bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Coronary Artery Disease on the Coronary Vasomotor Response to Nonionic Contrast Media
Authors: Limbruno Ugo , Petronio Anna Sonia , Amoroso Giovanni , Baglini Roberto , Paterni Giovanni , Merelli Antonella , Mariotti Rita , Raffaele De Caterina  , Mariani Mario
Published: June 2012

Background
—Coronary artery disease (CAD) alters the vasomotor response to a variety of pharmacological agents. We tested the hypothesis that CAD also has an impact on the coronary vasomotor response to radiologic contrast media.

Methods and Results
—We performed quantitative coronary angiography in 42 patients without angiographic evidence of CAD and 38 patients with CAD in the left coronary artery. Angiographically smooth coronary segments (n=235) were analyzed for changes on luminal diameters and coronary venous oxygen saturation in response to 3 media: the nonionic dimer iodixanol, the nonionic monomer iopromide, and the ionic agent ioxaglate. In subjects without CAD, we assessed the effects of intracoronary administration of the nitric oxide synthase inhibitor N
G
-monomethyl-
l
-arginine and of the cyclooxygenase inhibitor indomethacin on such changes. Iodixanol induced coronary vasodilation in subjects without CAD (8.8±8.6%,
P
<0.001). Patients with CAD exhibited no significant diameter changes in segments ≥20 mm apart from a stenosis (4.7±9.4%,
P
=NS) and significant constriction in segments <20 mm from a stenosis (−3.8±4.6%,
P
<0.05). Similar results were obtained with iopromide, but no changes were found with ioxaglate. All contrast media induced transient (<35 seconds) increases in coronary venous oxygen saturation in all subjects. Indomethacin, but not N
G
-monomethyl-
l
-arginine, blunted the vasodilating effect of iodixanol and iopromide (by 80% and 76%, respectively;
P
<0.001).

Conclusions
—Nonionic contrast media induce a vasodilatory response in normal vessels not by a mechanism involving increased flow or endothelial nitric oxide synthesis, but rather by depending on preserved vascular cyclooxygenase activity. CAD changes normal epicardial vasodilatory response into vasoconstriction.
Atherosclerotic Plaque Burden and CK-MB Enzyme Elevation After Coronary Interventions
Authors: Mehran Roxana , Dangas George , Mintz Gary S. , Lansky Alexandra J. , Pichard Augusto D. , Satler Lowell F. , Kent Kenneth M. , Stone Gregg W. , Leon Martin B.
Published: June 2012

Background
—Elevation of serum creatine kinase MB fraction (CK-MB) after percutaneous coronary interventions has been associated with early and late mortality; however, the pathogenesis of CK-MB elevation is still unknown. We hypothesized that CK-MB elevation was related to atherosclerotic plaque burden as assessed by preintervention intravascular ultrasound (IVUS).

Methods and Results
—We studied 2256 consecutive patients who underwent intervention of 2780 native coronary lesions and had complete high-quality preintervention IVUS imaging in the era before routine use of platelet glycoprotein IIb/IIIa inhibitors. Patients were divided into 3 groups: CK-MB within normal range (1675 patients; 2061 lesions); CK-MB elevation 1 to 5 times upper limit of normal (292 patients; 355 lesions); and CK-MB elevation ≥5 times upper limit of normal (289 patients; 364 lesions). Qualitative angiographic lesion morphology and quantitative analysis were similar among the 3 groups. On preintervention IVUS, progressively more reference segment and lesion site plaque burden and lesion site calcium occurred in the groups with CK-MB elevation. Positive remodeling was more common in lesions with CK-MB elevation. As levels of CK-MB increased, cross-sectional narrowing (percentage plaque burden) increased, both at the reference site (mean cross-sectional narrowing values were 45.1%, <49.3%, and <52.2% for normal CK-MB, 1 to 5 times upper limit of normal, and ≥5 times upper limit of normal groups, respectively;
P
=0.03) and at the lesion site (81.9%, <85.4%, and <87.1%, respectively;
P
=0.04). Multivariate analysis indicated that de novo lesions, atheroablative technique, plaque burden at the lesion and reference segments, and final minimal lumen diameter were independent predictors of CK-MB elevation.

Conclusions
—CK-MB elevation correlates with a greater atherosclerotic plaque burden. CK-MB elevation after intervention may be a marker of diffuse atherosclerotic disease or a consequence of catheter-based intervention in more diseased arteries or both.
Assessment of Aortic Valve Stenosis Severity
Authors: Garcia Damien , Pibarot Philippe , Dumesnil Jean G. , Sakr Frédéric , Durand Louis-Gilles
Published: June 2012

Background
—Fluid energy loss across stenotic aortic valves is influenced by factors other than the valve effective orifice area (EOA). We propose a new index that will provide a more accurate estimate of this energy loss.

Methods and Results
—An experimental model was designed to measure EOA and energy loss in 2 fixed stenoses and 7 bioprosthetic valves for different flow rates and 2 different aortic sizes (25 and 38 mm). The results showed that the relationship between EOA and energy loss is influenced by both flow rate and aortic cross-sectional area (A
A
) and that the energy loss is systematically higher (15±2%) in the large aorta. The coefficient (EOA×A
A
)/(A
A
−EOA) accurately predicted the energy loss in all situations (
r
2
=0.98). This coefficient is more closely related to the increase in left ventricular workload than EOA. To account for varying flow rates, the coefficient was indexed for body surface area in a retrospective study of 138 patients with moderate or severe aortic stenosis. The energy loss index measured by Doppler echocardiography was superior to the EOA in predicting the end points, which were defined as death or aortic valve replacement. An energy loss index ≤0.52 cm
2
/m
2
was the best predictor of adverse outcomes (positive predictive value of 67%).

