bluuebunny/crossref_metadata_2025 huggingface dataset:
Nebivolol: A Third-Generation β-Blocker That Augments Vascular Nitric Oxide Release
Authors: Broeders Martijn A. W. , Doevendans Pieter A. , Bekkers Bas C. A. M. , Bronsaer Ronald , van Gorsel Erik , Heemskerk Johan W. M. , Egbrink Mirjam G. A. oude , van Breda Eric , Reneman Robert S. , van der Zee Rien
Published: June 2012

Background
—Nebivolol is a β
1
-selective adrenergic receptor antagonist with proposed nitric oxide (NO)–mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production.

Methods and Results
—Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective β
2
-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of β
2
- but not β
1
-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca
2+
concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment.

Conclusions
—In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial β
2
-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca
2+
]
i
and endothelial NO synthase–dependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.
Effects of Biatrial Pacing in Prevention of Postoperative Atrial Fibrillation After Coronary Artery Bypass Surgery
Authors: Fan Katherine , Lee Kathy L. , Chiu Clement S.W. , Lee Jan W.T. , He Guo-Wei , Cheung David , Sun Man Ping , Lau Chu-Pak
Published: June 2012

Background
—Atrial fibrillation (AF) is common after coronary artery bypass surgery (CABG) and results in prolonged hospitalization. The purpose of this study was to evaluate the efficacy of biatrial pacing in preventing post-CABG AF compared with single-site atrial pacing.

Methods and Results
—A total of 132 patients who had no history of AF and who underwent CABG were randomized to 1 of the following 4 groups: biatrial pacing (BiA), left atrial pacing (LA), right atrial pacing (RA), or no pacing (control) in postoperative period. Overdrive atrial pacing was performed for 5 days. The incidence of AF was significantly reduced in the BiA group (12.5%) compared with the other 3 groups (LA, 36.4%; RA, 33.3%; control, 41.9%;
P
<0.05). The mean length of hospital stay was significantly reduced in the BiA group. At baseline, the mean P-wave duration (P
dur
) and dispersion (P
dis
) were not prolonged. BiA pacing resulted in the most significant percentage of reduction in P
dis
when compared with the LA or RA groups (BiA, 42±8%; LA, 13±6%; RA, 10±9%;
P
<0.05 for BiA versus LA or RA). No significant differences existed in mean P
dur
and P
dis
between patients who developed AF and those who remained in sinus rhythm at baseline. However, only those patients who remained in sinus rhythm had a significant reduction in mean P
dur
and P
dis
after pacing therapy.

Conclusions
—Biatrial overdrive pacing is more effective in preventing post-CABG AF than single-site atrial pacing; this therapy also results in a shortened hospital stay. The overall reduction in atrial activation time with BiA pacing was reflected in the reduction in P
dis
.
Quantitative Ultrasonic Tissue Characterization Can Identify High-Risk Atherosclerotic Alteration in Human Carotid Arteries
Authors: Takiuchi Shin , Rakugi Hiromi , Honda Katsuya , Masuyama Tohru , Hirata Nobuaki , Ito Hiroshi , Sugimoto Ken , Yanagitani Yoshihiro , Moriguchi Koichi , Okamura Atsunori , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Background
—Recently, ultrasonic tissue characterization of the composition of plaques has been performed in a quantitative fashion on the basis of integrated backscatter (IBS) analysis, but most of those studies have used high-frequency ultrasound to obtain microscopic images.

Methods and Results
—We performed B-mode measurement and IBS signal analysis with acoustic densitometry with a 7.5-MHz linear-array transducer in freshly excised human aortas (n=58) (normal, atheromatous, and fibrous tissue) obtained at autopsy. Atheromatous and fibrous tissue had a similar intima-media thickness (IMT), but the IBS value in atheromatous specimens was lower than that in fibrous specimens. We further applied this method to human carotid ultrasonography. The subjects were young (80 regions), middle aged with 1 or no coronary risk factors (low risk) (120 regions), middle aged with ≥2 coronary risk factors (high risk) (240 regions), or elderly (80 regions) or were patients with myocardial infarction (MI) with multivessel disease (90 regions). The IMT was similar in middle-aged, elderly, and MI subjects. In contrast, the IBS value was significantly higher in elderly subjects and lower in high-risk middle-aged and MI subjects compared with that in low-risk middle-aged subjects. The percent of regions diagnosed as atheromatous (IBS less than mean minus 2-SD value of IBS in young subjects) was 11% in low-risk middle-aged subjects, 29% in high-risk middle-aged subjects, and 63% in the MI group.

Conclusions
—In conjunction with conventional B-mode imaging, IBS analysis with carotid ultrasonography appeared to provide prognostic information to identify a high-risk group with systemic atherosclerosis, which could lead to coronary heart disease in individuals with early-stage disease.
Transcatheter Implantation of a Bovine Valve in Pulmonary Position
Authors: Bonhoeffer Philipp , Boudjemline Younes , Saliba Zakhia , Hausse Ana Olga , Aggoun Yacine , Bonnet Damien , Sidi Daniel , Kachaner Jean
Published: June 2012

Background
—Pulmonary regurgitation can lead to severe right ventricular dysfunction, which is a delicate postoperative problem in the long-term follow-up of patients who had surgery for congenital heart diseases. Clinical conditions of patients suffering from pulmonary valve incompetence are improved by valve replacement with a prosthetic valve. To date, the surgical approach is the only option to replace a pulmonary valve. We report the first experience of percutaneous pulmonary valve implantation.

