bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Between Human Aldosterone Synthase (CYP11B2) Gene Polymorphisms and Left Ventricular Size, Mass, and Function
Authors: Kupari Markku , Hautanen Aarno , Lankinen Laura , Koskinen Pekka , Virolainen Juha , Nikkila Heli , White Perrin C.
Published: June 2012

Background
—Aldosterone has direct and indirect effects on the heart, and genetic variations in aldosterone synthesis could therefore influence cardiac structure and function. Such variations might be associated with polymorphisms in the gene encoding aldosterone synthase (
CYP11B2
), the enzyme catalyzing the last steps of aldosterone biosynthesis.

Methods and Results
—A Finnish population sample of 84 persons (44 women) aged 36 to 37 years was studied by M-mode and Doppler echocardiography to assess left ventricular size, mass, and function. Subjects were genotyped through the use of the polymerase chain reaction for two diallelic polymorphisms in
CYP11B2
: one in the transcriptional regulatory region (promoter) and the other in the second intron. In multiple regression analyses, the
CYP11B2
promoter genotype predicted statistically significant variations in left ventricular end-diastolic diameter (β=.40,
P
<.0001), end-systolic diameter (β=.33,
P
=.0009), and mass (β=.17,
P
=.023). These effects were independent of potentially confounding factors, including sex, body size, blood pressure, physical activity, smoking, and ethanol consumption. Genotype groups also differed in a measure of left ventricular diastolic function, the heart rate–adjusted atrial filling fraction (
P
=.018). Increased dietary salt, which is known to predict increased left ventricular mass, had this effect only in association with certain
CYP11B2
genotypes (
P
<.001).

Conclusions
—Genetic variations in or near the aldosterone synthase (
CYP11B2
) gene strongly affect left ventricular size and mass in young adults free of clinical heart disease. These polymorphisms may also influence the response of the left ventricle to increases in dietary salt.
Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries
Authors: Gallo Richard , Padurean Adrian , Toschi Vincenzo , Bichler Johan , Fallon John T. , Chesebro James H. , Fuster Valentin , Badimon Juan J.
Published: June 2012

Background
—Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA.

Methods and Results
—Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolus+0.7 mg/kg per day for 2 days), and long-term (bolus+0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58±3% versus 35±3%;
P
<.001). No differences were observed among the bolus and short-term hirudin groups and the control group.

Conclusions
—Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA. Therefore an adequate and prolonged administration of thrombin inhibitors is needed to “passivate” the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach.
Induction of Neoangiogenesis in Ischemic Myocardium by Human Growth Factors
Authors: Schumacher B. , Pecher P. , von Specht B. U. , Stegmann Th.
Published: June 2012

Background
—The present article is a report of our animal experiments and also of the first clinical results of a new treatment for coronary heart disease using the human growth factor FGF-I (basic fibroblast growth factor) to induce neoangiogenesis in the ischemic myocardium.

Methods and Results
—FGF-I was obtained from strains of
Escherichia coli
by genetic engineering, then isolated and highly purified. Several series of animal experiments demonstrated the apathogenic action and neoangiogenic potency of this factor. After successful conclusion of the animal experiments, it was used clinically for the first time. FGF-I (0.01 mg/kg body weight) was injected close to the vessels after the completion of internal mammary artery (IMA)/left anterior descending coronary artery (LAD) anastomosis in 20 patients with three-vessel coronary disease. All the patients had additional peripheral stenoses of the LAD or one of its diagonal branches. Twelve weeks later, the IMA bypasses were selectively imaged by intra-arterial digital subtraction angiography and quantitatively evaluated. In all the animal experiments, the development of new vessels in the ischemic myocardium could be demonstrated angiographically. The formation of capillaries could also be demonstrated in humans and was found in all cases around the site of injection. A capillary network sprouting from the proximal part of the coronary artery could be shown to have bypassed the stenoses and rejoined the distal parts of the vessel.