Conclusions
—This new energy loss index has the potential to reflect the severity of aortic stenosis better than EOA. Further prospective studies are necessary to establish the relevance of this index in terms of clinical outcomes.
Restoration of Diastolic Function in Senescent Rat Hearts Through Adenoviral Gene Transfer of Sarcoplasmic Reticulum Ca
2+
-ATPase
Authors: Schmidt Ulrich , del Monte Federica , Miyamoto Michael I. , Matsui Takashi , Gwathmey Judith K. , Rosenzweig Anthony , Hajjar Roger J.
Published: June 2012

Background
—Senescent hearts are characterized by diastolic dysfunction and a decrease in sarcoplasmic reticulum (SR) Ca
2+
-ATPase protein (SERCA2a).

Methods and Results
—To test the hypothesis that an increase in SERCA2a could improve cardiac function in senescent rats (age 26 months), we used a catheter-based technique of adenoviral gene transfer to achieve global myocardial transduction of SERCA2a in vivo. Adult rat hearts aged 6 months and senescent rat hearts infected with an adenovirus containing the reporter gene β-galactosidase were used as controls. Two days after infection, parameters of systolic and diastolic function were measured in open-chest rats. Cardiac SERCA2a protein and ATPase activity were significantly decreased in senescent hearts compared with adult rats (Δ −30±4% and −49±5%) and were restored to adult levels after infection with Ad.SERCA2a. At baseline, left ventricular systolic pressure and +dP/dt were unaltered in senescent hearts; however, diastolic parameters were adversely affected with an increase in the left ventricular time constant of isovolumic relaxation and diastolic pressure (Δ +29±9% and +38±12%) and a decrease in −dP/dt (Δ −26±11%). Overexpression of SERCA2a did not significantly affect left ventricular systolic pressure but did increase +dP/dt (Δ +28±10%) in the senescent heart. Overexpression of SERCA2a restored the left ventricular time constant of isovolumic relaxation and −dP/dt to adult levels. Infection of senescent hearts with Ad.SERCA2a markedly improved rate-dependent contractility and diastolic function in senescent hearts.

Conclusions
—These results support the hypothesis that decreased Ca
2+
-ATPase activity contributes to the functional abnormalities observed in senescent hearts and demonstrates that Ca
2+
cycling proteins can be targeted in the senescent heart to improve cardiac function.
Heterogeneous Sympathetic Innervation Influences Local Myocardial Repolarization in Normally Perfused Rabbit Hearts
Authors: Yoshioka Koichiro , Gao Dong-Wei , Chin Michael , Stillson Carol , Penades Elizabeth , Lesh Michael , O’Connell William , Dae Michael
Published: June 2012

Background
—Heterogeneity of sympathetic innervation is thought to contribute to the potential for fatal arrhythmia. However, little is known about the effects of heterogeneous innervation on repolarization.

Methods and Results
—To assess this relationship, we measured activation recovery intervals (ARIs) from 64 epicardial sites in 11 rabbits studied 2 weeks after regional denervation produced by phenol and 4 sham-operated rabbits. ARI results were compared with the distribution of sympathetic innervation measured from 3D reconstructions of serial autoradiographs of [
125
I]metaiodobenzylguanidine and
99m
Tc-sestamibi. ARIs were recorded during baseline sinus rhythm, norepinephrine (NE) infusion (0.1 μg · kg
−1
· min
−1
), and left stellate ganglion stimulation (SS). NE shortened ARI in 98% of electrodes in the denervated region. The degree of ARI shortening and dispersion increased (
P
<0.001 and
P
<0.01, respectively) as denervation became more severe. SS shortened ARI in 30% of electrodes in the denervated area, with increased shortening and dispersion related to increased severity of denervation (
P
<0.01). SS prolonged ARI in 70% of electrodes in the denervated area, with no correlation with severity of denervation.

Conclusions
—The magnitude and dispersion of local repolarization responses are related to the severity of denervation, as well as the type of stimulation: neural (SS) versus humoral (NE). The differences may relate to the concentration of NE released.
Endogenous Tissue Factor Pathway Inhibitor Modulates Thrombus Formation in an In Vivo Model of Rabbit Carotid Artery Stenosis and Endothelial Injury
Authors: Ragni Massimo , Golino Paolo , Cirillo Plinio , Scognamiglio Annalisa , Piro Orlando , Esposito Nicolino , Battaglia Carmine , Botticella Filomena , Ponticelli Paola , Ramunno Luigi , Chiariello Massimo
Published: June 2012

Background
—Tissue factor pathway inhibitor (TFPI) is the sole known inhibitor of the extrinsic coagulation pathway of physiological importance; however, its role in modulating thrombosis in vivo is still unclear.