Methods and Results
—A fresh bovine jugular vein containing a native valve was sutured into a vascular stent and then cross-linked with a 0.6% glutaraldehyde solution for 36 hours. After being hand-crimped onto a balloon catheter, the device was inserted percutaneously according to standard stent-placing techniques. The valved stent was finally deployed in the position of the native pulmonary valve of the lamb. Hemodynamic evaluation was carried out before and 2 months after implantation. Anatomic evaluation was finally performed. Percutaneous pulmonary valve replacement was successful in 5 lambs. No complications were noted. Early and late angiographic and hemodynamic studies confirmed a good position of the stents with a competent valve at the end of the protocol. One stent was slightly stenotic, with macroscopically visible calcifications.

Conclusions
—Nonsurgical implantation of pulmonary valves is possible in the lamb. This new technique is similar to standard stent implantation. Thus, it should be feasible in humans, in whom it will lead to a significant reduction of reoperations in patients in need of pulmonary valve replacement.
Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Modulates the Human In Vivo Metabolism of Bradykinin
Authors: Murphey Laine J. , Gainer James V. , Vaughan Douglas E. , Brown Nancy J.
Published: June 2012

Background
—Bradykinin is a cardioprotective peptide metabolized by the angiotensin-converting enzyme (ACE). An insertion/deletion (I/D) polymorphism in the
ACE
gene determines plasma ACE levels. The D allele is associated with cardiovascular disease, which may relate to enhanced angiotensin II production or to increased bradykinin degradation to the inactive metabolite bradykinin 1–5 (BK1–5). Therefore, we determined the effect of the
ACE
I/D polymorphism on human bradykinin metabolism in vivo.

Methods and Results
—Bradykinin (400 ng/min) was infused into the brachial artery of volunteers with
ACE
I/I, I/D, or D/D genotypes (n=9 each). The bradykinin and BK1–5 levels in forearm venous return were quantified by liquid chromatography–mass spectroscopy. Plasma ACE activity was highest in those with the D/D genotype (36.8±6.2 U/mL), intermediate in those with the I/D genotype (25.3±3.3 U/mL), and lowest in those with the I/I genotype (20.3±2.3 U/mL;
P
=0.017 for effect of number of D alleles). Bradykinin concentrations were 726±242, 469±50, and 545±104 fmol/mL in I/I, I/D, and D/D subjects, respectively (
P
>0.10). Significant correlations existed between the number of D alleles and BK1–5 concentrations (1113±290, 1520±318, and 1887±388 fmol/mL in the I/I, I/D, and D/D groups, respectively;
P
=0.027) and the ratio of BK1–5 to bradykinin (1.87±0.35, 3.09±0.40, and 4.31±0.97 in the I/I, I/D, and D/D volunteers, respectively;
P
=0.010). The venous blood BK1–5:bradykinin ratio correlated with plasma ACE activity (
r
2
=0.16,
P
=0.039), and total kinin concentration correlated with net tissue plasminogen activator release across the forearm (
r
2
=0.20,
P
=0.027).

Conclusions
—The
ACE
D allele has a significant effect on the in vivo degradation of bradykinin in humans. The ratio of BK1–5:bradykinin may serve as a marker for tissue ACE activity.
Effect of Cholesterol-Lowering Therapy on Coronary Endothelial Vasomotor Function in Patients With Coronary Artery Disease
Authors: Vita Joseph A. , Yeung Alan C. , Winniford Michael , Hodgson John M. , Treasure Charles B. , Klein J. Larry , Werns Steven , Kern Morton , Plotkin Diane , Shih W. Joseph , Mitchel Yale , Ganz Peter
Published: June 2012

Background
—Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy.

Methods and Results
—In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40±12% from 130±28 mg/dL (
P
<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (−17±13%) and placebo (−24±16%) groups. After treatment, acetylcholine produced less constriction in both groups (−12±19% and −15±14%, respectively,
P
=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42±50%) and placebo (55±71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82±81% in the simvastatin group and 63±53% in the placebo group (
P
=0.16).

Conclusions
—Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.
Sudden Death and Cardiovascular Collapse in Children With Restrictive Cardiomyopathy
Authors: Rivenes Shannon M. , Kearney Debra L. , Smith E. O’Brian , Towbin Jeffrey A. , Denfield Susan W.
Published: June 2012

Background
—Restrictive cardiomyopathy (RCM) is rare in children, and the prognosis is poor. In the present study, we evaluated all pediatric patients with RCM who were at our institution during a 31-year period to determine the clinical outcome and cause of death. Those who sustained sudden, unanticipated cardiac arrests were evaluated for risk factors that are predictive of sudden death.

Methods and Results
—Eighteen consecutive patients were reviewed. Presentation, clinical course, laboratory data, and histopathological evidence of ischemia were compared between patients with and without sudden death events. The results demonstrated that patients who were at risk for sudden death were girls with chest pain, syncope, or both at presentation and without congestive heart failure. Although not statistically significant for sudden death, Holter monitor evidence of ischemia predicted death within months. Histopathological evidence of acute or chronic ischemia was found in the majority of patients, with acute ischemia more common among those who sustained sudden death events.