Conclusions
—We believe that the use of FGF-I for myocardial revascularization is in principle a new concept and that it may be particularly suitable for patients with additional peripheral stenoses that cannot be revascularized surgically.
Dissolution of Mural Thrombus by Specific Thrombin Inhibition With r-Hirudin
Authors: Meyer Beat J. , Badimon Juan J. , Chesebro James H. , Fallon John T. , Fuster Valentin , Badimon Lina
Published: June 2012

Background
—The presence of residual mural thrombus may predispose to recurrent thrombotic events in acute coronary syndromes. The purpose of this study was to evaluate the effects of antithrombotic and antiplatelet agents on a preformed, fresh mural thrombus during growth of thrombus.

Methods and Results
—A fresh mural thrombus was formed by perfusing severely injured arterial wall with porcine blood for 5 minutes at a shear rate of 1690 s
−1
. Thrombus formation was measured by morphometric analysis (mm
2
/mm). The average size of a mural thrombus formed in 5 minutes was 0.14±0.03 mm
2
/mm. Progression of thrombus growth within 10 minutes triggered by the preformed thrombus was evaluated in pigs treated with r-hirudin (1 mg/kg per hour IV) as a probe for thrombin, high-dose heparin (250 IU/kg per hour IV), moderate-dose heparin (100 IU/kg per hour), moderate-dose heparin (100 IU/kg per hour) plus aspirin, aspirin alone (5 mg/kg IV), and placebo. Hirudin was associated with a significant decrease (48%) of mural thrombus area and significantly reduced growth of thrombus (0.07±0.01), even compared with the highest dose of heparin (0.15±0.03), although at lower levels of anticoagulation. Inhibition of growth of thrombus with heparin was dose dependent, showing an inverse correlation of thrombus area with mean plasma heparin concentrations (
r
=.77,
P
=.0001). Thrombus size was unchanged by aspirin (0.29±0.07) compared with controls (0.28±0.07).

Conclusions
—Direct inhibition of thrombin activity with r-hirudin completely inhibits growth of thrombus, causes dissolution of a preexisting mural thrombus, and is more effective at lower levels of anticoagulation than the highest dose of heparin at shear rates typical of a moderate coronary stenosis.
Lipoprotein(a) Enhances the Expression of Intercellular Adhesion Molecule-1 in Cultured Human Umbilical Vein Endothelial Cells
Authors: Takami Shigeki , Yamashita Shizuya , Kihara Shinji , Ishigami Masato , Takemura Kaoru , Kume Noriaki , Kita Toru , Matsuzawa Yuji
Published: June 2012

Background
—We reported an increase in serum lipoprotein(a) [Lp(a)] levels in patients with thromboangiitis obliterans, suggesting that Lp(a) could also contribute to the pathogenesis of cardiovascular diseases by a mechanism different from atherosclerosis. Adhesion molecules were shown to contribute to the development of not only atherosclerotic but also inflammatory vascular diseases.

Methods and Results
—We evaluated the effect of Lp(a) on the expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in human umbilical vein endothelial cells by a cell ELISA. Lp(a) dramatically enhanced the levels of ICAM-1 in a dose-dependent manner. A discernible increase in ICAM-1 expression was observed at a physiological concentration of 0.26 mmol cholesterol/L Lp(a) after 48-hour incubation. A 1.8-fold increase in ICAM-1 expression was observed 48 hours after the addition of Lp(a) (1.04 mmol cholesterol/L). Northern blot analysis demonstrated that the amount of ICAM-1 mRNA was increased after treatment with Lp(a). In contrast to ICAM-1, the expression of VCAM-1 and E-selectin was not significantly affected by Lp(a). Lp(a−) [apolipoprotein(a)-removed Lp(a) by reduction with dithiothreitol] and LDL had no significant effect on the expression of ICAM-1. In contrast, recombinant apolipoprotein(a) protein alone significantly enhanced ICAM-1 expression. Lp(a) decreased the level of active transforming growth factor (TGF)-β in the conditioned medium. Furthermore, recombinant TGF-β significantly decreased the Lp(a)-induced ICAM-1 expression. These findings suggested that Lp(a) may enhance the ICAM-1 expression by decreasing active TGF-β level.

