

Background—Lectin-like oxidized LDL receptor-1 (LOX-1) was originally identified as a receptor expressed predominantly in endothelial cells. LOX-1 can also be expressed in other cell types, and the activation of the LOX-1 pathway has been implicated in apoptosis. There have been no reports, however, about LOX-1 expression in cardiac myocytes or regulation of myocardial cell apoptosis by LOX-1.

Methods and Results—In primary cardiac myocytes from neonatal rats, immunohistochemical analyses using a specific monoclonal antibody against LOX-1 demonstrated that LOX-1 expression was markedly induced by stimulation with norepinephrine and endothelin-1. LOX-1 expression was upregulated in cardiac myocytes as well as in vessel walls of failing rat hearts in vivo. In the presence of a low concentration of oxidized LDL that did not induce apoptosis by itself, artificial overexpression of LOX-1 in cardiac myocytes in culture resulted in apoptosis. LOX-1 overexpression induced activation of p38 mitogen-activated protein kinase (MAPK) and oxidative stress in cardiac myocytes, as demonstrated by an increase in positive immunostaining for 8-hydroxy-2′-deoxyguanosine. Inhibition of p38 MAPK by cotransfection of a dominant-negative form of MKK6 as well as by administration of a specific inhibitor, SB203580 or FR167653, almost completely blocked the induction of apoptosis by LOX-1 activation. Antioxidant catalase also blocked LOX-1-induced apoptosis as well as activation of p38 MAPK.

Conclusions—These findings demonstrate that LOX-1 expression in cardiac myocytes is induced by neurohormonal factors activated in heart failure and that LOX-1-dependent apoptosis in these cells requires p38 MAPK, a component of oxidant stress-sensitive signaling pathways.
Role for Sulfatides in Platelet Aggregation
Authors: Merten Michael , Thiagarajan Perumal
Published: September 2007

Background
—

Sulfatides are sulfated glycosphingolipids present on the surface of oligodendrocytes, renal tubular cells, and certain tumor cells. They appear to be involved in nerve conduction and cell adhesion, but their precise physiological function is not known.

Methods and Results
—

Here, we show a novel role for sulfatides as a major ligand for P-selectin in platelet adhesion and aggregation. Sulfatides are expressed on the platelet surface, and platelets expressing sulfatides adhere to P-selectin. Both sulfatide micelles and sulfatide-binding recombinant malaria circumsporozoite protein (MCSP) inhibit this adhesion. In parallel, platelets and CHO cells expressing P-selectin adhere to sulfatides, and anti-P-selectin antibodies inhibit this adhesion. Furthermore, both anti-P-selectin antibodies and sulfatide antagonist MCSP significantly reverse platelet aggregation induced by ADP, collagen, or thrombin receptor-activating peptide, suggesting that sulfatide-P-selectin interactions are necessary for the formation of stable platelet aggregates.

Conclusions
—

These results show that sulfatide interactions with P-selectin are important in platelet adhesion and platelet aggregation. The sulfatide interactions with P-selectin stabilize platelet aggregates, representing a new mechanism of platelet aggregation that may play a significant role in hemostasis and thrombosis.
Increased Aortic Intima-Media Thickness
Authors: Järvisalo Mikko J. , Jartti Laura , Näntö-Salonen Kirsti , Irjala Kerttu , Rönnemaa Tapani , Hartiala Jaakko J. , Celermajer David S. , Raitakari Olli T.
Published: September 2007

Background
—

Autopsy studies in children have shown that atherosclerotic lesions begin to develop first in the intima of the aorta. Recent developments in ultrasound techniques have made it possible to visualize the intima-medial thickness of the abdominal aorta directly (aIMT). Therefore, we examined the feasibility of measuring aIMT in children and studied its value in distinguishing high-risk children from healthy controls compared with a more established marker of subclinical atherosclerosis, the common carotid artery intima-medial thickness (cIMT).

Methods and Results
—

IMTs were measured using high-resolution (13 MHz) ultrasound in 88 children (aged 11±2 years); 16 had hypercholesterolemia (LDL cholesterol, 5.1±1.2 mmol/L), 44 had type 1 diabetes (mean duration, 4.4±3.1 years; LDL cholesterol, 2.3±0.7 mmol/L), and 28 were healthy (controls; LDL cholesterol, 2.5±0.8 mmol/L). High-risk children had significantly increased aIMTs and cIMTs (both
P
<0.001) compared with controls. In controls, aIMT was similar to cIMT (
P
=NS), but aIMT was higher than cIMT in the children with hypercholesterolemia and diabetes (both
P
<0.01). Both markers showed excellent and approximately equal between-observer (<4%) and between-subject variation (<5%).