Conclusions
—All children with RCM are at risk for ischemia-related complications and death, and some are at risk of sudden death. In the present study, patients at risk of sudden death appeared well and had no evidence of ongoing heart failure but often had signs or symptoms of ischemia characterized by chest pain, syncope, or both. ECGs and Holter monitors may be useful screening tools. The use of β-blockade, the placement of an implantable cardioverter-defibrillator, and preferential status 1A or B listing for cardiac transplantation are proposed for pediatric patients with RCM and evidence of ongoing ischemia.
Cognitive Development After the Fontan Operation
Authors: Wernovsky Gil , Stiles Karen M. , Gauvreau Kimberlee , Gentles Thomas L. , duPlessis Adre J. , Bellinger David C. , Walsh Amy Z. , Burnett Janice , Jonas Richard A. , Mayer John E. , Newburger Jane W.
Published: June 2012

Background
—Patients with a single ventricle have multiple risk factors for central nervous system injury, both before and after the Fontan procedure.

Methods and Results
—A geographically selected cohort was invited to undergo standardized testing, including age-appropriate measures of intelligence quotient (IQ) and achievement tests. Historical information was obtained by chart review and patient questionnaires. Of the 222 eligible patients, 133 (59.9%) participated. Median age at testing was 11.1 years (range, 3.7 to 41.0 years), 6.0 years (range, 1.6 to 19.6 years) after surgery. Mean full-scale IQ was 95.7±17.4 (
P
<0.006 versus normal); 10 patients (7.8%) had full-scale IQ scores <70 (
P
=0.001). After adjustment for socioeconomic status, lower IQ was associated with the use of circulatory arrest before the Fontan operation (
P
=0.002), the anatomic diagnoses of hypoplastic left heart syndrome (
P
<0.001) and “other complex” (
P
=0.05), and prior placement of a pulmonary artery band (
P
=0.04). Mean composite achievement score was 91.6±15.4 (
P
<0.001 versus normal); 14 patients (10.8%) scored <70 (
P
<0.001). After adjustment for socioeconomic status, independent risk factors for low achievement scores included the diagnoses of hypoplastic left heart syndrome (
P
=0.004) and “other complex” (
P
=0.003) or prior use of circulatory arrest (
P
=0.03), as well as a reoperation with cardiopulmonary bypass within 30 days of the Fontan (
P
=0.01).

Conclusions
—Most individual patients palliated with the Fontan procedure in the 1970s and 1980s have cognitive outcome and academic function within the normal range, but the performance of the cohort is lower than that of the general population.
VEGF Gene Delivery to Myocardium
Authors: Lee Randall J. , Springer Matthew L. , Blanco-Bose William E. , Shaw Robin , Ursell Philip C. , Blau Helen M.
Published: June 2012

Background
—Vascular endothelial growth factor (VEGF) is being investigated for therapeutic angiogenesis in ischemic myocardium. Primarily, transient delivery systems have been tested. The goal of this study was to investigate the effects of continuous expression of VEGF in myocardium by use of myoblast-mediated delivery.

Methods and Results
—Primary murine myoblasts (5×10
5
cells in 10 μL of PBS with 0.5% BSA) expressing both the murine VEGF gene and the β-galactosidase (β-gal) gene from a retroviral promoter were implanted in the ventricular wall of immunodeficient mice (n=11) via a subdiaphragmatic approach. Control immunodeficient mice (n=12) were injected with the same number of myoblasts expressing only the β-gal gene. Between days 14 and 16, surviving mice were euthanized and the hearts processed for histology. In the experimental group, 11 of 11 mice demonstrated failure to thrive by day 13; 5 deaths occurred between days 8 and 15. There were no complications in the control mice. Histochemistry documented successful implantation of myoblasts (positive β-gal reaction product) in 6 of 6 surviving experimental mice and 12 of 12 controls. Histology disclosed intramural vascular tumors resembling hemangiomas in the VEGF-myoblast–injected myocardium in 6 of 6 surviving mice. β-Gal–expressing cells were present at the site of the vascular tumors. Immunohistochemistry localized abundant endothelial nitric oxide synthase and CD31 (platelet and endothelial cell adhesion molecule) within the lesion, consistent with the presence of endothelial cells.

Conclusions
—In this model, unregulated continuous expression of VEGF is associated with (1) a high rate of failure to thrive/death and (2) formation of endothelial cell–derived intramural vascular tumors in the implantation site. These results underscore the importance of regulating VEGF expression for therapeutic angiogenesis.
Involvement of CD95/Apo1/Fas in Cell Death After Myocardial Ischemia
Authors: Jeremias I. , Kupatt C. , Martin-Villalba A. , Habazettl H. , Schenkel J. , Boekstegers P. , Debatin K. M.
Published: June 2012

Background
—The death of cardiac cells during ischemia and reperfusion is partially mediated by apoptosis, as seen, eg, in autopsy material of patients after acute myocardial infarction.

Methods and Results
—To study the role of CD95/Fas/Apo1 for induction of postischemic cell death, we used an ischemia/reperfusion model of isolated rat and mouse hearts in Langendorff perfusion. In this model, caspase-dependent apoptosis occurred during postischemic reperfusion. Moreover, soluble CD95 ligand/Fas ligand was released by the postischemic hearts early after the onset of reperfusion. In addition, this ligand was synthesized de novo under these circumstances. Similar findings were observed for other “death-inducing” ligands, such as tumor necrosis factor (TNF)-α and TNF-related apoptosis-inducing ligand. In primary adult rat myocyte culture, hypoxia and reoxygenation caused a marked increase in sensitivity to the apoptotic effects of CD95 ligand. Isolated hearts from mice lacking functional CD95 (
lpr
) display marked reduction in cell death after ischemia and reperfusion compared with wild-type controls.

