bluuebunny/crossref_metadata_2025 huggingface dataset:
Troglitazone Improves Recovery of Left Ventricular Function After Regional Ischemia in Pigs
Authors: Zhu Peili , Lu Li , Xu Ya , Schwartz Gregory G.
Published: June 2012

Background
—This study determined whether treatment of normal (nondiabetic) pigs with the insulin-sensitizing agent troglitazone improves recovery of left ventricular (LV) function after acute ischemia and whether such effects are associated with altered myocardial substrate metabolism.

Methods and Results
—Juvenile pigs (n=6) were treated with troglitazone (75 mg · kg
−1
· d
−1
PO) for 8 weeks. Untreated pigs (n=8) served as controls. Under anesthetized, open-chest conditions, pigs underwent 90 minutes of moderate regional LV ischemia and 90 minutes of reperfusion. Regional LV function was assessed with subendocardial sonomicrometry crystals. Fasting plasma insulin and free fatty acid levels were lower in troglitazone-treated pigs than in untreated pigs, whereas blood glucose did not differ between groups. These findings suggest that treatment enhanced systemic insulin sensitivity. Baseline hemodynamics and regional LV function did not differ between groups. After ischemia and reperfusion, systolic function (external work) of the ischemic region recovered to 44±6% of baseline in troglitazone-treated pigs versus 18±6% of baseline in untreated pigs (
P
<0.05). Regional diastolic function (maximum rate of wall expansion) recovered to 78±7% of baseline in treated pigs versus 52±7% of baseline in untreated pigs (
P
<0.05). Recovery of global LV systolic and diastolic function was also significantly greater in treated pigs. Myocardial glucose uptake did not differ between groups under any condition; however, net myocardial lactate uptake after reperfusion was 7 times greater in troglitazone-treated pigs than in untreated pigs, suggesting that treatment enhanced myocardial carbohydrate oxidation after reperfusion.

Conclusions
—In nondiabetic pigs, chronic troglitazone treatment improves recovery of LV systolic and diastolic function after acute ischemia.
Cellular Arrhythmogenic Effects of Congenital and Acquired Long-QT Syndrome in the Heterogeneous Myocardium
Authors: Viswanathan Prakash C. , Rudy Yoram
Published: June 2012

Background
—Certain alterations by mutations or drugs of the potassium currents
I
Ks
and
I
Kr
and the sodium current
I
Na
give rise to several types of the long-QT syndrome.
I
Ks
is heterogeneously distributed across the ventricular wall.

Methods and Results
—We investigated the effects of reducing
I
Ks
or
I
Kr
or enhancing late
I
Na
(to simulate the 3 forms of long-QT syndrome) on action potential duration (APD) in the context of
I
Ks
heterogeneity. We introduced
I
Ks
heterogeneity in the Luo-Rudy dynamic cell model to simulate epicardial, endocardial, and midmyocardial (M) cells. Results demonstrated higher susceptibility of M cells to the development of arrhythmogenic early afterdepolarizations (EADs) in isolated cells and poorly coupled tissue. An important observation is that
I
Kr
block or late
I
Na
acts to increase APD differences between the cell types, whereas
I
Ks
block minimizes such differences. Also, for normal transverse coupling, EADs develop in the endocardial region rather than in the M region as the result of strong electrotonic interaction.

Conclusions
—
I
Ks
heterogeneity and intercellular coupling strongly influence EAD development during interventions or disorders that prolong APD. M cells in isolation or in poorly coupled tissue are more susceptible to EAD development than epicardial or endocardial cells. In well-coupled myocardium, EAD formation in the subendocardium can be the source of focal arrhythmias or provide the trigger for reentrant excitation. The efficacy of
I
Ks
block in minimizing APD dispersion could have important implications for antiarrhythmic therapy.
Vascular Effects Following Homozygous Disruption of p47
phox
Authors: Hsich Eileen , Segal Brahm H. , Pagano Patrick J. , Rey Federico E. , Paigen Beverly , Deleonardis John , Hoyt Robert F. , Holland Steven M. , Finkel Toren
Published: June 2012

Background
—Evidence suggests that the vessel wall contains an oxidase similar, if not identical, to phagocytic NADPH oxidase. We tested the contribution of this specific oxidase to the progression of atherosclerosis and the regulation of blood pressure.

Methods and Results
—An examination of aortic rings from wild-type mice and mice with homozygous targeted disruptions in p47
phox
revealed that p47
phox
knockout mice had a reduction in vascular superoxide production. However, analyses of apoE −/− p47
phox
+/+ and apoE −/− p47
phox
−/− strains of mice demonstrated no significant differences in atherosclerotic lesion sizes. Similarly, analyses of wild-type and p47
phox
knockout mice revealed no differences in either basal blood pressure or the rise in blood pressure seen after the pharmacological inhibition of nitric oxide synthase.

Conclusions
—NADPH oxidase contributes to basal vascular superoxide production. However, the absence of a functional oxidase does not significantly affect the progression of atherosclerosis in the standard mouse apoE −/− model, nor does it significantly influence basal blood pressure.
Effect of Native and Oxidized Low-Density Lipoprotein on Endothelial Nitric Oxide and Superoxide Production
Authors: Vergnani Luciana , Hatrik Stefan , Ricci Franco , Passaro Angelina , Manzoli Nadia , Zuliani Giovanni , Brovkovych Viktor , Fellin Renato , Malinski Tadeusz
Published: June 2012

Background
—Native and oxidized LDLs (n-LDL and ox-LDL) are involved in the atherogenic process and affect endothelium-dependent vascular tone through their interaction with nitric oxide (NO).