Conclusions
—Lp(a) could contribute to the development of cardiovascular diseases by enhancing the expression of ICAM-1 in endothelial cells.
Endothelin-A Receptor Antagonist–Mediated Vasodilatation Is Attenuated by Inhibition of Nitric Oxide Synthesis and by Endothelin-B Receptor Blockade
Authors: Verhaar Marianne C. , Strachan Fiona E. , Newby David E. , Cruden Nicholas L. , Koomans Hein A. , Rabelink Ton J. , Webb David J.
Published: June 2012

Background
—The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET
A
receptors are clear, the contribution from endothelial and vascular smooth muscle ET
B
receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET
A
and ET
B
receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET
A
-selective receptor antagonist BQ-123.

Methods and Results
—Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% (
P
=.006) with inhibition of the endogenous generation of nitric oxide and by 38% (
P
<.001) with coinfusion of the ET
B
receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow (
P
<.001).

Conclusions
—Selective ET
A
receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET
B
receptor antagonism either alone or on a background of ET
A
antagonism causes local vasoconstriction, indicating that ET
B
receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.
Relationships of Abdominal Obesity and Hyperinsulinemia to Angiographically Assessed Coronary Artery Disease in Men With Known Mutations in the LDL Receptor Gene
Authors: Gaudet Daniel , Vohl Marie-Claude , Perron Patrice , Tremblay Gérald , Gagné Claude , Lesiège Daniel , Bergeron Jean , Moorjani Sital , Després Jean-Pierre
Published: June 2012

Background
—Patients with a mutation in the LDL receptor gene (familial hypercholesterolemia, or FH) are characterized by substantial elevations in plasma LDL cholesterol and are at higher risk of developing coronary artery disease (CAD). Correlates of abdominal obesity may also contribute to the risk of ischemic cardiac events. Whether the hyperinsulinemic–insulin-resistant state of abdominal obesity affects coronary atherosclerosis among FH patients has not been determined.

Methods and Results
—The relation of abdominal adiposity and hyperinsulinemia to angiographically assessed CAD was evaluated in a sample of 120 French Canadian men aged <60 years who were heterozygotes for FH and in a group of 280 men without FH. In the present study, the risk of CAD associated with abdominal obesity, as estimated by the waist circumference, was largely dependent on the concomitant variation in plasma lipoprotein and insulin concentrations. In contrast, the association between fasting insulin and CAD was independent of variations in waist girth, triglyceride, HDL, and apolipoprotein B concentrations (odds ratio, 1.86;
P
=.0005). However, the most substantial increase in the risk of CAD was observed among abdominally obese (waist circumference >95 cm) and hyperinsulinemic FH patients (odds ratio, 12.9;
P
=.0009). This increase in risk remained significant even after adjustment for LDL cholesterol or apolipoprotein B concentrations.

Conclusions
—Results of the present study provide support for the notion that the hyperinsulinemic–insulin-resistant state of abdominal obesity is a powerful predictor of CAD in men, even in a group of patients with raised LDL cholesterol concentrations due to FH.
Histopathology of Human Coronary Atherosclerosis by Quantifying Its Chemical Composition With Raman Spectroscopy
Authors: Römer Tjeerd J. , Brennan James F. , Fitzmaurice Maryann , Feldstein Michael L. , Deinum Geurt , Myles Jonathan L. , Kramer John R. , Lees Robert S. , Feld Michael S.
Published: June 2012

Background
—Lesion composition, rather than size or volume, determines whether an atherosclerotic plaque will progress, regress, or rupture, but current techniques cannot provide precise quantitative information about lesion composition. We have developed a technique to assess the pathological state of human coronary artery samples by quantifying their chemical composition with near-infrared Raman spectroscopy.