Conclusions
—

Children with hypercholesterolemia and diabetes show increased IMTs compared with healthy controls, with a relatively greater increase in the aIMT than in the cIMT. Because atherosclerosis begins first in the intima of the aorta, these data suggest that the aIMT might provide the best currently available noninvasive marker of preclinical atherosclerosis in children.
Noninvasive Determination of Spatially Resolved and Time-Resolved Tissue Perfusion in Humans During Nitric Oxide Inhibition and Inhalation by Use of a Visible-Reflectance Hyperspectral Imaging Technique
Authors: Zuzak Karel J. , Schaeberle Michael D. , Gladwin Mark T. , Cannon Richard O. , Levin Ira W.
Published: September 2007

Background
—

Vascular disease is commonly associated with reduced local synthesis of nitric oxide (NO) and impaired tissue perfusion. We introduce a novel noninvasive, visible-reflectance, hyperspectral imaging technique for quantifying the percentage of hemoglobin existing as oxyhemoglobin (HbO
2
) as an index of skin tissue perfusion.

Methods and Results
—

To simulate vascular endothelial dysfunction,
N
G
-monomethyl-
l
-arginine (L-NMMA) was infused into the brachial arteries of 9 healthy subjects for 5 minutes to inhibit forearm NO synthesis, first with the subject breathing room air and subsequently during NO inhalation at 80 ppm for 1 hour. Blood flow was measured by venous occlusion plethysmography, and the percentage of HbO
2
perfusing skin tissue was imaged noninvasively with a visible-reflectance hyperspectral technique. L-NMMA reduced blood flow by 31.7±4.9% and percentage of HbO
2
by 6.5±0.1 (
P
=0.002 and
P
<0.001 versus baseline, respectively). With subjects inhaling NO, blood flow fell during L-NMMA infusion by only 10.9±7.3%, and the percentage of HbO
2
decreased by 3.6±0.1 (
P
=0.007 and
P
<0.001, respectively, versus room air L-NMMA responses).

Conclusions
—

Visible-reflectance hyperspectral imaging demonstrates (1) a significant decline in the percentage of HbO
2
in skin tissue when blood flow is reduced after inhibition of forearm NO synthesis and (2) restoration of HbO
2
toward basal values with improved blood flow during inhalation of NO. This imaging method may provide an effective approach for time-resolved noninvasive monitoring of skin hemoglobin oxygen saturation and assessment of responses to therapeutic interventions in patients with vascular disease.
Cyclooxygenase-2 Blockade Does Not Impair Endothelial Vasodilator Function in Healthy Volunteers
Authors: Verma Subodh , Raj Satish R. , Shewchuk Lana , Mather Kieren J. , Anderson Todd J.
Published: September 2007

Background—From a cardiovascular standpoint, the safety of cyclooxygenase-2 (COX-2) blockers has been a topic of increasing concern. This concern stemmed from observations indicating that the COX-2 isoform is the major source of endothelium-derived prostacyclin and, hence, that selective blockade of this enzyme may impair endothelial health. To investigate this matter, we examined the effects of 7 days of treatment with rofecoxib versus naproxen on endothelial function in healthy volunteers.

Methods and Results—Thirty-five healthy volunteers were randomized to receive 7-day treatment with either rofecoxib (25 mg/d, n=18) or naproxen (750 mg/d, n=17). Vascular response measurements were conducted using forearm strain-gauge plethysmography. Changes in forearm blood flow in response to the endothelium-dependent vasodilator acetylcholine (3, 10, and 30 μg/min) and the endothelium-independent vasodilator sodium nitroprusside (1 and 10 μg/min) were assessed before and after treatment. Acetylcholine evoked a dose-dependent increase in forearm blood flow in all groups. Importantly, treatment resulted in no change in acetylcholine-mediated increases in forearm blood flow in either group (naproxen,P=0.27; rofecoxib,P=0.58). Similarly, there was no change in forearm blood flow in response to sodium nitroprusside (naproxen,P=0.55; rofecoxib,P=0.63).

Conclusions—We herein describe, for the first time, the effects of COX-2-selective inhibition on endothelium-dependent vasodilatation in healthy adults. COX-2 blockade, when used at the doses employed therapeutically (which are known to inhibit vascular prostacyclin production) did not result in significant changes in endothelial vasodilator responses in healthy volunteers. The effects of COX-2 inhibitors on vasodilator responses in patients with coronary artery disease remain to be determined.
Influence of Low High-Density Lipoprotein Cholesterol and Elevated Triglyceride on Coronary Heart Disease Events and Response to Simvastatin Therapy in 4S
Authors: Ballantyne Christie M. , Olsson Anders G. , Cook Thomas J. , Mercuri Michele F. , Pedersen Terje R. , Kjekshus John
Published: September 2007

Background
—

Patients with low HDL cholesterol (HDL-C) and elevated triglyceride had an increased risk for coronary heart disease (CHD) events and received the greatest benefit with fibrate therapy in substudy analyses of the Helsinki Heart Study and the Bezafibrate Infarction Prevention Study.