Methods and Results
—In this study we evaluated directly, by using a porphyrinic microsensor, the effect of increasing lipoprotein concentrations on endothelial NO and superoxide (O
2
−
) production. We investigated where lipoproteins may affect the
l
-arginine–NO pathway by pretreating cells with
l
-arginine,
l
-
N
-arginine methyl ester (L-NAME), and superoxide dismutase. Bovine aortic endothelial cells were exposed for 1 hour to increasing concentrations of n-LDL (from 0 to 240 mg cholesterol/dL) and ox-LDL (from 0 to 140 mg cholesterol/dL). A stimulated (calcium ionophore) NO concentration decreased to 29% of the control at n-LDL concentration of 80 mg cholesterol/dL and to 15% of the control at 20 mg cholesterol/dL of ox-LDL.
l
-Arginine partially neutralized the inhibitory effect of n-LDL and ox-LDL on the NO generation. Superoxide dismutase pretreatment did not modify NO production, whereas L-NAME blunted NO generation at all LDL concentrations. O
2
−
production was increased at low n-LDL and very low ox-LDL concentrations; this was reversed by
l
-arginine.

Conclusions
—These findings confirm the inhibitory role of n-LDL and ox-LDL on NO generation and suggest that lipoproteins may induce a decreased uptake of
l
-arginine. The local depletion of the
l
-arginine substrate may derange the NO synthase, leading to overproduction of O
2
−
from oxygen, the other substrate of NO synthase.
Expression and Function of PPARγ in Rat and Human Vascular Smooth Muscle Cells
Authors: Law Ronald E. , Goetze Stephan , Xi Xiao-Ping , Jackson Simon , Kawano Yasuko , Demer Linda , Fishbein Michael C. , Meehan Woerner P. , Hsueh Willa A.
Published: June 2012

Background
—Peroxisome proliferator–activated receptor-γ (PPARγ) is activated by fatty acids, eicosanoids, and insulin-sensitizing thiazolidinediones (TZDs). The TZD troglitazone (TRO) inhibits vascular smooth muscle cell (VSMC) proliferation and migration in vitro and in postinjury intimal hyperplasia.

Methods and Results
—Rat and human VSMCs express mRNA and nuclear receptors for PPARγ1. Three PPARγ ligands, the TZDs TRO and rosiglitazone and the prostanoid 15-deoxy-Δ
12,14
-prostaglandin J2 (15d-PGJ2), all inhibited VSMC proliferation and migration. PPARγ is upregulated in rat neointima at 7 days and 14 days after balloon injury and is also present in early human atheroma and precursor lesions.

Conclusions
—Pharmacological activation of PPARγ expressed in VSMCs inhibits their proliferation and migration, potentially limiting restenosis and atherosclerosis. These receptors are upregulated during vascular injury.
Coronary Physiology Revisited
Authors: Kern Morton J.
Published: June 2012

Abstract
—Various coronary physiological measurements can be made in the cardiac catheterization laboratory using sensor-tipped guidewires; they include the measurement of poststenotic absolute coronary flow reserve, the relative coronary flow reserve, and the pressure-derived fractional flow reserve of the myocardium. Ambiguity regarding abnormal microcirculation has been reduced or eliminated with measurements of relative coronary flow reserve and fractional flow reserve. The role of microvascular flow impairment can be separately determined with coronary flow velocity reserve measurements. In addition to lesion assessment before and after intervention, emerging applications of coronary physiology include the determination of physiological responses to new pharmacological agents, such as glycoprotein IIb/IIIa blockers, in patients with acute myocardial infarction. Measurements of coronary physiology in the catheterization laboratory provide objective data that complement angiography for clinical decision-making.
L-NMMA (a Nitric Oxide Synthase Inhibitor) is Effective in the Treatment of Cardiogenic Shock
Authors: Cotter Gad , Kaluski Edo , Blatt Alex , Milovanov Olga , Moshkovitz Yaron , Zaidenstein Ronit , Salah Ahmed , Alon Daniela , Michovitz Yoav , Metzger Michael , Vered Zvi , Golik Ahuva
Published: June 2012

Background
—The objective was to assess the safety and efficacy of L-NMMA in the treatment of cardiogenic shock.

Methods
—We enrolled 11 consecutive patients with cardiogenic shock that persisted after >24 hours from admission, despite coronary catheterization and primary percutaneous transluminal coronary revascularization, when feasible, and treatment with mechanical ventilation, intraaortic balloon pump (IABP), and high doses of catecholamines. L-NMMA was administered as an IV bolus of 1 mg/kg and continuous drip of 1 mg · kg
−1
· h
−1
for 5 hours. Treatment with catecholamines, mechanical ventilation, and IABP was kept constant throughout the study.

Results
—Within 10 minutes of L-NMMA administration, mean arterial blood pressure (MAP) increased from 76±9 to 109±22 mm Hg (+43%). Urine output increased within 5 hours from 63±25 to 156±63 cc/h (+148%). Cardiac index decreased during the steep increase in MAP from 2.0±0.5 to 1.7±0.4 L/(min · m
2
) (−15%); however, it gradually increased to 1.85±0.4 L/(min · m
2
) after 5 hours. The heart rate and the wedge pressure remained stable. Twenty-four hours after L-NMMA discontinuation, MAP (+36%) and urine output (+189%) remained increased; however, cardiac index returned to pretreatment level. No adverse events were detected. Ten out of eleven patients could be weaned off mechanical ventilation and IABP. Eight patients were discharged from the coronary intensive care unit, and seven (64%) were alive at 1-month follow-up.