Methods and Results
—Intravascular thrombosis was initiated by placing an external constrictor around endothelially injured rabbit carotid arteries (n=10). Carotid blood flow velocity was measured by a Doppler flow probe. After placement of the constrictor, cyclic flow reductions (CFRs), due to recurrent thrombosis, developed at the site of stenosis. Transstenotic TFPI plasma activity was measured in blood samples before induction of CFRs and after 30, 60, and 180 minutes of CFRs. TFPI plasma activity distal to the site of thrombosis was significantly lower than the corresponding proximal values at 30, 60, and 180 minutes of CFRs. In addition, a progressive decrease in TFPI plasma activity was observed in both the proximal and the distal samples, indicating consumption of TFPI during thrombus formation. In 10 additional rabbits, CFRs were abolished by administration of aspirin (10 mg/kg). In the animals in which aspirin abolished CFRs, endogenous TFPI was depleted by a bolus of a polyclonal antibody against rabbit TFPI, and the effects on restoration of CFRs were monitored. In 5 of 6 animals in which aspirin abolished CFRs, depletion of endogenous TFPI activity caused full restoration of CFRs.

Conclusions
—The data of the present study support the involvement of endogenous TFPI in the process of thrombus formation in vivo and its active role in modulating arterial thrombosis
.
Serum Soluble Heat Shock Protein 60 Is Elevated in Subjects With Atherosclerosis in a General Population
Authors: Xu Qingbo , Schett Georg , Perschinka Hannes , Mayr Manuel , Egger Georg , Oberhollenzer Friedrich , Willeit Johann , Kiechl Stefan , Wick Georg
Published: June 2012

Background
—Work from our laboratory has proven that increased titers of anti-heat shock protein 60 (HSP60) antibodies are associated with atherosclerosis and that HSP60-reactive T-cells are present in atherosclerotic lesions. Recent studies from others demonstrated that HSP60 directly activates endothelial cells and macrophages.

Methods and Results
—To explore the possibility that HSP60 exists in the circulation, where it could exert its functions, we performed a population-based study with 826 subjects aged 40 to 79 years. The following items were measured in all participants: serum soluble HSP60 (sHSP60); anti-
Escherichia coli
lipopolysaccharide; anti-HSP65, anti-
Chlamydia
, and anti-
Helicobacter pylori
antibodies; and a variety of acute phase reactants (C-reactive protein, α
1
-antitrypsin, and ceruloplasmin) and markers of systemic inflammation. Carotid atherosclerosis was assessed twice (1990 and 1995), and 15 other risk factors were evaluated. Our data show that levels of sHSP60 were significantly elevated in subjects with prevalent/incident carotid atherosclerosis and that these levels were correlated with common carotid artery intima/media thickness. Multiple logistic regression analysis documented these associations as independent of age, sex, and other risk factors. Interestingly, sHSP60 was also correlated with anti-lipopolysaccharide, anti-
Chlamydia
and anti-HSP60 antibodies, various markers of inflammation, and the presence of chronic infections. The risk of atherosclerosis associated with high sHSP60 levels was amplified when subjects had clinical and/or laboratory evidence of chronic infections.

Conclusions
—Our data provide the first evidence of a strong correlation between sHSP60 and atherosclerosis, suggesting that sHSP60 may play important roles in activating vascular cells and the immune system during the development of atherosclerosis.
Chronic Subclinical Inflammation as Part of the Insulin Resistance Syndrome
Authors: Festa Andreas , D’Agostino Ralph , Howard George , Mykkänen Leena , Tracy Russell P. , Haffner Steven M.
Published: June 2012

Background
—Inflammation has been suggested as a risk factor for the development of atherosclerosis. Recently, some components of the insulin resistance syndrome (IRS) have been related to inflammatory markers. We hypothesized that insulin insensitivity, as directly measured, may be associated with inflammation in nondiabetic subjects.

Methods and Results
—We studied the relation of C-reactive protein (CRP), fibrinogen, and white cell count to components of IRS in the nondiabetic population of the Insulin Resistance Atherosclerosis Study (IRAS) (n=1008; age, 40 to 69 years; 33% with impaired glucose tolerance), a multicenter, population-based study. None of the subjects had clinical coronary artery disease. Insulin sensitivity (S
I
) was measured by a frequently sampled intravenous glucose tolerance test, and CRP was measured by a highly sensitive competitive immunoassay. All 3 inflammatory markers were correlated with several components of the IRS. Strong associations were found between CRP and measures of body fat (body mass index, waist circumference), S
I
, and fasting insulin and proinsulin (all correlation coefficients >0.3,
P
<0.0001). The associations were consistent among the 3 ethnic groups of the IRAS. There was a linear increase in CRP levels with an increase in the number of metabolic disorders. Body mass index, systolic blood pressure, and S
I
were related to CRP levels in a multivariate linear regression model.

Conclusions
—We suggest that chronic subclinical inflammation is part of IRS. CRP, a predictor of cardiovascular events in previous reports, was independently related to S
I
. These findings suggest potential benefits of anti-inflammatory or insulin-sensitizing treatment strategies in healthy individuals with features of IRS.
Endothelial Responses to Oxidized Lipoproteins Determine Genetic Susceptibility to Atherosclerosis in Mice
Authors: Shi Weibin , Haberland Margaret E. , Jien Ming-Len , Shih Diana M. , Lusis Aldons J.
Published: June 2012

Background
—Oxidized LDL has been found within the subendothelial space, and it exhibits numerous atherogenic properties, including induction of inflammatory genes. We examined the possibility that variations in endothelial response to minimally modified LDL (MM-LDL) constitute one of the genetic components in atherosclerosis.