Conclusions
—These data suggest that CD95/Apo1/Fas is directly involved in cell death after myocardial ischemia. The CD95 system might thus represent a novel target for therapeutic prevention of postischemic cell death in the heart.
Elevated C-Reactive Protein Levels and Impaired Endothelial Vasoreactivity in Patients With Coronary Artery Disease
Authors: Fichtlscherer Stephan , Rosenberger Gunter , Walter Dirk H. , Breuer Susanne , Dimmeler Stefanie , Zeiher Andreas M.
Published: June 2012

Background
—Elevated C-reactive protein (CRP) serum levels, an exquisitely sensitive objective marker of inflammation, relate to long-term prognosis in patients with coronary artery disease and in apparently healthy men. Because abnormalities of endothelial regulation of vascular function may contribute to the occurrence of coronary events, we tested the hypothesis that elevated CRP levels are associated with an abnormal systemic endothelial vascular reactivity.

Methods and Results
—Endothelium-dependent (10 to 50 μg/min acetylcholine) and endothelium-independent (2 to 8 μg/min sodium nitroprusside) forearm blood flow responses were measured with venous occlusion plethysmography in 60 male patients with angiographically documented coronary artery disease. Forearm blood flow responses to acetylcholine were inversely correlated with CRP serum levels (
r
=−0.46,
P
=0.001). With multivariate analysis that included the classic risk factors for coronary artery disease, elevated CRP serum level remained a statistically significant independent predictor of a blunted endothelial vasodilator capacity. Most important, normalization of elevated CRP levels over time was associated with a normalization of endothelium-mediated forearm blood flow responses after 3 months.

Conclusions
—Thus, elevated CRP serum levels indicative of a systemic inflammatory response are associated with a blunted systemic endothelial vasodilator function. The identification of elevated CRP levels as a transient independent risk factor for endothelial dysfunction might provide an important clue to link a systemic marker of inflammation to atherosclerotic disease progression.
Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension
Authors: Feinstein Jeffrey A. , Goldhaber Samuel Z. , Lock James E. , Ferndandes Susan M. , Landzberg Michael J.
Published: June 2012

Background
—Although pulmonary thromboendarterectomy is increasingly successful for the definitive treatment of chronic thromboembolic pulmonary hypertension (CTEPH), not all patients have surgically accessible disease. Others are poor surgical candidates because of comorbid illness. Therefore, for selected patients, we defined and implemented an alternative interventional strategy of balloon pulmonary angioplasty (BPA).

Methods and Results
—Eighteen patients (mean age, 51.8 years; range, 14 to 75 years) with CTEPH underwent BPA; they averaged 2.6 procedures (range, 1 to 5) and 6 dilations (range, 1 to 12). Selection of pulmonary artery segments for dilation required (1) complete occlusion, (2) filling defects, or (3) signs of intravascular webs. After an average of 36 months of follow-up (range, 0.5 to 66 months), the average New York Heart Association class improved from 3.3 to 1.8 (
P
<0.001), and 6-minute walking distances increased from 209 to 497 yards (
P
<0.0001). Pulmonary artery mean pressures decreased from 43.0±12.1 to 33.7±10.2 mm Hg (
P
=0.007). Eleven patients developed reperfusion pulmonary edema; 3 required mechanical ventilation.

Conclusions
—BPA reduces pulmonary artery hypertension in patients with CTEPH and is associated with long-term improvement in New York Heart Association class and 6-minute walking distances. BPA is a promising interventional technique that warrants randomized comparison with medical therapy in CTEPH patients who are not surgical candidates.
Local Delivery of Enoxaparin to Decrease Restenosis After Stenting: Results of Initial Multicenter Trial
Authors: Kiesz R. Stefan , Buszman Pawel , Martin Jack L. , Deutsch Ezra , Rozek M. Marius , Gaszewska Ewa , Rewicki Marek , Seweryniak Piotr , Kosmider Maciej , Tendera Michal
Published: June 2012

Background
—Enoxaparin inhibits smooth muscle cell proliferation in experimental models. Intimal hyperplasia has been found to be the principal cause of restenosis after coronary stent implantation. We sought to determine whether the intramural delivery of enoxaparin before stenting of de novo lesions decreases restenosis.

Methods and Results
—One hundred patients who were undergoing stenting were randomly assigned to either local administration of enoxaparin during predilation with reduced systemic heparinization or stenting with standard, systemic heparinization. All patients were treated with the same type of stent (NIR). The primary study end point was late luminal loss. The secondary end points were major adverse cardiac events, target lesion revascularization, and angiographic restenosis at 6 months. Angiographic follow-up at 6 months was completed in all except 1 patient. Late luminal loss was reduced to 0.76±0.42 mm in the local enoxaparin delivery group versus 1.07±0.49 mm in the systemic heparinization group (
P
<0.001). Restenosis, using a binary definition, occurred in 10% of patients in the enoxaparin group and in 24% of patients in the systemic heparinization group (
P
<0.05). Target lesion revascularization rates occurred in 8% of the enoxaparin group and 22% of the systemic heparinization group (
P
<0.05). There were no deaths and no emergent CABGs were performed. The only subacute stent closure and non–Q-wave infarction occurred in a patient assigned to the systemic heparinization group.