Conclusions
—L-NMMA administration in patients with cardiogenic shock is safe and has favorable clinical and hemodynamic effects.
Electrophysiological End Point for Catheter Ablation of Atrial Fibrillation Initiated From Multiple Pulmonary Venous Foci
Authors: Haïssaguerre Michel , Jaïs Pierre , Shah Dipen C. , Garrigue Stéphane , Takahashi Atsushi , Lavergne Thomas , Hocini Mélèze , Peng Jing Tian , Roudaut Raymond , Clémenty Jacques
Published: June 2012

Background
—The end point for catheter ablation of pulmonary vein (PV) foci initiating atrial fibrillation (AF) has not been determined.

Methods and Results
—Ninety patients underwent mapping during spontaneous or induced ectopy and/or AF initiation. Ostial PV ablation was performed by use of angiograms to precisely define targeted sites. Success defined by elimination of AF without drugs was correlated with the procedural end point of the abolition of distal PV potentials. A total of 197 arrhythmogenic PV foci (97%)—single in 31% and multiple in 69%—and 6 atrial foci were identified. A discrete radiofrequency (RF) application eliminated the PV potentials in 9 PV foci, whereas 2 foci from the same PV required RF applications at separate sites in 19 cases. In others, a wider region was targeted with progressive elimination of ectopy. In 49 patients, multiple sessions were necessary owing to recurrent or new ectopy. The clinical success rates were 93%, 73%, and 55% in patients with 1, 2, and ≥3 arrhythmogenic PV foci. Recovery of local PV potential and the inability to abolish it were significantly associated with AF recurrences (90% success rate with versus 55% without PV potential abolition). PV stenosis was noted acutely in 5 of 6 cases, remained unchanged at restudy, and was associated with RF power >45 W.

Conclusions
—Multiple PV foci are involved in initiation of AF, and elimination of PV muscle conduction is associated with clinical success.
Regulation of PKA Binding to AKAPs in the Heart
Authors: Zakhary Daniel R. , Moravec Christine S. , Bond Meredith
Published: June 2012

Background
—cAMP-dependent protein kinase (PKA) regulates a broad range of cellular responses in the cardiac myocyte. Downstream regulation of the PKA pathway is mediated by a class of scaffolding proteins called A-kinase anchoring proteins (AKAPs), which sequester PKA to specific subcellular locations through binding to its regulatory subunit (R). However, the effect of RII autophosphorylation on AKAP binding and the degree of RII autophosphorylation in failing and nonfailing human hearts remains unknown.

Methods and Results
—We investigated AKAP-RII binding by overlay analysis and surface plasmon resonance spectroscopy and measured RII autophosphorylation in human hearts by backphosphorylation. Binding of Ht31 peptide (representing the RII-binding region of AKAPs) to cardiac RII was increased ≈145% (
P
<0.01) for autophosphorylated RII relative to unphosphorylated control. By surface plasmon resonance, RII autophosphorylation significantly increased binding affinity to Ht31 by ≈200% (
P
<0.01). Baseline PKA-dependent phosphorylation of RII was significantly decreased ≈30% (
P
<0.05) in human hearts with dilated cardiomyopathy compared with nonfailing controls.

Conclusions
—These results suggest that AKAP binding of PKA in the heart is regulated by RII autophosphorylation. Therefore AKAP targeting of PKA may be reduced in patients with end-stage heart failure. This mechanism may be responsible for the decreased cAMP-dependent phosphorylation of proteins in dilated cardiomyopathy that we and others have previously observed.
Cholesterol and Arterial Distensibility in the First Decade of Life
Authors: Leeson C. P. M. , Whincup P. H. , Cook D. G. , Mullen M. J. , Donald A. E. , Seymour C. A. , Deanfield J. E.
Published: June 2012

Background
—Blood cholesterol levels are a key determinant of coronary heart disease risk in adults, but the importance of lipid levels in the general population during childhood is less clear. We related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9 to 11 years.

Methods and Results
—A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. This measure was related to their pulse pressure to assess arterial distensibility. All the children had previously had a comprehensive assessment of cardiovascular risk including a full lipid profile, cotinine-assessed smoke exposure, serum glucose, and questionnaire data on socioeconomic and dietary factors. Mean total cholesterol in the population was 4.72 [SD 0.75] mmol/L. There was a significant, inverse relation between cholesterol and distension of the artery across this range (linear regression coefficient −11.8 μm · mmol
−1
· L
−1
,
P
=0.003). Similar relationships were demonstrated with LDL and apolipoprotein B (−12.9 μm · mmol
−1
· L
−1
,
P
=0.005 and −36.9 μm/mmol/L,
P
=0.01). HDL and triglyceride levels showed no consistent association with distensibility.

Conclusions
—LDL cholesterol levels had an impact on arterial distensibility in the first decade of life. Furthermore, the functional differences in the arterial wall were demonstrated within the lipid range found in normal children, a finding that raises the possibility that cholesterol levels in the general population during childhood may already be relevant to the development of vascular disease.
Inhibition of Early Atherogenesis by Losartan in Monkeys With Diet-Induced Hypercholesterolemia
Authors: Strawn William B. , Chappell Mark C. , Dean Richard H. , Kivlighn Salah , Ferrario Carlos M.
Published: June 2012

Background
—Angiotensin II may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. This study determined, in a primate model of diet-induced atherosclerosis, the effect of AT
1
blockade on fatty-streak formation, plasma lipids, and surrogate markers of vascular injury.