Methods and Results
—By a novel explant technique, endothelial cells (ECs) were isolated from the aorta of inbred mouse strains with different susceptibilities to diet-induced atherosclerosis. Responses to MM-LDL were evaluated by examining the expression of inflammatory genes involved in atherosclerosis, including monocyte chemotactic protein-1 (MCP-1) and macrophage-colony–stimulating factor (M-CSF), an oxidative stress gene, heme oxygenase-1 (HO-1), and other, noninflammatory, genes. ECs from the susceptible mouse strain C57BL/6J exhibited dramatic induction of MCP-1, M-CSF, and HO-1, whereas ECs from the resistant strain C3H/HeJ showed little or no induction. In contrast, ECs from the 2 strains responded similarly to lipopolysaccharide.

Conclusions
—These data provide strong evidence that genetic factors in atherosclerosis act at the level of the vessel wall.
Prospective Study Correlating Fibrinopeptide A, Troponin I, Myoglobin, and Myosin Light Chain Levels With Early and Late Ischemic Events in Consecutive Patients Presenting to the Emergency Department With Chest Pain
Authors: Sonel Ali , Sasseen Brett M. , Fineberg Naomi , Bang Nils , Wilensky Robert L.
Published: June 2012

Background
—Although thrombus formation plays a major role in acute coronary syndromes, few studies have evaluated a thrombus marker in risk stratification of patients with chest pain. Furthermore, the relation between markers that reflect myocardial injury and thrombus formation that may predict events in a heterogeneous patient population is unknown. This study correlated markers of thrombus and myocardial injury with early and late ischemic events in consecutive patients with chest pain.

Methods and Results
—Serum troponin I (TnI), myoglobin, and myosin light chain levels were obtained from 247 patients and urinary fibrinopeptide A (FPA) from 178 of the 247. By multivariate analysis, patients with an elevated FPA level were 4.82 times more likely to die or have myocardial infarction, unstable angina, and coronary revascularization at 1 week (
P
=0.002, 95% CI 1.78, 13.03), whereas those with an elevated TnI (>0.2 ng/mL) were 9.41 times more likely (
P
<0.001, 95% CI 2.84, 31.17). At 6 months (excluding the index event), an elevated FPA level was an independent predictor of events, with an odds ratio of 9.57 (
P
<0.001, C1 3.29, 27.8), and was the only marker to predict a shorter event-free survival (
P
<0.001). The other markers did not independently correlate with cardiac events, although MLC incrementally increased early predictive accuracy in combination with the FPA and TnI.

Conclusions
—Elevated FPA and TnI correlated with cardiac events during the initial week in patients presenting to the Emergency Department with chest pain. FPA predicted adverse events and a shorter event-free survival at 6 months.
Spectrum of Mutations in Long-QT Syndrome Genes
Authors: Splawski Igor , Shen Jiaxiang , Timothy Katherine W. , Lehmann Michael H. , Priori Silvia , Robinson Jennifer L. , Moss Arthur J. , Schwartz Peter J. , Towbin Jeffrey A. , Vincent G. Michael , Keating Mark T.
Published: June 2012

Background
—Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS:
KVLQT1
,
HERG
,
SCN5A
,
KCNE1
, and
KCNE2
. Mutations in
KVLQT1
and
KCNE1
also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.

Methods and Results
—We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals).

Conclusions
—
KVLQT1
(42%) and
HERG
(45%) accounted for 87% of identified mutations, and
SCN5A
(8%),
KCNE1
(3%), and
KCNE2
(2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.
Low Heart Rate Variability in a 2-Minute Rhythm Strip Predicts Risk of Coronary Heart Disease and Mortality From Several Causes
Authors: Dekker Jacqueline M. , Crow Richard S. , Folsom Aaron R. , Hannan Peter J. , Liao Duanping , Swenne Cees A. , Schouten Evert G.
Published: June 2012

Background
—Low heart rate variability (HRV) is associated with a higher risk of death in patients with heart disease and in elderly subjects and with a higher incidence of coronary heart disease (CHD) in the general population.

Methods and Results
—We studied the predictive value of HRV for CHD and death from several causes in a population study of 14 672 men and women without CHD, aged 45 to 65, by using the case-cohort design. At baseline, in 1987 to 1989, 2-minute rhythm strips were recorded. Time-domain measures of HRV were determined in a random sample of 900 subjects, for all subjects with incident CHD (395 subjects), and for all deaths (443 subjects) that occurred through 1993. Relative rates of incident CHD and cause-specific death in tertiles of HRV were computed with Poisson regression for the case-cohort design. Subjects with low HRV had an adverse cardiovascular risk profile and an elevated risk of incident CHD and death. The increased risk of death could not be attributed to a specific cause and could not be explained by other risk factors.

Conclusions
—Low HRV was associated with increased risk of CHD and death from several causes. It is hypothesized that low HRV is a marker of less favorable health.
Anticardiolipin Antibodies and Recurrent Coronary Events
Authors: Bili Androniki , Moss Arthur J. , Francis Charles W. , Zareba Wojciech , Watelet Luc F. Miller , Sanz Ignacio , Factors for the Thrombogenic , Investigators Recurrent Coronary Events
Published: June 2012

Background
—The association of anticardiolipin (aCL) antibodies with coronary artery disease has been shown in several studies but remains controversial. We evaluated the association of aCL and anti–β
2
-glycoprotein I (aβ
2
GPI) antibodies with the risk of recurrent cardiac events in postinfarction patients.