Methods and Results
—

In this post hoc analysis of the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol (LDL-C) and CHD, subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy. Patients in the lowest HDL-C (<1.00 mmol/L [39 mg/dL]) and highest triglyceride (>1.80 mmol/L [159 mg/dL]) quartiles (lipid triad; n=458) had increased proportions of other features of the metabolic syndrome (increased body mass index, hypertension, diabetes), men, prior myocardial infarction, prior revascularization, and β-blocker use than patients in the highest HDL-C (>1.34 mmol/L [52 mg/dL]) and lowest triglyceride (<1.11 mmol/L [98 mg/dL]) quartiles (isolated LDL-C elevation; n=545). The major coronary event rate was highest in lipid triad patients on placebo (35.9%), and this subgroup had the greatest event reduction (relative risk 0.48, 95% CI 0.33 to 0.69); a significant treatment-by-subgroup interaction (
P
=0.03) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup.

Conclusions
—

Patients with elevated LDL-C, low HDL-C, and elevated triglycerides were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome, had increased risk for CHD events on placebo, and received greater benefit with simvastatin therapy.
Conjugation of Low-Molecular-Weight Heparin and Deoxycholic Acid for the Development of a New Oral Anticoagulant Agent
Authors: Lee Yong-kyu , Nam Jong Hee , Shin Ho-Chul , Byun Youngro
Published: September 2007

Background
—

Heparin administration is usually limited to intravenous or subcutaneous injection. Oral delivery of heparin is an alternative to this and has been in great demand for treating patients who are at a high risk of deep vein thrombosis or pulmonary embolism. In this study, new heparin derivatives were synthesized to enhance the oral absorption of heparin in the gastrointestinal tract.

Methods and Results
—

By using heparin of 3000 Da [LMWH(3 kDa)], heparin of 6000 Da [LMWH(6 kDa)], and unfractionated heparin (UFH), we synthesized 3 kinds of conjugates of heparin and deoxycholic acid (DOCA): LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA. After oral administration of 100 mg/kg of heparin-DOCA, the maximum activated partial thromboplastin times of the LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 31.0±6.0, 87.8±11.1, and 51.0±8.7 seconds, respectively. The peak plasma concentrations of LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 0.06±0.02, 0.76±0.15, and 0.41±0.13 IU/mL, respectively. The bioavailability of LMWH(6 kDa)-DOCA at the 20-mg/kg dosage was calculated to be 7.8%.

Conclusions
—

LMWH(6 kDa)-DOCA was found to have a high anticoagulant effect when administered orally and could be used as a new oral anticoagulant agent. Furthermore, the present work proposed a new method for oral delivery of macromolecules and polysaccharide drugs.
Cost-Effectiveness of Coronary Stenting in Acute Myocardial Infarction
Authors: Cohen David J. , Taira Deborah A. , Berezin Ronna , Cox David A. , Morice Marie-Claude , Stone Gregg W. , Grines Cindy L.
Published: September 2007

Background
—

Although several randomized trials have demonstrated that coronary stenting improves angiographic and clinical outcomes for patients with acute myocardial infarction (AMI), the cost-effectiveness of this practice is unknown. The objective of the present study was to evaluate the long-term costs and cost-effectiveness (C/E) of coronary stenting compared with primary balloon angioplasty as treatment for AMI.

Methods and Results
—

Between December 1996 and November 1997, 900 patients with AMI were randomized to undergo balloon angioplasty (PTCA, n=448) or coronary stenting (n=452). Detailed resource utilization and cost data were collected for each patient’s initial hospitalization and for 1 year after randomization. Compared with conventional PTCA, stenting increased procedural costs by ≈$2000 per patient ($6538±1778 versus $4561±1598,
P
<0.001). During the 1-year follow-up period, stenting was associated with significant reductions in the need for repeat revascularization and rehospitalization. Although follow-up costs were significantly lower with stenting ($3613±7743 versus $4592±8198,
P
=0.03), overall 1-year costs remained ≈$1000/patient higher with stenting than with PTCA ($20 571±10 693 versus 19 595±10 990,
P
=0.02). The C/E ratio for stenting compared with PTCA was $10 550 per repeat revascularization avoided. In analyses that incorporated recent changes in stent technology and pricing, the 1-year cost differential fell to <$350/patient, and the C/E ratio improved to $3753 per repeat revascularization avoided. The cost-utility ratio for primary stenting was <$50 000 per quality-adjusted life year gained only if stenting did not increase 1-year mortality by >0.2% compared with PTCA.