Methods and Results
—Male cynomolgus monkeys fed a diet containing 0.067 mg cholesterol/kJ for 20 weeks were given losartan (180 mg/d, n=6) or vehicle (n=8) for 6 weeks starting at week 12 of the dietary regimen. Arterial pressure, heart rate, plasma total and lipoprotein cholesterol concentrations, and lipoprotein particle sizes and subclass distributions were unaffected by treatment. Losartan caused significant (
P
<0.05) increases in plasma angiotensin II and angiotensin-(1–7). Compared with vehicle-treated controls, losartan reduced the extent of fatty streak in the aorta, the coronary arteries, and the carotid arteries by ≈50% (
P
<0.05). A significant (
P
<0.05) reduction in the susceptibility of LDL to in vitro oxidation, serum levels of monocyte chemoattractant protein-1, and circulating monocyte CD11b expression were also associated with losartan treatment. In addition, serum levels of vascular cell adhesion molecule-1 and E-selectin did not change during treatment but increased after discontinuation of losartan. Serum C-reactive protein, platelet aggregability, and white cell counts were not modified by losartan.

Conclusions
—This study demonstrates for the first time an antiatherogenic effect of AT
1
receptor blockade in nonhuman primates. Losartan inhibited fatty-streak formation through mechanisms that may include protection of LDL from oxidation and suppression of vascular monocyte activation and recruitment factors.
Cell-Surface Estrogen Receptors Mediate Calcium-Dependent Nitric Oxide Release in Human Endothelia
Authors: Stefano George B. , Prevot Vincent , Beauvillain Jean-Claude , Cadet Patrick , Fimiani Caterina , Welters Ingeborg , Fricchione Gregory L. , Breton Christophe , Lassalle Philippe , Salzet Michel , Bilfinger Thomas V.
Published: June 2012

Background
—Although estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanism for this benefit remains unclear. Because nitric oxide (NO) is considered an important endothelium-derived relaxing factor and may function to protect blood vessels against atherosclerotic development, we investigated the acute effects of physiological levels of estrogen on NO release from human internal thoracic artery endothelia and human arterial endothelia in culture.

Methods and Results
—We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase activity in human endothelial cells by acting on a cell-surface receptor. NO release was measured in real time with an amperometric probe. 17β-Estradiol exposure to internal thoracic artery endothelia and human arterial endothelia in culture stimulated NO release within seconds in a concentration-dependent manner. 17β-Estradiol conjugated to bovine serum albumin also stimulated NO release, suggesting action through a cell-surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized this action. We further showed with the use of dual emission microfluorometry that 17β-estradiol–stimulated release of endothelial NO was dependent on the initial stimulation of intracellular calcium transients.

Conclusions
—Physiological doses of estrogen immediately stimulate NO release from human endothelial cells through activation of a cell-surface estrogen receptor that is coupled to increases in intracellular calcium.
Genetic Manipulation of the Rabbit Heart via Transgenesis
Authors: James Jeanne , Sanbe Atsushi , Yager Karen , Martin Lisa , Klevitsky Raisa , Robbins Jeffrey
Published: June 2012

Background
—Transgenesis using cardiac-specific expression has been valuable in exploring cardiac structure-function relationships. To date, cardiac-selective studies have been confined to the mouse. However, the utility of the mouse is limited in certain, possibly critical, aspects with respect to cardiovascular function.

Methods and Results
—To establish the potential validity of transgenic methodology for remodeling a larger mammalian heart, we explored cardiac-selective expression in transgenic rabbits. The murine α- and β-cardiac myosin heavy chain gene promoters were used to express a reporter gene, and transgene expression was quantified in cardiac, skeletal, and smooth muscles as well as in nonmuscle tissues. Although neither promoter exactly mimics endogenous patterns of myosin heavy chain expression, both are able to drive high levels of transgene expression in the cardiac compartment. Neither promoter is active in smooth muscle or nonmuscle tissues.

Conclusions
—Directed organ-specific expression is feasible in a larger animal with existing reagents, and cardiac-selective transgenic manipulation is possible in the rabbit.
Pathological Effects of Extensive Radiofrequency Energy Applications in the Pulmonary Veins in Dogs
Authors: Taylor Gregg W. , Kay G. Neal , Zheng Xiangsheng , Bishop Sanford , Ideker Raymond E.
Published: June 2012

Introduction
—The long-term complications of catheter ablation within the pulmonary veins are unknown. The development of pulmonary vein stenosis has recently been described after catheter ablation to treat either chronic or paroxysmal atrial fibrillation. The purpose of this study was to examine the pathological and hemodynamic effects of radiofrequency (RF) energy application within the pulmonary veins.

Methods and Results
—Right heart and transseptal catheterization were performed in 9 anesthetized mongrel dogs. The pulmonary vein ostia were cannulated and pulmonary venous pressure was measured before RF energy application in up to 4 separate pulmonary veins. Animals were euthanized at intervals of 2 to 4 weeks (n=3), 6 to 8 weeks (n=3), or 10 to 14 weeks (n=3) after ablation. Repeat catheterization before euthanasia demonstrated statistically significant differences in pulmonary capillary wedge pressure, cardiac output, pulmonary vascular resistance, and systemic vascular resistance (
P
<0.05) compared with the baseline. Luminal narrowing was observed in 22 of 33 pulmonary veins to which RF energy was applied. Of these, 7 were totally occluded, 7 had severe stenosis, and 8 were only minimally narrowed. Histological examination revealed intimal proliferation with organizing thrombus, necrotic myocardium in various stages of collagen replacement, endovascular contraction, and a proliferation of elastic lamina.