Methods and Results
—The study population consisted of 1150 patients with acute myocardial infarction. Levels of IgG and IgM aCL and aβ
2
GPI antibodies were determined on sera collected before hospital discharge. There were 131 recurrent cardiac events (nonfatal myocardial infarctions or cardiac deaths) over a mean follow-up period of 24.6 months. Patients with elevated IgG aCL antibodies had a higher event rate than patients with low levels (
P
=0.05). Multivariate Cox analysis after adjustment for relevant clinical covariates showed that elevated levels of IgG aCL (hazard ratio=1.63;
P
=0.01) and low levels of IgM aCL (hazard ratio of 1.76;
P
=0.02) antibodies contribute independent risks for recurrent cardiac events. Patients with elevated IgG aCL and low IgM aCL antibody levels had a 3-fold higher risk of recurrent cardiac events than patients with low IgG aCL and elevated IgM aCL antibody levels (
P
<0.001). There was no significant association of the aβ
2
GPI antibodies with recurrent cardiac events.

Conclusions
—In postinfarction patients, elevated IgG aCL and low IgM aCL antibodies are independent risk factors for recurrent cardiac events. Patients with both elevated IgG aCL and low IgM aCL antibodies have the highest risk. These findings shed additional light on the mechanistic role of aCL antibodies in coronary artery disease in patients without autoimmune diseases.
Nitric Oxide Provokes Tumor Necrosis Factor-α Expression in Adult Feline Myocardium Through a cGMP-Dependent Pathway
Authors: Kalra Dinesh , Baumgarten Georg , Dibbs Ziad , Seta Yukihiro , Sivasubramanian Natarajan , Mann Douglas L.
Published: June 2012

Background
—The mechanism(s) responsible for the persistent coexpression of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) in the failing heart is unknown.

Methods and Results
—To determine whether NO was sufficient to provoke TNF-α biosynthesis, we examined the effects of an NO donor, S-nitroso-N-acetyl penicillamine (SNAP), in buffer-perfused Langendorff hearts. SNAP (1 μmol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF-α mRNA and protein biosynthesis in adult cat hearts. The effects of SNAP were completely abrogated by a NO quenching agent, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (C-PTIO), and mimicked by sodium nitroprusside. Electrophoretic mobility shift assays demonstrated that SNAP treatment led to the rapid induction of nuclear factor kappa-beta (NF-κB) but not AP-1. The importance of the cGMP pathway in terms of mediating NO-induced TNF-α biosynthesis was shown by studies that demonstrated that 8-bromo-cGMP mimicked the effects of SNAP and that the effects of SNAP could be completely abrogated using a cGMP antagonist, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or protein kinase G antagonist (Rp-8-Br-cGMPS). SNAP and 8-Br-cGMP were both sufficient to lead to the site-specific phosphorylation (serine 32) and degradation of IκBα in isolated cardiac myocytes. Finally, protein kinase G was sufficient to directly phosphorylate IκBα on serine 32, a critical step in the activation of NF-κB.

Conclusions
—These studies show that NO provokes TNF-α biosynthesis through a cGMP-dependent pathway, which suggests that the coincident expression of TNF-α and NO may foster self-sustaining positive autocrine/paracrine feedback inflammatory circuits within the failing heart.
Canadian-American Differences in the Management of Acute Coronary Syndromes in the GUSTO IIb Trial
Authors: Fu Yuling , Chang Wei-Ching , Mark Dan , Califf Robert M. , Mackenzie Brian , Granger Christopher B. , Topol Eric J. , Hlatky Mark , Armstrong Paul W.
Published: June 2012

Background
—Little information exists concerning practice patterns between Canada and the United States in the management of myocardial infarction (MI) patients without ST-segment elevation and unstable angina.

Methods and Results
—We examined the practice patterns and 1-year outcomes of 2250 US and 922 Canadian patients without ST-elevation acute coronary syndromes in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb trial. The US hospitals more commonly had on-site facilities for angiography and revascularization. These procedures were performed more often and sooner in the United States than Canada, whereas Canadian patients were more likely to undergo noninvasive stress testing. The length of initial hospital stay was 1 day longer for Canadian than US patients. Recurrent and refractory ischemia was more common in Canada. One-year mortality was comparable between the 2 countries. However, at 6 months, even after baseline differences were accounted for, the (re)MI rate was significantly higher in Canadian than US patients with unstable angina (8.8% versus 5.8%,
P
=0.039), as was the composite rate of death or (re)MI (13.1% versus 9.1%,
P
=0.016).

Conclusions
—One-year mortality was comparable between Canada and the United States in both MI and unstable angina cohorts despite higher intervention rates in the United States. However, outcomes at 6 months among patients with unstable angina differed. Whereas more frequent coronary interventions were not associated with reduced recurrent MI or death among MI patients without ST elevation, they may favorably affect outcomes in patients with unstable angina.
Anticipatory Blood Pressure Responses to Exercise Are Associated With Left Ventricular Mass in Finnish Men
Authors: Kamarck Thomas W. , Eränen Jaakko , Jennings J. Richard , Manuck Stephen B. , Everson Susan A. , Kaplan George A. , Salonen Jukka T.
Published: June 2012

Background
—Exaggerated cardiovascular reactivity to psychological demands may contribute to the development of left ventricular (LV) hypertrophy. We examined the cross-sectional association between anticipatory blood pressure (BP) responses to bicycle exercise and LV mass in the Kuopio Ischemic Heart Disease Risk Factor Study, a population-based epidemiological sample.