Conclusions
—

As performed in Stent-PAMI, primary stenting for AMI increased 1-year medical care costs compared with primary PTCA. The overall cost-effectiveness of primary stenting depends on the societal value attributed to avoidance of symptomatic restenosis, as well as on the relative mortality rates of primary PTCA and stenting.
Coronary Endothelial Dysfunction After Heart Transplantation Predicts Allograft Vasculopathy and Cardiac Death
Authors: Hollenberg Steven M. , Klein Lloyd W. , Parrillo Joseph E. , Scherer Markus , Burns Durand , Tamburro Paul , Oberoi Monica , Johnson Maryl R. , Costanzo Maria Rosa
Published: September 2007

Background
—

Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. Using serial studies with intravascular ultrasound and Doppler flow-wire measurements, we have previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. The present study tested whether endothelial dysfunction predicts subsequent clinical events, including cardiac death and CAV development.

Methods and Results
—

Seventy-three patients were studied yearly beginning at transplantation until a prespecified end point was reached. End points were angiographic evidence of CAV (>50% stenosis) or cardiac death (graft failure or sudden death). At each study, coronary endothelial function was measured with intracoronary infusions of adenosine (32-μg bolus), acetylcholine (54 μg over 2 minutes), and nitroglycerin (200 μg) into the left anterior descending coronary artery; intravascular ultrasound images and Doppler velocities were recorded simultaneously. Of the 73 patients studied, 14 reached an end point during the study (6 CAV and 8 deaths, including 4 with known CAV, 1 graft failure, and 3 sudden). On the last study performed, the group with an end point had decreased epicardial (constriction of 11.1±2.9% versus dilation of 1.7±2.2%,
P
=0.01) and microvascular (flow increase of 75±20% versus 149±16%,
P
=0.03) endothelium-dependent responses to acetylcholine compared with the patients who did not reach an end point. Responses to adenosine and nitroglycerin did not differ significantly.

Conclusions
—

Endothelial dysfunction, as detected by abnormal responses to acetylcholine, preceded the development of clinical end points. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function have clinical utility.
NovelSCN5AMutation Leading Either to Isolated Cardiac Conduction Defect or Brugada Syndrome in a Large French Family
Authors: Kyndt Florence , Probst Vincent , Potet Franck , Demolombe Sophie , Chevallier Jean-Christophe , Baro Isabelle , Moisan Jean-Paul , Boisseau Pierre , Schott Jean-Jacques , Escande Denis , Le Marec Hervé
Published: September 2007

Background—TheSCN5Agene encoding the human cardiac sodium channel α subunit plays a key role in cardiac electrophysiology. Mutations inSCN5Alead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease).

Methods and Results—In the present study, we report the identification of a novel singleSCN5Amissense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406RSCN5Amutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutatedSCN5Ashowed no detectable Na+current but normal protein trafficking.

Conclusions—We conclude that the same mutation in theSCN5Agene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of aSCN5Amutation.
Application of C1-Esterase Inhibitor During Reperfusion of Ischemic Myocardium
Authors: Horstick Georg , Berg Oliver , Heimann Axel , Götze Otto , Loos Michael , Hafner Gerd , Bierbach Benjamin , Petersen Steffen , Bhakdi Sucharit , Darius Harald , Horstick Marina , Meyer Jürgen , Kempski Oliver
Published: September 2007

Background—Complement activation during reperfusion of ischemic myocardium augments myocardial injury, and complement inhibition with C1-esterase inhibitor (C1-INH) at the time of reperfusion exerts marked cardioprotective effects in experimental studies. Application of C1-INH in newborns, however, was recently reported to have dangerous and even lethal side effects. This study addresses the essential role of dosage in studies using C1-INH.

Methods and Results—Cardioprotection by C1-INH was examined in a pig model with 60 minutes of coronary occlusion followed by 120 minutes of reperfusion. C1-INH was administered intravenously 5 to 10 minutes before coronary reperfusion without heparin at a dose of 40, 100, and 200 IU/kg body wt. Compared with the NaCl controls, C1-INH 40 IU/kg reduced myocardial injury (44.1±13.8% versus 76.7±4.6% necrosis of area at risk,P≤0.05) and significantly suppressed local C3a and C5a generation. Myocardial protection was accompanied by reduced plasma concentrations of creatine kinase and troponin T. In contrast, no beneficial effects were observed when 100 IU/kg C1-INH was used. Furthermore, application of 200 IU/kg C1-INH provoked severe side effects and coagulation disorders.