Conclusions
—This is the first prospective randomized trial in which the local delivery of a drug, enoxaparin, resulted in significant reduction in late luminal loss and restenosis after stent implantation in de novo coronary lesions.
Regulation of Cardiomyocyte Mechanotransduction by the Cardiac Cycle
Authors: Yamamoto Keiji , Dang Quynh N. , Maeda Yoshikazu , Huang Hayden , Kelly Ralph A. , Lee Richard T.
Published: June 2012

Background
—Overloading the left ventricle in systole (pressure overload) is associated with a distinct morphological response compared with overload in diastole (volume overload).

Methods and Results
—We designed a novel computer-controlled experimental system that interfaces biaxially uniform strain with electrical pacing, so that cellular deformation can be imposed during a specified phase of the cardiac cycle. Cardiomyocytes were exposed to strain (4%) during either the first third (systolic phase) or last third (diastolic phase) of the cardiac cycle. Strain imposed during the systolic phase selectively activated p44/42 mitogen-activated protein kinase (MAPK) and MAPK/extracellular signal–regulated protein kinase kinase (MEK1/2, an activator of p44/42 MAPK) compared with strain imposed during the diastolic phase. In contrast, there was no difference in activation of p38 and c-Jun NH
2
-terminal kinases induced by strain imposed during the systolic phase (5.8- and 3.3-fold versus control, n=4) compared with the diastolic phase (5.5- and 3.1-fold). Induction of both brain natriuretic peptide (5.8-fold versus control,
P
<0.05, n=3) and tenascin-C (7.0-fold,
P
<0.02) mRNA expression by strain imposed during the systolic phase was greater than during the diastolic phase (3.9- and 3.6-fold, respectively). [
3
H]leucine incorporation induced by strain imposed during the systolic phase (4.0-fold versus control) was greater than during the diastolic phase (2.7-fold,
P
<0.02, n=4); a selective inhibitor of MEK1/2 inhibited this difference.

Conclusions
—Mechanical activation of p44/42 MAPK and MEK1/2, gene expression, and protein synthesis is regulated by the cardiac cycle, suggesting that mechanotransduction at the cellular level may underlie differences between pressure and volume overload of the heart.
Increased Wave Break During Ventricular Fibrillation in the Epicardial Border Zone of Hearts With Healed Myocardial Infarction
Authors: Ohara Toshihiko , Ohara Keiko , Cao Ji-Min , Lee Moon-Hyoung , Fishbein Michael C. , Mandel William J. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: June 2012

Background
—The action potential duration (APD) restitution hypothesis of wave break during ventricular fibrillation (VF) in the epicardial border zone (EBZ) of hearts with chronic myocardial infarction is unknown.

Methods and Results
—VF was induced by rapid pacing, and the EBZ with the two adjoining sites (right ventricle and lateral left ventricle) were sequentially mapped in random order in 7 open-chest anesthetized dogs 6 to 8 weeks after left anterior descending artery occlusion and in 4 control dogs. At each site, 3 seconds of VF was mapped with 477 bipolar electrodes 1.6 mm apart. The number of wave fronts and approximate entropy were significantly (
P
<0.01) higher in the EBZ than all other sites in both groups independent of the rate of invasion of new wave fronts and epicardial breakthroughs. The higher wavelet density in the EBZ was caused by increased (
P
<0.01) incidence of spontaneous wave breaks. There was no difference between the two groups in either reentry period (80 episodes) or VF cycle length. Reentry in the EBZ had a smaller core perimeter, slower rotational speed, and a small or no excitable gap (
P
<0.01), often causing termination after one rotation. The dynamic monophasic action potential duration restitution curve in the EBZ had longer (
P
<0.01) diastolic intervals, over which the slope was >1. Connexin43-positive staining was significantly (
P
<0.01) and selectively reduced in the EBZ.

Conclusions
—A selective increase in wave break and alteration of reentry occur in the EBZ during VF in hearts with healed myocardial infarction. Increased wave break in the EBZ is compatible with the action potential duration restitution hypothesis.
Recombinant Hirudin in Clinical Practice
Authors: Greinacher Andreas , Lubenow Norbert
Published: June 2012

Abstract
—Clinical applications for recombinant hirudins have been investigated for the past 10 years. The first indication for which a hirudin—lepirudin—has been approved is treatment of heparin-induced thrombocytopenia (HIT). Also, the recently completed trials for use of lepirudin in unstable angina indicate a potentially new indication. This review describes pharmacology and clinical applications of lepirudin with an emphasis on HIT and unstable angina. An overview of usage of lepirudin in acute coronary syndromes is given, as well as a summary of rare indications for lepirudin, such as extracorporeal circulation, for which comprehensive data are lacking.
Acetylcholine Release in Human Heart Atrium
Authors: Oberhauser Vitus , Schwertfeger Eckhard , Rutz Tobias , Beyersdorf Friedhelm , Rump Lars Christian
Published: June 2012

Background
—An imbalance of sympathetic and parasympathetic drive to the heart is an important risk factor for cardiac death in patients with coronary heart disease, diabetes, and renal insufficiency. The amount of neurotransmitter released from peripheral autonomic nerves is modulated by presynaptic receptor systems. In analogy to α-autoreceptors on sympathetic nerves, muscarinic autoreceptors activated by endogenous acetylcholine may exist on parasympathetic nerves in the human heart.