Conclusions
—Applications of RF current within the pulmonary veins may result in pulmonary vein narrowing or complete occlusion. These observations should be considered in treatment of arrhythmias originating within the pulmonary veins.
Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors Modify the Inflammatory Response of Human Macrophages and Endothelial Cells Infected With
Chlamydia pneumoniae
Authors: Kothe H. , Dalhoff K. , Rupp J. , Müller A. , Kreuzer J. , Maass M. , Katus H. A.
Published: June 2012

Background
—In patients with atherosclerosis, hepatic hydroxymethylglutaryl coenzyme A reductase (CSE) inhibitors may reduce the activation of inflammation. Because
Chlamydia pneumoniae
infection has been linked to coronary artery disease through the induction of plaque inflammation, we investigated whether cerivastatin affects the infection rate of human macrophages and endothelial cells (ECs) and their proinflammatory activation after chlamydial infection.

Methods and Results
—Macrophages were collected from the alveolar compartment of 6 volunteers and 10 patients with chronic bronchitis. ECs were obtained from 10 umbilical cords. The
C. pneumoniae
strain CWL was incubated with macrophages or ECs in the presence and absence of the CSE inhibitor cerivastatin. The infection rate was determined by immunofluorescence microscopy. The release of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and tumor necrosis factor (TNF)-α was quantified by ELISA. The release of oxygen radicals was determined by ferricytochrome assay. Infection rates were tendentially lower after the preincubation of macrophages with CSE inhibitors (17.2% versus 9.3% and 18.2% versus 10.4%, respectively;
P=
NS). The secretion of MCP-1, IL-8, and TNF-α by infected macrophages from volunteers increased. Coincubation with cerivastatin resulted in significantly lower MCP-1 and IL-8 production, whereas the release of TNF-α remained unaffected. Similar effects regarding chemokine release were observed in ECs.

Conclusions
—CSE inhibitors modify the inflammatory response of human immune cells to
C. pneumoniae
. This finding could be relevant for the therapeutic potential of CSE statins in patients with atherosclerosis and
C. pneumoniae
infection.
Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction Among Apparently Healthy Men
Authors: Ridker Paul M. , Rifai Nader , Stampfer Meir J. , Hennekens Charles H.
Published: June 2012

Background
—Interleukin-6 (IL-6) plays a central role in inflammation and tissue injury. However, epidemiological data evaluating the role of IL-6 in atherogenesis are sparse.

Methods and Results
—In a prospective study involving 14 916 apparently healthy men, we measured baseline plasma concentration of IL-6 in 202 participants who subsequently developed myocardial infarction (MI) and in 202 study participants matched for age and smoking status who did not report vascular disease during a 6-year follow-up. Median concentrations of IL-6 at baseline were higher among men who subsequently had an MI than among those who did not (1.81 versus 1.46 pg/mL;
P
=0.002). The risk of future MI increased with increasing quartiles of baseline IL-6 concentration (
P
for trend <0.001) such that men in the highest quartile at entry had a relative risk 2.3 times higher than those in the lowest quartile (95% CI 1.3 to 4.3,
P
=0.005); for each quartile increase in IL-6, there was a 38% increase in risk (
P
=0.001).This relationship remained significant after adjustment for other cardiovascular risk factors, was stable over long periods of follow-up, and was present in all low-risk subgroups, including nonsmokers. Although the strongest correlate of IL-6 in these data was C-reactive protein (
r
=0.43,
P
<0.001), the relationship of IL-6 with subsequent risk remained after control for this factor (
P
<0.001).

Conclusions
—In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis.
Early and Intermediate Outcomes After Repair of Pulmonary Atresia With Ventricular Septal Defect and Major Aortopulmonary Collateral Arteries
Authors: Reddy V. Mohan , McElhinney Doff B. , Amin Zahid , Moore Phillip , Parry Andrew J. , Teitel David F. , Hanley Frank L.
Published: June 2012

Background
—Pulmonary atresia with ventricular septal defect (VSD) and major aortopulmonary collaterals (MAPCAs) is a complex lesion with marked heterogeneity of pulmonary blood supply. Traditional management has involved staged unifocalization of pulmonary blood supply. Our approach has been to perform early 1-stage complete unifocalization in almost all patients.

Methods and Results
—Since 1992, 85 patients with pulmonary atresia, VSD, and MAPCAs have undergone unifocalization (median age, 7 months). Complete 1-stage unifocalization and intracardiac repair were performed through a midline approach in 56 patients, whereas 23 underwent unifocalization in a single stage with the VSD left open, and 6 underwent staged unifocalization through sequential thoracotomies. There were 9 early deaths. During follow-up (1 to 69 months), there were 7 late deaths. Actuarial survival was 80% at 3 years. Among early survivors, actuarial survival with complete repair was 88% at 2 years. Reintervention on the neo–pulmonary arteries was performed in 24 patients.

Conclusions
—Early 1-stage complete unifocalization can be performed in >90% of patients with pulmonary atresia and MAPCAs, even those with absent true pulmonary arteries, and yields good functional results. Complete repair during the same operation is achieved in two thirds of patients. There remains room for improvement; actuarial survival 3 years after surgery is 80%, and there is a significant rate of reintervention. These results must be appreciated within the context of the natural history of this lesion: 65% of patients survive to 1 year of age and slightly >50% survive to 2 years even with surgical intervention.
Impaired Endothelium-Dependent Regulation of Ventricular Relaxation in Pressure-Overload Cardiac Hypertrophy
Authors: MacCarthy Philip A. , Shah Ajay M.
Published: June 2012

Background
—Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation and may benefit diastolic function. Left ventricular hypertrophy (LVH) is characterized by abnormal myocardial relaxation and endothelial dysfunction. We investigated endothelium-dependent regulation of LV relaxation in moderate pressure-overload LVH induced by aortic banding in guinea pigs.