Conclusions—When applied at the correct dose, C1-INH significantly protects ischemic tissue from reperfusion damage. However, overly high doses (≥100 IU/kg) of C1-INH will provoke detrimental side effects, probably via its procoagulatory action.
Attenuation of Hypoxic Pulmonary Vasoconstriction by Endotoxemia Requires 5-Lipoxygenase in Mice
Authors: Ichinose Fumito , Zapol Warren M. , Sapirstein Adam , Ullrich Roman , Tager Andrew M. , Coggins Kenneth , Jones Rosemary , Bloch Kenneth D.
Published: September 2007

Abstract
—Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing systemic oxygenation. To assess the role of leukotrienes (LTs) in the attenuation of HPV during endotoxemia, the increase in left lung pulmonary vascular resistance (LPVR) before and during left mainstem bronchus occlusion (LMBO) was measured in mice with and without a deletion of the gene encoding 5-lipoxygenase (5-LO). LMBO increased the LPVR equally in saline-challenged wild-type and 5-LO–deficient mice (96±20% and 94±19%, respectively). Twenty-two hours after challenge with
Escherichia coli
endotoxin, the ability of LMBO to increase LPVR was markedly impaired in wild-type mice (27±7%;
P
<0.05) but not in 5-LO–deficient mice (72±9%) or in wild-type mice pretreated with MK886, an inhibitor of 5-LO activity (76±10%). Compared with wild-type mice, endotoxin-induced disruption of lung structures and inflammatory cell influx in the lung were markedly attenuated in 5-LO–deficient mice. Administration of MK571, a selective cysteinyl LT
1
receptor antagonist, 1 hour before endotoxin challenge preserved HPV and attenuated pulmonary injury in wild-type mice but did not prevent the endotoxin-induced increase in pulmonary myeloperoxidase activity. Taken together, these findings demonstrate that a 5-LO product, most likely a cysteinyl LT, contributes to the attenuation of HPV and to pulmonary injury after challenge with endotoxin.
Hypothesis for the Initiation of Vasomotion
Authors: Peng Hongli , Matchkov Vladimir , Ivarsen Anders , Aalkjær Christian , Nilsson Holger
Published: September 2007

Abstract
—Vasomotion is the regular variation in tone of arteries. In our study, we suggest a model for the initiation of vasomotion. We suggest that intermittent release of Ca
2+
from the sarcoplasmic reticulum (SR, cytosolic oscillator), which is initially unsynchronized between the vascular smooth muscle cells, becomes synchronized to initiate vasomotion. The synchronization is achieved by an ion current over the cell membrane, which is activated by the oscillating Ca
2+
release. This current results in an oscillating membrane potential, which synchronizes the SR in the vessel wall and starts vasomotion. Therefore, the pacemaker of the vascular wall can be envisaged as a diffuse array of individual cytosolic oscillators that become entrained by a reciprocal interaction with the cell membrane. The model is supported by experimental data. Confocal [Ca
2+
]
i
imaging and isometric force development in isolated rat resistance arteries showed that low norepinephrine concentrations induced SR-dependent unsynchronized waves of Ca
2+
in the vascular smooth muscle. In the presence of the endothelium, the waves converted to global synchronized oscillations of [Ca
2+
]
i
after some time, and vasomotion appeared. Synchronization was also seen in the absence of endothelium if 8-bromo-cGMP was added to the bath. Using the patch-clamp technique and microelectrodes, we showed that Ca
2+
release can activate an inward current in isolated smooth muscle cells from the arteries and cause depolarization. These electrophysiological effects of Ca
2+
release were cGMP dependent, which is consistent with the possibility that they are important for the cGMP-dependent synchronization. Further support for the model is the observation that a short-lasting current pulse can initiate vasomotion in an unsynchronized artery as expected from the model.
Ceramide Reduces Endothelium-Dependent Vasodilation by Increasing Superoxide Production in Small Bovine Coronary Arteries
Authors: Zhang David X. , Zou Ai-Ping , Li Pin-Lan
Published: September 2007