Methods and Results
—We developed a technique to study acetylcholine release from human atria and investigated muscarinic autoreceptor function. A pharmacological and molecular approach was used to characterize the subtype involved. Of the 5 muscarinic receptor subtypes cloned, only mRNA encoding for M
2
- and M
3
-receptors were detected. Potencies of several muscarinic antagonists against the release-inhibiting effect of the nonselective muscarinic agonist carbachol at the cardiac autoreceptor were correlated with published data for human cloned M
1
- through M
5
-receptors.

Conclusions
—This analysis clearly indicates that acetylcholine release in human atria is controlled by muscarinic M
2
-receptors. Blockade of these receptors by atropine doubles the amount of acetylcholine released at a stimulation frequency of 5 Hz. In atria of patients >70 years of age and patients with late diabetic complications, acetylcholine release is reduced. Locally impaired cardiac acetylcholine release may therefore represent a pathophysiological link to sudden cardiac death in elderly and diabetic patients.
H
mox-1
Constitutes an Adaptive Response to Effect Antioxidant Cardioprotection
Authors: Yoshida Tetsuya , Maulik Nilanjana , Ho Ye-Shih , Alam Jawed , Das Dipak K.
Published: June 2012

Background
—Heme oxygenase-1 (H
mox-1
) has been implicated in protection of cells against ischemia/reperfusion injury.

Methods and Results
—To examine the physiological role of H
mox-1
, a line of heterozygous H
mox-1
-knockout mice was developed by targeted disruption of the mouse H
mox-1
gene. Transgene integration was confirmed and characterized at the protein level. A 40% reduction of H
mox-1
protein occurred in the hearts of H
mox-1
+/
−
mice compared with those of wild-type mice. Isolated mouse hearts from H
mox-1
+/
−
mice and wild-type controls perfused via the Langendorff mode were subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. The H
mox-1
+/
−
hearts displayed reduced ventricular recovery, increased creatine kinase release, and increased infarct size compared with those of wild-type controls, indicating that these H
mox-1
+/
−
hearts were more susceptible to ischemia/reperfusion injury than wild-type controls. These results also suggest that H
mox-1
+/
−
hearts are subjected to increased amounts of oxidative stress. Treatment with 2 different antioxidants, Trolox or
N
-acetylcysteine, only partially rescued the H
mox-1
+/
−
hearts from ischemia/reperfusion injury. Preconditioning, which renders the heart tolerant to subsequent lethal ischemia/reperfusion, failed to adapt the hearts of the H
mox-1
+/
−
mice compared with wild-type hearts.

Conclusions
—These results demonstrate that H
mox-1
plays a crucial role in ischemia/reperfusion injury not only by functioning as an intracellular antioxidant but also by inducing its own expression under stressful conditions such as preconditioning.
Low-Dose Metoprolol CR/XL and Fluvastatin Slow Progression of Carotid Intima-Media Thickness
Authors: Hedblad B. , Wikstrand J. , Janzon L. , Wedel H. , Berglund G.
Published: June 2012

Background
—Statins reduce cardiovascular events and progression of carotid intima-media thickness (IMT). β-Blockers are also known to reduce cardiovascular events, but less is known about their effects on carotid IMT.

Methods and Results
—We conducted a randomized, double-blind, placebo-controlled, single-center trial to compare the effects of low-dose metoprolol CR/XL (25 mg once daily) and fluvastatin (40 mg once daily) on the progression of carotid IMT during 36 months of treatment in 793 subjects who had carotid plaque but no symptoms of carotid artery disease. Changes in mean IMT in the common carotid artery and maximal IMT in the bulb were the main outcome variables. Death and cardiovascular events were monitored. Progression of IMT
max
in the carotid bulb at both 18 and 36 months was reduced by metoprolol CR/XL (−0.058 mm/y; 95% CI, −0.094 to −0.023;
P
=0.004; and −0.023 mm/y; 95% CI, −0.044 to −0.003;
P
=0.014, respectively). Incidence of cardiovascular events tended to be lower in metoprolol CR/XL–treated patients (5 versus 13 patients,
P
=0.055). Rate of IMT
mean
progression in the common carotid at 36 months was reduced by fluvastatin (−0.009 mm/y; 95% CI, −0.015 to −0.003;
P
=0.002). Women in the fluvastatin group had increased frequency of transiently high liver enzymes.

Conclusions
—This is the first randomized trial to show that a β-blocker can reduce the rate of progression of carotid IMT in clinically healthy, symptom-free subjects with carotid plaque. This suggests that β-blockers may have a favorable effect on atherosclerosis development.
Effect of Non–Insulin-Dependent Diabetes Mellitus on Myocardial Insulin Responsiveness in Patients With Ischemic Heart Disease
Authors: Jagasia Dinesh , Whiting Jennifer M. , Concato John , Pfau Steven , McNulty Patrick H.
Published: June 2012

Background
—Patients with non–insulin-dependent diabetes mellitus (NIDDM) exhibit poor clinical outcomes from myocardial ischemia. This may reflect an impairment in their cardiac insulin-response system.