Methods and Results
—Isolated ejecting hearts of banded or sham-operated animals (shams) were studied. The specific agonists for endothelial release of NO, bradykinin (10 nmol/L), and substance P (100 nmol/L) both induced earlier onset of LV relaxation in shams (time to LV dP/dt
min
[tdP/dt
min
], −13.4±3.0 and −10.4±2.5 ms, respectively) without altering peak LV pressure or LV dP/dt
max
. Neither agent altered tdP/dt
min
in banded animals. The ACE inhibitor captopril (1 μmol/L) also selectively reduced tdP/dt
min
in shams via a bradykinin/NO-dependent mechanism but had no effect in banded animals. An exogenous NO donor, sodium nitroprusside (0.1 μmol/L), selectively reduced tdP/dt
min
to a similar extent in both shams and banded animals. Endothelial-type NO synthase (eNOS) protein expression in whole LV homogenate was unaltered in banded animals.

Conclusions
—Endothelium-dependent enhancement of LV relaxation is impaired in moderate pressure-overload LVH, despite a preserved response to exogenous NO. This is not accounted for by altered eNOS expression. These abnormalities may contribute to diastolic dysfunction in LVH.
Endothelial Cell Activation by Pore-Forming Structures
Authors: Saadi Soheyla , Holzknecht Robert A. , Patte Christian P. , Platt Jeffrey L.
Published: June 2012

Background
—Interaction of complement with endothelial cells (ECs) underlies the development of inflammation and coagulation in disease. Assembly of the membrane attack complex (MAC) of complement on EC membrane, like stimulation with cytokines, upregulates tissue factor and cyclooxygenase-2 but does so via the intermediary action of IL-1α. We asked whether the MAC activates porcine aortic and microvascular ECs in a global manner by this mechanism and whether this mechanism is used by membrane pore-forming structures.

Methods and Results
—Exposure of ECs to complement caused upregulation of mRNAs for E-selectin, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, Iκ-Bα, interleukin (IL)-1α, IL-1β, IL-8, and plasminogen activator inhibitor-1 over a period of 6 hours. The expression of these genes was not a primary response to stimulation, however, because IL-1 receptor antagonist inhibited expression of these genes. Activation of ECs by complement depended on the autocrine action of IL-1α, because complement-mediated EC activation was inhibited by anti–IL-1α antibodies. Melittin and mastoparan, amphiphilic pore-forming peptides like the MAC, induced E-selectin through intermediary action of IL-1.

Conclusions
—These findings suggest that transmembrane pore-forming proteins, as a class of molecules, activate ECs through the autocrine effects of IL-1α.
Relationship Between Regional Cardiac Hyperinnervation and Ventricular Arrhythmia
Authors: Cao Ji-Min , Fishbein Michael C. , Han Jay B. , Lai William W. , Lai Angela C. , Wu Tsu-Juey , Czer Lawrence , Wolf Paul L. , Denton Timothy A. , Shintaku I. Peter , Chen Peng-Sheng , Chen Lan S.
Published: June 2012

Background
—Sympathetic nerve activity is known to be important in ventricular arrhythmogenesis, but there is little information on the relation between the distribution of cardiac sympathetic nerves and the occurrence of spontaneous ventricular arrhythmias in humans.

Methods and Results
—We studied 53 native hearts of transplant recipients, 5 hearts obtained at autopsy of patients who died of noncardiac causes, and 7 ventricular tissues that had been surgically resected from the origin of ventricular tachycardia. The history was reviewed to determine the presence (group 1A) or absence (group 1B) of spontaneous ventricular arrhythmias. Immunocytochemical staining for S100 protein, neurofilament protein, tyrosine hydroxylase, and protein gene product 9.5 was performed to study the distribution and the density of sympathetic nerves. The average left ventricular ejection fraction was 0.22±0.07. A total of 30 patients had documented ventricular arrhythmias, including ventricular tachycardia and sudden cardiac death. A regional increase in sympathetic nerves was observed around the diseased myocardium and blood vessels in all 30 hearts. The density of nerve fibers as determined morphometrically was significantly higher in group 1A patients (total nerve number 19.6±11.2/mm
2
, total nerve length 3.3±3.0 mm/mm
2
) than in group 1B patients (total nerve number 13.5±6.1/mm
2
, total nerve length 2.0±1.1 mm/mm
2
,
P
<0.05 and
P
<0.01, respectively).

Conclusions
—There is an association between a history of spontaneous ventricular arrhythmia and an increased density of sympathetic nerves in patients with severe heart failure. These findings suggest that abnormally increased postinjury sympathetic nerve density may be in part responsible for the occurrence of ventricular arrhythmia and sudden cardiac death in these patients.
Type II Diabetes Abrogates Sex Differences in Endothelial Function in Premenopausal Women
Authors: Steinberg Helmut O. , Paradisi Giancarlo , Cronin Jessica , Crowde Kristin , Hempfling Annette , Hook Ginger , Baron Alain D.
Published: June 2012

Background
—Obesity is a more potent cardiovascular risk factor (CVRF) in men than in women. Because traditional CVRFs cannot fully account for this sex difference, we tested the hypothesis that compared with men, women exhibit more robust endothelial function independent of obesity and that this sex difference is abrogated by diabetes.