Abstract—Ceramide serves as a second messenger in a variety of mammalian cells. Little is known regarding the role of ceramide in the regulation of vascular endothelial function. The present study was designed to determine whether ceramide affects endothelium-dependent vasodilation in coronary arteries and to explore the mechanism of action of ceramide. In isolated and pressurized small bovine coronary arteries, cell-permeable C2-ceramide (10−5mol/L) markedly attenuated vasodilator responses to bradykinin and A23187 (by 40% and 60%, respectively). In the presence ofKG-nitro-l-arginine methyl ester, ceramide produced no further inhibition on the vasodilation induced by these vasodilators. Ceramide had no effect on DETA NONOate–induced vasodilation. By use of a fluorescence NO indicator (4,5-diaminofluorescein diacetate), intracellular NO was measured in the endothelium of freshly isolated small coronary arteries. It was found that ceramide significantly inhibited bradykinin-induced NO increase within endothelial cells. However, it had no effect on the activity of arterial or endothelial NO synthase. Pretreatment of the arteries with sodium dihydroxybenzene disulfonate (Tiron, 10−3mol/L), a cell-permeable superoxide scavenger, or polyethylene glycol superoxide dismutase (100 U/mL) largely restored the inhibitory effects of ceramide on the vasodilation and NO increase induced by bradykinin or A23187. Moreover, ceramide time-dependently increased intracellular superoxide (O2− ·) in the endothelium, as measured by a fluorescent O2− ·indicator, dihydroethidium. These results demonstrate that ceramide inhibits endothelium-dependent vasodilation in small coronary arteries by decreasing NO in vascular endothelial cells and that this decrease in NO is associated with increased O2− ·but not with the inhibition of NO synthase activity within these cells.
Evidence That Rho-Kinase Activity Contributes to Cerebral Vascular Tone In Vivo and Is Enhanced During Chronic Hypertension
Authors: Chrissobolis Sophocles , Sobey Christopher G.
Published: September 2007

Abstract
—The small G protein Rho and its target Rho-kinase may participate in the mechanisms underlying vascular contractile tone via inhibition of myosin light chain phosphatase. The present study has tested the hypothesis that Rho-kinase activity normally contributes to cerebral vascular tone in vivo, and that this effect is augmented during chronic hypertension. Comparative studies also examined the role of protein kinase C (PKC) in regulation of cerebral artery tone. Two Rho-kinase inhibitors, Y-27632 (0.1 to 100 μmol/L) and HA1077 (1 to 10 μmol/L), caused marked concentration-dependent increases in basilar artery diameter of anesthetized normotensive rats (Sprague-Dawley and Wistar-Kyoto [WKY] strains), as measured using a cranial window approach. By comparison, the selective PKC inhibitors calphostin C (0.01 to 0.5 μmol/L) and Ro 31-8220 (5 μmol/L) had little or no effect on basilar artery diameter. Vasodilator responses to Y-27632 were unaffected by PKC inhibition or activation. In two models of chronic hypertension (spontaneously hypertensive rats and WKY rats treated with
N
-nitro-
l
-arginine methyl ester for 4 weeks), Y-27632 elicited cerebral vasodilator responses that were significantly greater than in control WKY rats (
P
<0.05), indicating that the chronically hypertensive state and not genetic factors contributed to the increased responses to Rho-kinase inhibition. PKC inhibition had no significant effect on basilar artery diameter in chronically hypertensive rats. These data suggest that Rho-kinase, but not PKC, activity contributes substantially to cerebral artery tone in vivo, and this effect is augmented in the cerebral circulation during chronic hypertension.
Anti-Inflammatory Mechanisms in the Vascular Wall
Authors: Tedgui Alain , Mallat Ziad
Published: September 2007

Abstract
—The role of vascular cells during inflammation is critical and is of particular importance in inflammatory diseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the IκB/nuclear factor-κB system. Much recent work shows that vascular inflammation can be limited by anti-inflammatory counteregulatory mechanisms that maintain the integrity and homeostasis of the vascular wall. The anti-inflammatory mechanisms in the vascular wall involve anti-inflammatory external signals and intracellular mediators. The anti-inflammatory external signals include the anti-inflammatory cytokines, transforming growth factor-β, interleukin-10 and interleukin-1 receptor antagonist, HDL, as well as some angiogenic and growth factors. Physiological laminar shear stress is of particular importance in protecting endothelial cells against inflammatory activation. Its effects are partly mediated through NO production. Finally, endogenous cytoprotective genes or nuclear receptors, such as the peroxisome proliferator–activated receptors, can be expressed by vascular cells in response to proinflammatory stimuli to limit the inflammatory process and the injury.
Improved Adenoviral Vector for Vascular Gene Therapy
Authors: Qian Hu Sheng , Channon Keith , Neplioueva Valentina , Wang Qing , Finer Mitchell , Tsui Lisa , George Samuel E. , McArthur James
Published: September 2007