Methods and Results
—Among 876 men from 4 age cohorts (ages 42, 48, 58, and 64 years), we collected echocardiographic assessments of LV mass along with measures of BP response taken before bicycle ergometry testing. Anticipatory BP responses were positively associated with LV mass, with significant associations only among younger (age <50 years) subjects with elevated resting pressures (3-way interactions for anticipatory BP×age×resting pressure for systolic and diastolic BP, all
P
<0.05; for younger subjects with elevated systolic BP,
P
<0.01; and for younger subjects with elevated diastolic BP,
P
<0.001). Among these subgroups, exaggerated anticipatory BP responses (top quartile) were associated with an incremental increase in LV mass of 10% or greater, corrected for body surface area. Results remained significant after adjusting for age, education, salt consumption, and resting BP, and the pattern of findings was maintained among men with no previous history of cardiovascular disease.

Conclusions
—The tendency to show exaggerated pressor responses to psychological demands may be a significant independent correlate of LV mass, especially among young men with high resting pressures. This is the first study to examine such associations in a middle-aged population sample.
Functional Protection by Acute Phase Proteins α
1
-Acid Glycoprotein and α
1
-Antitrypsin Against Ischemia/Reperfusion Injury by Preventing Apoptosis and Inflammation
Authors: Daemen Marc A. R. C. , Heemskerk Vincent H. , van ’t Veer Cornelis , Denecker Geertrui , Wolfs Tim G. A. M. , Vandenabeele Peter , Buurman Wim A.
Published: June 2012

Background
—Ischemia followed by reperfusion (I/R) causes apoptosis, inflammation, and tissue damage leading to organ malfunction. Ischemic preconditioning can protect against such injury. This study investigates the contribution of the acute phase proteins α
1
-acid glycoprotein (AGP) and α
1
-antitrypsin (AAT) to the protective effect of ischemic preconditioning in the kidney.

Methods and Results
—Exogenous AGP and AAT inhibited apoptosis and inflammation after 45 minutes of renal I/R in a murine model. AGP and AAT administered at reperfusion prevented apoptosis at 2 hours and 24 hours, as evaluated by the presence of internucleosomal DNA cleavage, terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling, and the determination of renal caspase-1– and caspase-3–like activity. AGP and AAT exerted anti-inflammatory effects, as reflected by reduced renal tumor necrosis factor-α expression and neutrophil influx after 24 hours. In general, these agents improved renal function. Similar effects were observed when AGP and AAT were administered 2 hours after reperfusion but to a lesser extent and without functional improvement. Moreover, I/R elicited an acute phase response, as reflected by elevated serum AGP and serum amyloid P (SAP) levels after 24 hours, and increased hepatic acute phase protein mRNA levels after 18 hours of renal reperfusion.

Conclusions
—We propose that the antiapoptotic and anti-inflammatory effects of AGP and AAT contribute to the delayed type of protection associated with ischemic preconditioning and other insults. This mechanism is potentially involved in the course of many clinical conditions associated with I/R injury. Moreover, exogenous administration of these proteins may provide new therapeutic means of treatment.
Effects of Combined Angiotensin II and Endothelin Receptor Blockade With Developing Heart Failure
Authors: New R. Brent , Sampson Angela C. , King Mary K. , Hendrick Jennifer W. , Clair Mark J. , McElmurray James H. , Mandel Jeffrey , Mukherjee Rupak , Marc de Gasparo  , Spinale Francis G.
Published: June 2012

Background
—The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT
1
) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF).

Methods and Results
—Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT
1
receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT
1
and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT
1
or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with the rapid pacing group. Plasma norepinephrine levels were increased by >3-fold after rapid pacing, remained increased in the monotherapy groups, but were reduced after combination treatment. LV myocyte velocity of shortening was reduced after rapid pacing–induced CHF, remained reduced after AT
1
receptor blockade, increased after ET receptor blockade (compared with rapid pacing–induced CHF values), and returned to within control values after combined blockade.

Conclusions
—Combined AT
1
and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance. Thus, combined receptor blockade may provide a useful combinatorial therapeutic approach in CHF.
Three-Dimensional Intravascular Ultrasound Assessment of Noninjured Edges of β-Irradiated Coronary Segments
Authors: Kozuma Ken , Costa Marco A. , Sabaté Manel , Kay I. Patrick , Marijnissen Johannes P. A. , Coen Veronique L. M. A. , Serrano Pedro , Ligthart Jurgen M. R. , Levendag Peter C. , Serruys Patrick W.
Published: June 2012

Background
—The “edge effect,” late lumen loss at the margins of the treated segment, has become an important issue in the field of coronary brachytherapy. The aim of the present study was to assess the edge effect in noninjured margins adjacent to the irradiated segments after catheter-based intracoronary β-irradiation.

Methods and Results
—Fifty-three vessels were assessed by means of 3-dimensional intravascular ultrasound after the procedure and at 6- to 8-month follow-up. Fourteen vessels (placebo group) did not receive radiation (sham source), whereas 39 vessels were irradiated. In the irradiated group, 48 edges (5 mm in length) were identified as noninjured, whereas 18 noninjured edges were selected in the placebo group. We compared the volumetric intravascular ultrasound measurements of the noninjured edges of the irradiated vessels with the fully irradiated nonstented segments (IRS, n=27) (26-mm segments received the prescribed 100% isodose) and the noninjured edges of the vessels of the placebo patients. The lumen decreased (6 mm
3
) in the noninjured edges of the irradiated vessels at follow-up (
P
=0.001). We observed a similar increase in plaque volume in all segments: noninjured edges of the irradiated group (19.6%), noninjured edges of the placebo group (21.5%), and IRS (21.0%). The total vessel volume increased in the IRS in the 3 groups. No edge segment was subject to repeat revascularization.