Methods and Results
—We used AV balance and intracoronary infusion techniques to compare the intrinsic cardiac responsiveness to insulin in 26 coronary disease patients with (n=13) and without (n=13) NIDDM. During fasting, NIDDM hearts demonstrated lower fractional extraction of glucose from arterial plasma than controls (1.0±0.5% versus 2.1±0.5%,
P
<0.05) despite higher circulating insulin levels (26±5 versus 13±4 μU · mL,
P
<0.05). This was compensated for by higher circulating glucose levels, so that net cardiac glucose uptake in the 2 groups was equivalent (5.2±1.1 versus 5.3±1.1 μmol · min). Intracoronary insulin infusion produced an ≈3-fold increase in fractional extraction and net uptake of glucose across the heart in both groups (to 3.7±0.4% and 18.3±3.5 μmol · min in NIDDM and to 5.4±0.7% and 17.7±4.3 μmol · min in controls) accompanied by an ≈30% increase in net lactate uptake, suggesting preserved insulin action on both glucose uptake and glucose oxidation in the NIDDM heart. In nondiabetics, insulin consistently increased coronary blood flow, but this effect was absent in NIDDM.

Conclusions
—In contrast to their peripheral tissues and coronary vasculature, the myocardium of patients with NIDDM expresses a competent insulin-response system with respect to glucose metabolism. This suggests that insulin resistance is mediated at the level of individual organs and that different mechanisms are involved in muscle and vascular tissue.
Relationship Between Neointimal Thickness and Shear Stress After Wallstent Implantation in Human Coronary Arteries
Authors: Wentzel Jolanda J. , Krams Rob , Schuurbiers Johan C. H. , Oomen Jan A. , Kloet Jeroen , van der Giessen Willem J. , Serruys Patrick W. , Slager Cornelis J.
Published: June 2012

Background
—In-stent restenosis by excessive intimal hyperplasia reduces the long-term clinical efficacy of coronary stents. Because shear stress (SS) is related to plaque growth in atherosclerosis, we investigated whether variations in SS distribution are related to variations in neointima formation.

Methods and Results
—In 14 patients, at 6-month follow-up after coronary Wallstent implantation, 3D stent and vessel reconstruction was performed with a combined angiographic and intravascular ultrasound technique (ANGUS). The bare stent reconstruction was used to calculate in-stent SS at implantation, applying computational fluid dynamics. The flow was selected to deliver an average SS of 1.5 N/m
2
. SS and neointimal thickness (Th) values were obtained with a resolution of 90° in the circumferential and 2.5 mm in the longitudinal direction. For each vessel, the relationship between Th and SS was obtained by linear regression analysis. Averaging the individual slopes and intercepts of the regression lines summarized the overall relationship. Average Th was 0.44±0.20 mm. Th was inversely related to SS: Th=(0.59±0.24)−(0.08±0.10)×SS (mm) (
P
<0.05).

Conclusions
—These data show for the first time in vivo that the Th variations in Wallstents at 6-month follow-up are inversely related to the relative SS distribution. These findings support a hemodynamic mechanism underlying in-stent neointimal hyperplasia formation.
Argatroban Anticoagulant Therapy in Patients With Heparin-Induced Thrombocytopenia
Authors: Lewis B. E. , Wallis D. E. , Berkowitz S. D. , Matthai W. H. , Fareed J. , Walenga J. M. , Bartholomew J. , Sham R. , Lerner R. G. , Zeigler Z. R. , Rustagi P. K. , Jang I. K. , Rifkin S. D. , Moran J. , Hursting M. J. , Kelton J. G.
Published: June 2012

Background
—Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome caused by heparin. Complications range from thrombocytopenia to thrombocytopenia with thrombosis. We report a prospective, historical- controlled study evaluating the efficacy and safety of argatroban, a direct thrombin inhibitor, as anticoagulant therapy in patients with HIT or HIT with thrombosis syndrome (HITTS).

Methods and Results
—Patients with HIT (isolated thrombocytopenia, n=160) or HITTS (n=144) received 2 μg · kg
−1
· min
−1
IV argatroban, adjusted to maintain the activated partial thromboplastin time 1.5 to 3.0 times baseline value. Treatment was maintained for 6 days, on average. Clinical outcomes over 37 days were compared with those of 193 historical control subjects with HIT (n=147) or HITTS (n=46). The incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or new thrombosis, was reduced significantly in argatroban-treated patients versus control subjects with HIT (25.6% versus 38.8%,
P
=0.014). In HITTS, the composite incidence in argatroban-treated patients was 43.8% versus 56.5% in control subjects (
P
=0.13). Significant between-group differences by time-to-event analysis of the composite end point favored argatroban treatment in HIT (
P
=0.010) and HITTS (
P
=0.014). Argatroban therapy, relative to control subjects, also significantly reduced new thrombosis and death caused by thrombosis (
P
<0.05). Argatroban-treated patients achieved therapeutic activated partial thromboplastin times generally within 4 to 5 hours of starting therapy and, compared with control subjects, had a significantly more rapid rise in platelet counts (
P
=0.0001). Bleeding events were similar between groups.

Conclusions
—Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.
Myocardial Blood Flow and Flow Reserve After Coronary Reimplantation in Patients After Arterial Switch and Ross Operation
Authors: Hauser Michael , Bengel Frank M. , Kühn Andreas , Sauer Ursula , Zylla Solvig , Braun Siegmund L. , Nekolla Stephan G. , Oberhoffer Renate , Lange Rüdiger , Schwaiger Markus , Hess John
Published: June 2012

Background
—Coronary reimplantation is used in therapy for congenital heart disease, such as in the arterial switch (ASO) and Ross operations. The adequacy of myocardial perfusion may remain a matter of concern. The aim of the present study was to stratify the effect of coronary reimplantation on myocardial perfusion and to highlight the clinical relevance of any attenuation in myocardial perfusion.