Abstract
—First-generation, E1-deleted adenoviral vectors (ΔE1-AV) can transduce the vascular endothelium with high efficiency, but their use is limited by the resulting acute endothelial injury and the long-term development of intimal hyperplasia. To reduce the impact of viral proteins on the gene-modified cells, a second-generation adenoviral vector with an additional pair of deletions in the E4 region was developed. To determine whether this ΔE1/ΔE4-AV vector would be useful for vascular gene transfer, we directly compared the efficiency of gene transfer to uninjured rabbit carotid arteries using either an ΔE1/ΔE4-AV or an ΔE1-AV vector encoding β-galactosidase. Both vectors efficiently transduced vascular endothelium; however, the ΔE1/ΔE4-AV vector gene–modified vessels showed higher β-galactosidase expression 10 days after gene transfer. Importantly, the ΔE1/ΔE4-AV vector produced substantially less endothelial cell activation, less inflammation, and reduced neointimal hyperplasia compared with the ΔE1-AV vector–treated vessels. The ΔE1-AV vector–transduced vessels also demonstrated significantly impaired endothelium-dependent relaxation whereas the ΔE1/ΔE4-AV vector did not impact vasomotor function, even at doses of virus in 5-fold excess of the amount required for >90% transduction of the endothelium. We conclude that the ΔE1/ΔE4-AV vector is superior to the ΔE1-AV vector for vascular gene therapy because of the prolonged transgene expression, reduced vascular inflammation, reduced intimal hyperplasia, and maintenance of normal vasomotor function.
Coexpression of Mutant p53 and p193 Renders Embryonic Stem Cell–Derived Cardiomyocytes Responsive to the Growth-Promoting Activities of Adenoviral E1A
Authors: Pasumarthi Kishore B. S. , Tsai Shih-Chong , Field Loren J.
Published: September 2007

Abstract
—Expression of adenoviral E1A in cardiomyocytes results in the activation of DNA synthesis followed by apoptosis. In contrast, expression of simian virus 40 large T antigen induces sustained cardiomyocyte proliferation. Previous studies have shown that T antigen binds to 2 proapoptotic proteins in cardiomyocytes, namely the p53 tumor suppressor and p193 (a new member of the BH3-only proapoptosis subfamily). Structure-function analyses identified a p193 C-terminal truncation mutant that encodes prosurvival activity. This mutant was used to test the role of p193 in E1A-induced cardiomyocyte apoptosis. E1A induced apoptosis in cardiomyocytes derived from differentiating embryonic stem cells. Expression of the prosurvival p193 mutant alone or a mutant p53 alone did not block E1A-induced apoptosis. In contrast, combinatorial expression of mutant p193 and mutant p53 blocked E1A-induced apoptosis, resulting in a proliferative response indistinguishable from that seen with T antigen. These results confirm the hypothesis that there are 2 proapoptotic pathways, encoded by p53 and p193, respectively, which restrict cardiomyocyte cell cycle activity in differentiating embryonic stem cell cultures. Furthermore, these results explain in molecular terms the phenotypic differences of E1A versus T-antigen gene transfer in cardiomyocytes.
Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1–Deficient Mice
Authors: Wiesel Philippe , Patel Anand P. , Carvajal Irvith M. , Wang Zhi Yuan , Pellacani Andrea , Maemura Koji , DiFonzo Nicole , Rennke Helmut G. , Layne Matthew D. , Yet Shaw-Fang , Lee Mu-En , Perrella Mark A.
Published: September 2007

Abstract
—Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney–one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1
+/+
), heterozygous (HO-1
+/−
), and homozygous null (HO-1
−/−
) mice at baseline. After 1K1C surgery, HO-1
+/+
mice developed hypertension (140±2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0±0.2 mg/g) compared with sham-operated HO-1
+/+
mice (108±5 mm Hg and 4.1±0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164±2 mm Hg) and cardiac hypertrophy (6.9±0.6 mg/g) in HO-1
−/−
mice. HO-1
−/−
mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1
+/+
(25%) and HO-1
+/−
(28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1
−/−
mice compared with HO-1
+/−
mice. Histological analysis of kidneys from 1K1C HO-1
−/−
mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1
−/−
and 1K1C HO-1
+/−
mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.
Phosphorylation of Troponin I by Protein Kinase A Accelerates Relaxation and Crossbridge Cycle Kinetics in Mouse Ventricular Muscle
Authors: Kentish Jonathan C. , McCloskey Diana T. , Layland Joanne , Palmer Sue , Leiden Jeffrey M. , Martin Anne F. , Solaro R. John
Published: September 2007