Methods and Results
—We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in groups of lean, obese (OB), and type II diabetic (DM) premenopausal women and age- and body mass index–matched men. LBF response to intrafemoral administration of L-NMMA, an inhibitor of nitric oxide synthase, was also assessed in normal men and women. Maximum LBF increments in response to Mch were 347±57% versus 231±22% in lean women versus men (
P
<0.05) and 203±25% versus 111±17% in OB women versus men (
P
<0.01), respectively. In DM, maximum LBF increments in response to Mch were 104±24% and 138±33% in women and men, respectively, (
P
=NS). LBF decrements in response to L-NMMA were 34.9±4.1% and 17.1±4.2% in women and men, respectively (
P
<0.01). The response to SNP was not different between sexes and groups.

Conclusions
—Premenopausal nondiabetic women exhibit more robust endothelium-dependent vasodilation owing to higher rates of nitric oxide release than men. Given the protective vascular action of nitric oxide, this difference may partially explain the lower incidence of macrovascular disease in women. In premenopausal women, DM causes impairment of endothelial function beyond that observed with obesity alone and leads to endothelial dysfunction similar to that observed in DM men. These findings may help explain the similar rates of coronary artery disease and mortality in diabetic men and women.
ATP Synthesis During Low-Flow Ischemia
Authors: Cave Alison C. , Ingwall Joanne S. , Friedrich Jan , Liao Ronglih , Saupe Kurt W. , Apstein Carl S. , Eberli Franz R.
Published: June 2012

Background
—Our goals were to (1) simulate the degree of low-flow ischemia and mixed anaerobic and aerobic metabolism of an acutely infarcting region; (2) define changes in anaerobic glycolysis, oxidative phosphorylation, and the creatine kinase (CK) reaction velocity; and (3) determine whether and how increased glycolytic substrate alters the energetic profile, function, and recovery of the ischemic myocardium in the isolated blood-perfused rat heart.

Methods and Results
—Hearts had 60 minutes of low-flow ischemia (10% of baseline coronary flow) and 30 minutes of reperfusion with either control or high glucose and insulin (G+I) as substrate. In controls, during ischemia, rate-pressure product and oxygen consumption decreased by 84%. CK velocity decreased by 64%; ATP and phosphocreatine (PCr) concentrations decreased by 51% and 63%, respectively; inorganic phosphate (P
i
) concentration increased by 300%; and free [ADP] did not increase. During ischemia, relative to controls, the G+I group had similar CK velocity, oxygen consumption, and tissue acidosis but increased glycolysis, higher [ATP] and [PCr], and lower [P
i
] and therefore had a greater free energy yield from ATP hydrolysis. Ischemic systolic and diastolic function and postischemic recovery were better.

Conclusions
—During low-flow ischemia simulating an acute myocardial infarction region, oxidative phosphorylation accounted for 90% of ATP synthesis. The CK velocity fell by 66%, and CK did not completely use available PCr to slow ATP depletion. G+I, by increasing glycolysis, slowed ATP depletion, maintained lower [P
i
], and maintained a higher free energy from ATP hydrolysis. This improved energetic profile resulted in better systolic and diastolic function during ischemia and reperfusion. These results support the clinical use of G+I in acute MI.
β-Adrenergic Blockade in Developing Heart Failure
Authors: Prabhu Sumanth D. , Chandrasekar Bysani , Murray David R. , Freeman Gregory L.
Published: June 2012

Background
—Whether β-adrenergic blockade modulates myocardial expression of inflammatory cytokines and nitric oxide (NO) in heart failure is unclear.

Methods and Results
—We administered oral metoprolol or no therapy to rats for 12 weeks after large myocardial infarction and subsequently examined left ventricular (LV) remodeling; myocardial tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 expression; and NO. In untreated rats, echocardiography revealed significant (
P
<0.001) LV dilatation and systolic dysfunction compared with sham. Papillary muscle studies revealed isoproterenol hyporesponsiveness to be unaltered by NO synthase (NOS) inhibition. Circulating NO metabolites were undetectable. In noninfarcted myocardium, although inducible NOS (iNOS) mRNA was absent, TNF-α, IL-1β, and IL-6 mRNA and protein were markedly elevated compared with sham (
P
<0.001), with 2-fold higher expression (
P
<0.025) of IL-6 compared with TNF-α or IL-1β. Metoprolol administration starting 48 hours after infarction (1) attenuated (
P
<0.02) LV dilatation and systolic dysfunction, (2) preserved isoproterenol responsiveness (
P
<0.025) via NO-independent mechanisms, and (3) reduced myocardial gene expression and protein production of TNF-α and IL-1β (
P
<0.025) but not IL-6, which remained high.

Conclusions
—During heart failure development, adrenergic activation contributes to increased myocardial expression of TNF-α and IL-1β but not IL-6, and one mechanism underlying the beneficial effects of β-adrenergic blockade may involve attenuation of TNF-α and IL-1β expression independent of iNOS and NO.
Surface Potentials From the Region of the Atrioventricular Node and Their Relation to Dual Pathway Electrophysiology
Authors: Mazgalev Todor N. , Tchou Patrick J.
Published: June 2012

Background
—Clinical applications of the principles of dual atrioventricular nodal (AVN) electrophysiology in the treatment of AVN reentrant tachycardias rely on empirical findings, such as discontinued conduction curves or the presence of specific catheter-recorded signals. However, neither the shape of the conduction curve nor the surface electrograms have been validated as functionally related to the presence of slow or fast wavefronts.

Methods and Results
—We performed in vitro studies using 10 rabbit atrial-AVN preparations. A bipolar roving electrode was used to explore the endocardial surface of the triangle of Koch during programmed electrical stimulation. Microelectrodes were impaled in AVN cells to correlate surface and intracellular responses. In 7 preparations, a specific area near the compact cell region produced surface electrograms that were dissociated in 2 distinct components, with progressive shortening of prematurity. Similar dissociation was demonstrated during Wenckebach periodicity and increased vagal tone. Cellular recordings supported the presence of early (“fast”) and late (“slow”) wavefronts, with different refractory properties. Although the fast-slow transition was a basis for discontinued propagation, the AVN conduction curves were smooth in the majority of cases.