Conclusions
—The edge effect occurs in the noninjured margins of radiation source train in both irradiated and placebo patients. Thus, low-dose radiation may not play an important role in this phenomenon, whereas nonmeasurable device injury may be considered a plausible alternative explanation.
Value of Serum-Soluble Intercellular Adhesion Molecule-1 for the Noninvasive Risk Assessment of Transplant Coronary Artery Disease, Posttransplant Ischemic Events, and Cardiac Graft Failure
Authors: Labarrere Carlos A. , Nelson David R. , Miller Steven J. , Nieto Jennifer M. , Conner Jennifer A. , Pitts Douglas E. , Kirlin Philip C. , Halbrook Harold G.
Published: June 2012

Background
—Adhesion molecules on arterial endothelium have been implicated in spontaneous atherosclerosis and transplant coronary artery disease (CAD). We studied whether elevated serum-soluble intercellular adhesion molecule-1 (sICAM-1) during the immediate posttransplant period was a risk factor for CAD, posttransplant ischemic events, or cardiac graft failure.

Methods and Results
—We initially studied serum sICAM-1 in a subset of 16 cardiac allograft recipients (5.5±0.7 samples per patient) to determine a cutoff point that best correlated with presence of arterial and arteriolar endothelial ICAM-1 in matching endomyocardial biopsies. The cutoff value was 308 ng/mL. Subsequently, we prospectively evaluated serum sICAM-1 in serial samples (5.3±0.1 per patient) obtained during the first 3 months after transplantation in a validation subset of 130 recipients and correlated early sICAM-1 levels with long-term outcome. Serum sICAM-1 >308 ng/mL correlated significantly with ICAM-1 on arterial and arteriolar endothelium (
P
=0.02). Cardiac allograft recipients with serum sICAM-1 >308 ng/mL had 2.67 (95% CI, 1.28 to 5.59,
P
=0.009) times greater risk of CAD and 3.63 (95% CI, 1.05 to 12.5,
P
=0.04) times greater risk of graft failure. Recipients with sICAM-1 >308 ng/mL also developed more severe CAD (
P
=0.009) and more ischemic events (
P
=0.03) after transplantation.

Conclusions
—Serum sICAM-1 levels can be used to noninvasively assess risk of transplant CAD, posttransplant ischemic events, and cardiac graft failure.
17β-Estradiol Decreases Endothelin-1 Levels in the Coronary Circulation of Postmenopausal Women With Coronary Artery Disease
Authors: Webb Carolyn M. , Ghatei Mohammad A. , McNeill John G. , DCRR  , Collins Peter
Published: June 2012

Background
—Estrogen reverses acetylcholine-induced coronary vasoconstriction via the possible facilitation of endothelium-derived NO. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the effects of 17β-estradiol on coronary vasomotor responses to substance P (SP), and coronary sinus endothelin-1 and NO metabolite levels in postmenopausal women with coronary heart disease.

Methods and Results
—We studied 20 women; 14 received estrogen (mean age 65±2 years) and 6 served as ethanol control subjects (age 63±3 years). Intracoronary infusions of papaverine (8 mg) and SP were administered before and 20 minutes after 50 pg/min 17β-estradiol or 0.2 μL/min control. Coronary blood flow was calculated from the diameter, as measured with quantitative coronary angiography, and flow velocity, as measured with intracoronary Doppler. Coronary sinus plasma endothelin-1 and nitrite/nitrate (NO
2
/NO
3
) were measured at baseline, at peak velocity response to each infusion, and every 5 minutes during the estradiol infusion. Endothelin-1 levels were decreased after 20 minutes of estradiol (1.12±0.18 versus 0.86±0.17 pmol/L baseline2 versus estradiol,
P
=0.05). Endothelin-1 levels to SP decreased after 17β-estradiol (1.29±0.18 versus 1.04±0.15 and 1.3±0.16 versus 0.99±0.17 pmol/L for before versus after estradiol, 10 and 25 pmol/min SP; both
P
<0.05). NO
2
/NO
3
levels did not change. There was no change in vasomotor responses to estradiol alone or to papaverine or SP before versus after estradiol.

Conclusions
—Short-term intracoronary 17β-estradiol administration decreases coronary endothelin-1 levels. There was no enhancement of vasomotor responses to SP after the administration of estrogen, suggesting that the effects of estrogen on coronary acetylcholine responses may be a specific and not a generalized effect on coronary vasoreactivity.
Development of Antibody Against Epitope of Lipoprotein(a) Modified by Oxidation
Authors: Yamada Shingo , Morishita Ryuichi , Nakamura Shigefumi , Ogihara Toshio , Kusumi Yoshiaki , Sakurai Isamu , Kubo Nobuhiko , Sakurabayashi Ikunosuke
Published: June 2012

Background
—Recently, the biological effects of oxidized lipoprotein(a) [Lp(a)] have been reported to be more potent than Lp(a), the arteriosclerosis-relevant lipoprotein. Thus, investigations with oxidized Lp(a) are expected to provide viewpoints different from the conventional ones based on Lp(a).