Abstract
—Phosphorylation of cardiac myofibrils by cAMP-dependent protein kinase (PKA) can increase the intrinsic rate of myofibrillar relaxation, which may contribute to the shortening of the cardiac twitch during β-adrenoceptor stimulation. However, it is not known whether the acceleration of myofibrillar relaxation is due to phosphorylation of troponin I (TnI) or of myosin binding protein-C (MyBP-C). To distinguish between these possibilities, we used transgenic mice that overexpress the nonphosphorylatable, slow skeletal isoform of TnI in the myocardium and do not express the normal, phosphorylatable cardiac TnI. The intrinsic rate of relaxation of myofibrils from wild-type and transgenic mice was measured using flash photolysis of diazo-2 to rapidly decrease the [Ca
2+
] within skinned muscles from the mouse ventricles. Incubation with PKA nearly doubled the intrinsic rate of myofibrillar relaxation in muscles from wild-type mice (relaxation half-time fell from ≈150 to ≈90 ms at 22°C) but had no effect on the relaxation rate of muscles from the transgenic mice. In parallel studies with intact muscles, we assessed crossbridge kinetics indirectly by determining
f
min
(the frequency for minimum dynamic stiffness) during tetanic contractions. Stimulation of β-adrenoceptors with isoproterenol increased
f
min
from 1.9 to 3.1 Hz in muscles from wild-type mice but had no effect on
f
min
in muscles from transgenic mice. We conclude that the acceleration of myofibrillar relaxation rate by PKA is due to phosphorylation of TnI, rather than MyBP-C, and that this may be due, at least in part, to faster crossbridge cycle kinetics.
Clock Genes in the Heart
Authors: Young Martin E. , Razeghi Peter , Taegtmeyer Heinrich
Published: September 2007

Abstract
—We investigated whether the heart, like other mammalian organs, possesses internal clocks, and, if so, whether pressure overload–induced hypertrophy alters the clock mechanism. Clock genes are intrinsically maintained, as shown by rhythmic changes even in single cells. Clocks are believed to confer a selective advantage by priming the cell for the expected environmental stimulus. In this way, clocks allow anticipation, thereby synchronizing responsiveness of the cell with the timing of the stimulus. We have found that in rat heart all mammalian homologues of known
Drosophila
clock genes (
bmal1
,
clock
,
cry1
,
cry2
,
per1
,
per2
,
per3
,
dbp
,
hlf
, and
tef
) show circadian patterns of expression and that the induction of clock output genes (the PAR [rich in proline and acidic amino acid residues] transcription factors
dbp
,
hlf
, and
tef
) is attenuated in the pressure-overloaded hypertrophied heart. The results expose a new dynamic regulatory system in the heart, which is partially lost with hypertrophy. Although the target genes of these PAR transcription factors are not known in the heart, the results provide evidence for a diminished ability of the hypertrophied heart to anticipate and subsequently adapt to physiological alterations during the day.
Sodium-Coupled Glucose Transporter as a Functional Glucose Sensor of Retinal Microvascular Circulation
Authors: Wakisaka Masanori , Kitazono Takanari , Kato Masako , Nakamura Udai , Yoshioka Maki , Uchizono Yuji , Yoshinari Mototaka
Published: September 2007

Abstract
—To clarify the function of the Na
+
-coupled glucose transporter in the regulation of cellular tone of cultured retinal pericytes, we investigated the effects of extracellular glucose concentration on cell size. The surface area and diameter of cultured bovine retinal pericytes under different glucose concentrations were measured by using a light microscope with a digital camera. We also examined the effects of extracellular Na
+
and Ca
2+
, inhibitors of the Na
+
-coupled glucose transporter and Na
+
-Ca
2+
exchanger, a Ca
2+
channel blocker, and nonmetabolizable sugars on cell size. The surface area and diameter of the cells changed according to extracellular glucose concentrations. α-Methyl glucoside, which enters the cell through the Na
+
-coupled glucose transporter, induced cellular contraction. However, the cells did not contract in response to 2-deoxyglucose, which enters the cell through a facilitated glucose transporter. Glucose-induced cellular contraction was abolished in the absence of extracellular Na
+
and Ca
2+
. Moreover, phlorizin, an inhibitor of the Na
+
-coupled glucose transporter, and 2′,4′-dichlorobenzamil-HCl, an inhibitor of the Na
+
-Ca
2+
exchanger, also abolished glucose-induced cellular contraction, whereas nicardipine, a Ca
2+
channel blocker, did not. Our results indicate that high extracellular glucose concentrations induce contraction of bovine retinal pericytes via Na
+
entry through a Na
+
-coupled glucose transporter, suggesting that the Na
+
-coupled glucose transporter may act as a functional glucose sensor of retinal microvascular circulation.>