Conclusions
—Exploration of the triangle of Koch during programmed pacing reveals the presence of dual-wavefront surface potentials. Clinical confirmation of these AVN potentials could provide a new, sensitive tool in defining dual AVN electrophysiology.
Calcineurin Is Activated in Rat Hearts With Physiological Left Ventricular Hypertrophy Induced by Voluntary Exercise Training
Authors: Eto Yoko , Yonekura Katsunori , Sonoda Makoto , Arai Naoto , Sata Masataka , Sugiura Seiryo , Takenaka Katsu , Gualberto Antonio , Hixon Mary L. , Wagner Mark W. , Aoyagi Teruhiko
Published: June 2012

Background
—Calcineurin may play a pivotal role in the signaling of cardiac hypertrophy; since this hypothesis was first put forward, controversial reports have been published using various experimental models. This study was designed to compare the physiological left ventricular hypertrophy (LVH) induced by voluntary exercise with LVH induced by aortic constriction and to determine whether calcineurin participates in the signaling of exercise-induced LVH.

Methods and Results
—Wistar rats were assigned to 1 of the following 5 groups: 10 weeks of voluntary exercise (EX), a sedentary regimen, a 1-week (AC1) or 4-week (AC4) ascending aortic constriction period, or a sham operation. EX rats ran 2.4±0.7 km/day voluntarily in specially manufactured cages; this was associated with an increase of LV diastolic dimension and stroke volume. Myocardial calcineurin activity markedly increased in EX rats (46.4±8.3 versus 18.4±0.5 pmol · min
−1
· mg
−1
in sedentary rats;
P
<0.001) and in AC1 rats (44.9±6.7 versus 22.1±3.7 pmol · min
−1
· mg
−1
in sham-operated rats;
P
<0.001), but not in AC4 rats (29.0±3.4 pmol · min
−1
· mg
−1
). Treatment with cyclosporin A completely inhibited the development of LVH in EX rats, but it only partially attenuated the development of LVH in AC4 rats.

Conclusions
—Calcineurin was activated in exercise-induced physiological LVH and in the developing phase of LVH (AC1), but not in decompensated pressure-overload hypertrophy (AC4). Cyclosporin therapy for the prevention of LVH may be harmful because it does not block the development of pathological hypertrophy but rather that of favorable adaptive hypertrophy.
Regulation of Tissue Factor Expression in Human Microvascular Endothelial Cells by Nitric Oxide
Authors: Yang Yinke , Loscalzo Joseph
Published: June 2012

Background
—Tissue factor (TF) is a critical determinant of thrombin generation in normal hemostasis and in atherothrombotic disease. Nitric oxide has both antithrombotic and antiatherosclerotic actions in the vasculature, yet its role in the regulation of TF expression has not been examined.

Methods and Results
—To study the effect of endogenous endothelium-derived nitric oxide on TF expression and activity, we induced TF in human microvascular endothelial cells with lipopolysaccharide or interleukin-1β and observed a dose- and time-dependent increase in TF activity and expression by Northern and Western blotting.
l
-Arginine, the principal substrate for nitric oxide synthases, added to the media suppressed the induction of TF activity significantly (by 66% for lipopolysaccharide induction and by 59% for interleukin-1β induction) at 24 hours. These changes in activity were accompanied by correlative changes in TF protein and steady-state mRNA.
d
-Arginine had no effect, and inhibition of endogenous nitric oxide production failed to increase TF expression.

Conclusions
—These data suggest that enhanced production of endothelium-derived nitric oxide reduces endotoxin- and cytokine-induced expression of TF and, thereby, the prothrombotic phenotype of the endothelial cell.
Elevation of Tumor Necrosis Factor-α and Increased Risk of Recurrent Coronary Events After Myocardial Infarction
Authors: Ridker Paul M. , Rifai Nader , Pfeffer Marc , Sacks Frank , Lepage Serge , Braunwald Eugene
Published: June 2012

Background
—Levels of tumor necrosis factor-α (TNF-α) increase with acute ischemia. However, whether elevations of TNF-α in the stable phase after myocardial ischemia (MI) are associated with increased risk of recurrent coronary events is unknown.

Methods and Results
—A nested case-control design was used to compare TNF-α levels obtained an average of 8.9 months after initial MI among 272 participants in the Cholesterol And Recurrent Events (CARE) trial who subsequently developed recurrent nonfatal MI or a fatal cardiovascular event (cases) and from an equal number of age- and sex-matched participants who remained free of these events during follow-up (controls). Overall, TNF-α levels were significantly higher among cases than controls (2.84 versus 2.57 pg/mL,
P
=0.02). The excess risk of recurrent coronary events after MI was predominantly seen among those with the highest levels of TNF-α, such that those with levels in excess of 4.17 pg/mL (the 95th percentile of the control distribution) had an ≈3-fold increase in risk (RR=2.7, 95% CI 1.4 to 5.2,
P
=0.004). Risk estimates were independent of other risk factors and were similar in subgroup analyses limited to cardiovascular death (RR=2.1) or to recurrent nonfatal MI (RR=3.2).

Conclusions
—Plasma concentrations of TNF-α are persistently elevated among post-MI patients at increased risk for recurrent coronary events. These data support the hypothesis that a persistent inflammatory instability is present among stable patients at increased vascular risk. Novel therapies designed to attenuate inflammation may thus represent a new direction in the treatment of MI.