Methods and Results
—An anti-Lp(a) monoclonal antibody (161E2) was produced against synthetic peptide antigen (Arg-Asn-Pro-Asp-Val-Ala-Pro). This epitope was characterized as having various properties because its external exposure was induced as a result of oxidative modification. Using 161E2 antibody, we developed a new enzyme-linked immunosorbent assay to measure Lp(a) modified by oxidative stress. The present data demonstrated that oxidized Lp(a) that contains the epitope of 161E2 antibody was present in the serum of humans. Therefore, we used this new enzyme-linked immunosorbent assay to evaluate the role of oxidized Lp(a) in patients with hypertension, which induces oxidative stress . Interestingly, hypertensive patients with complications showed a significantly higher level of oxidized Lp(a) in serum than did normotensive subjects (
P
<0.01), whereas there was no significant difference in native Lp(a) between normotensive and hypertensive subjects. Importantly, positive immunostaining with 161E2 monoclonal antibody was found in the human arteriosclerotic tissue.

Conclusions
—We developed a new antibody against an epitope in Lp(a) as a result of oxidation treatment but not in native Lp(a). The present data demonstrated in vivo the presence of oxidized Lp(a) in the atherosclerotic tissue and its elevation in hypertensive patients. The presence of oxidized Lp(a) may be important in understanding the role of Lp(a) in cardiovascular disease.
Inhibitory Effect of Angiotensin II Type 2 Receptor on Coronary Arterial Remodeling After Aortic Banding in Mice
Authors: Akishita Masahiro , Iwai Masaru , Wu Lan , Zhang Lunan , Ouchi Yasuyoshi , Dzau Victor J. , Horiuchi Masatsugu
Published: June 2012

Background
—The renin-angiotensin system is thought to be critical for the development of cardiac hypertrophy, whereas the role of the angiotensin II type 2 (AT
2
) receptor in the process is not defined. Using the AT
2
receptor–null (
Agtr2
−) mouse, we tested the hypothesis that the AT
2
receptor could exert an antigrowth effect in cardiac hypertrophy.

Methods and Results
—Cardiac hypertrophy was induced by suprarenal abdominal aortic banding in 10- to 12-week-old
Agtr2
− and wild-type (
Agtr2
+) mice for 6 or 12 weeks. Carotid arterial pressure was not different between the strains, although aortic banding increased arterial pressure by ≈40 mm Hg. Aortic banding increased the heart-weight/body-weight ratio and the cross-sectional area of cardiomyocytes by 15%, resulting in comparable cardiomyocyte hypertrophy in the 2 strains. In contrast, coronary arterial thickening and perivascular fibrosis, determined by the media/lumen-area ratio and the collagen/vessel-area ratio, respectively, were 50% greater in
Agtr2
− than in
Agtr2
+ mice after banding, whereas these parameters were similar in sham-operated mice. Radioligand binding studies using the whole heart and immunohistochemistry showed that AT
2
receptor expression was limited and localized in the coronary artery and perivascular region.

Conclusions
—These results suggest that the AT
2
receptor mediates an inhibitory effect on coronary arterial remodeling, such as medial hypertrophy and perivascular fibrosis in response to pressure overload, and an activation of the renin-angiotensin system.
Functional Effect of the C242T Polymorphism in the NAD(P)H Oxidase p22phox Gene on Vascular Superoxide Production in Atherosclerosis
Authors: Guzik Tomasz J. , West Nick E. J. , Black Edward , McDonald Denise , Ratnatunga Chandi , Pillai Ravi , Channon Keith M.
Published: June 2012

Background
—Increased superoxide anion production increases oxidative stress and reduces nitric oxide bioactivity in vascular disease states. NAD(P)H oxidase is an important source of superoxide in human blood vessels, and some studies suggest a possible association between polymorphisms in the NAD(P)H oxidase
CYBA
gene and atherosclerosis; however, no functional data address this hypothesis. We examined the relationships between the
CYBA
C242T polymorphism and direct measurements of superoxide production in human blood vessels.

Methods and Results
—Vascular NAD(P)H oxidase activity was determined in human saphenous veins obtained from 110 patients with coronary artery disease and identified risk factors. Immunoblotting, reverse-transcription polymerase chain reaction, and DNA sequencing showed that p22phox protein, mRNA, and 242C/T allelic variants are expressed in human blood vessels. Vascular superoxide production, both basal and NADH-stimulated, was highly variable between patients, but the presence of the
CYBA
242T allele was associated with significantly reduced vascular NAD(P)H oxidase activity, independent of other clinical risk factors for atherosclerosis.

Conclusions
—Association of the
CYBA
242T allele with reduced NAD(P)H oxidase activity in human blood vessels suggests that genetic variation in NAD(P)H oxidase components may play a significant role in modulating superoxide production in human atherosclerosis.
Depressive Symptoms and Risks of Coronary Heart Disease and Mortality in Elderly Americans
Authors: Ariyo Abraham A. , Haan Mary , Tangen Catherine M. , Rutledge John C. , Cushman Mary , Dobs Adrian , Furberg Curt D.
Published: June 2012

Background
—Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort.

Methods and Results
—In a prospective cohort of 5888 elderly Americans (≥65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (
P
=0.006); the ratio for all-cause mortality was 1.29 (
P
<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (
P
=0.006) and that for all-cause mortality was 1.16 (
P
=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores.

Conclusions
—Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.