Methods and Results
—A total of 21 children with transposition of the great arteries at a mean interval of 11.2±2.9 years after ASO and 9 adolescents at a mean interval of 4.2±2.1 years after the Ross procedure were investigated. All patients were asymptomatic and had a normal exercise capacity. On stress echocardiography, 2 of the ASO patients had dyskinetic areas within the left ventricular myocardium, and 5 had adenosine-induced perfusion defects on positron emission tomography. No coronary obstruction was detected on coronary angiography in any patient, but a common finding was right coronary dominance and a small caliber of the distal part of the left anterior descending artery. Coronary flow reserve (CFR) was significantly reduced in all patients after ASO when compared with 10 normal healthy volunteers (age, 25.6±5.3 years). CFR was normal in the 9 patients who had the Ross operation (age, 19.2±7.6 years); exercise-induced perfusion defects were not detected in the Ross patients.

Conclusions
—Children after ASO are asymptomatic, without clinical signs of coronary dysfunction. In contrast to patients who had the Ross operation, stress-induced perfusion defects and an attenuated CFR were documented. The prognostic implications of these findings and the clinical consequences are unclear; nevertheless, close clinical follow-up of ASO patients is mandatory.
Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking
Authors: Newby David E. , McLeod Andrew L. , Uren Neal G. , Flint Laura , Ludlam Christopher A. , Webb David J. , Fox Keith A. A. , Boon Nicholas A.
Published: June 2012

Background
—The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart.

Methods and Results
—After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 μg/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5±0.8 mm
3
/mm vessel (range 0.6 to 13.7 mm
3
/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (
P
<0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (
P
<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (
r
=−0.61,
P
=0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31±23 IU/min; ex-smokers, 50±33 IU/min; nonsmokers 202±73 IU/min;
P
<0.05).

Conclusions
—We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.
Fluvastatin Lowers Atherogenic Dense Low-Density Lipoproteins in Postmenopausal Women With the Atherogenic Lipoprotein Phenotype
Authors: März Winfried , Scharnagl Hubert , Abletshauser Claudia , Hoffmann Michael M. , Berg Aloys , Keul Joseph , Wieland Heinrich , Baumstark Manfred W.
Published: June 2012

Background
—Although HMG-CoA reductase inhibitors (HMGRIs) are effective lipid-lowering agents, it remains controversial whether these agents also lower dense LDL (dLDL), a predominance of which is considered to contribute to the atherogenicity of the metabolic syndrome.

Methods and Results
—In a multicenter, double-blind, randomized, placebo-controlled study, we determined the effect of the HMGRI fluvastatin on lipids, apolipoproteins, and LDL subfractions (by equilibrium density gradient ultracentrifugation). A total of 52 postmenopausal women with combined hyperlipidemia and increased dLDL were treated with either fluvastatin 40 mg/d (n=35) or placebo (n=17). After 12 weeks’ treatment, significant reductions (
P
<0.001) in total cholesterol (−19%), IDL cholesterol (−35%), LDL cholesterol (−23%), apolipoprotein B (−21%), and apolipoprotein B in dLDL (−42%) were apparent among fluvastatin recipients. No significant changes in triglycerides or HDL cholesterol were observed. The effect of fluvastatin on dLDL was correlated with baseline values. There was no consistent relationship, however, between the effect of fluvastatin on triglycerides and the decrease in dLDL.

Conclusions
—Fluvastatin lowers total and LDL cholesterol and the concentration of dLDL. This profile may contribute to an antiatherogenic effect for fluvastatin that is greater than expected on the basis of changes in lipids and apolipoproteins.
Prognostic Value of Radionuclide Angiography in Patients With Right Ventricular Arrhythmias
Authors: Le Guludec Dominique , Gauthier Hélène , Porcher Raphael , Frank Robert , Daou Doumit , Benelhadj Salah , Leenhardt Antoine , Lavergne Thomas , Faraggi Marc , Slama Michel S.
Published: June 2012

Background
—The prognosis of patients with right ventricular (RV) arrhythmias remains uncertain. This study prospectively evaluated the prognostic value of RV and left ventricular (LV) involvement assessed by radionuclide angiography (RNA) as predictors for sudden death.

Methods and Results
—Patients (n=188) with severe arrhythmias originating from the RV were followed up for a mean of 45±34 months. Data on clinical presentation, resting and stress ECG, signal-averaged ECG, 24-hour Holter monitoring, and programmed stimulation were collected along with RNA. Patients were classified as group I (n=82) with normal RNA or group II (n=106) with an abnormal RV suggestive of arrhythmogenic RV cardiomyopathy, classified as diffuse or localized disease, with or without associated LV abnormalities. During follow-up, 14 patients died suddenly, all in group II. None of the clinical and electrical data were predictive of death. An abnormal RNA study was a highly predictive factor for death (
P
<0.005), as well as the presence of LV abnormalities (
P
<0.01).

Conclusions
—The present study confirms that arrhythmogenic RV cardiomyopathy is a severe disease with a high risk for cardiac death. Evidence of RV abnormalities in patients presenting with RV arrhythmias is highly predictive for sudden death, as is its association with LV involvement.