Methods and Results
—Coronary artery samples (n=165) obtained from explanted recipient hearts were illuminated with 830-nm infrared light. Raman spectra were collected from the tissue and processed to quantify the relative weights of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts in the examined artery location. The artery locations were then classified by a pathologist and grouped as either nonatherosclerotic tissue, noncalcified plaque, or calcified plaque. Nonatherosclerotic tissue, which included normal artery and intimal fibroplasia, contained an average of ≈4±3% cholesterol, whereas noncalcified plaques had ≈26±10% and calcified plaques ≈19±10% cholesterol in the noncalcified regions. The average relative weight of calcium salts was 1±2% in noncalcified plaques and 41±21% in calcified plaques. To make this quantitative chemical information clinically useful, we developed a diagnostic algorithm, based on a first set of 97 samples, that demonstrated a strong correlation of the relative weights of cholesterol and calcium salts with histological diagnoses of the same locations. This algorithm was then prospectively tested on a second set of 68 samples. The algorithm correctly classified 64 of these new samples, thus demonstrating the accuracy and robustness of the method.

Conclusions
—The pathological state of a given human coronary artery may be assessed by quantifying its chemical composition, which can be done rapidly with Raman spectroscopic techniques. When Raman spectra are obtained clinically via optical fibers, Raman spectroscopy may be useful in monitoring the progression and regression of atherosclerosis, predicting plaque rupture, and selecting proper therapeutic intervention.
Effect of Atherosclerosis on Endothelium-Dependent Inhibition of Platelet Activation in Humans
Authors: Diodati Jean G. , Dakak Nader , Gilligan David M. , Quyyumi Arshed A.
Published: June 2012

Background
—We investigated whether luminal release of nitric oxide (NO) contributes to inhibition of platelet activation and whether these effects are reduced in patients with atherosclerosis.

Methods and Results
—Femoral blood flow velocity and ex vivo whole blood platelet aggregation by impedance aggregometry were measured in femoral venous blood during femoral arterial infusion of acetylcholine (ACh; 30 μg/min) in 30 patients, 19 of whom had angiographic atherosclerosis. Measurements were repeated with sodium nitroprusside (40 μg/min),
l
-arginine (160 μmol/min), and
N
G
-monomethyl-
l
-arginine (L-NMMA; 16 μmol/min). There was significant inhibition of collagen-induced platelet aggregation with ACh (45±9.5% lower,
P
<0.001), and this inhibition was greater in patients without atherosclerosis (68.7±10.4% reduction) than in those with atherosclerosis (32.5±8.1%,
P
=0.04). The magnitude of inhibition correlated with vasodilation with ACh, indicating an association between the smooth muscle and antiplatelet effects of endothelium-dependent stimulation. Neither L-NMMA nor sodium nitroprusside altered platelet aggregation.
l
-Arginine inhibited platelet aggregation equally in vitro (34±8% reduction,
P
<0.01) and in vivo (37±13% reduction,
P
<0.01).

Conclusions
—Stimulation of NO release into the vascular lumen with ACh inhibits platelet aggregation, an effect that is attenuated in patients with atherosclerosis and endothelial dysfunction. Basal NO release does not appear to contribute to platelet passivation in vivo.
l
-Arginine inhibited platelet aggregation by its direct action on platelets. These findings provide a pathophysiological basis for the observed increase in thrombotic events in atherosclerosis. Use of
l
-arginine and other strategies to improve endothelial NO activity may impact favorably on thrombotic events in atherosclerosis.
Assessment of Atrioventricular Junction Ablation and VVIR Pacemaker Versus Pharmacological Treatment in Patients With Heart Failure and Chronic Atrial Fibrillation
Authors: Brignole Michele , Menozzi Carlo , Gianfranchi Lorella , Musso Giacomo , Mureddu Roberto , Bottoni Nicola , Lolli Gino
Published: June 2012

Background
—Uncontrolled studies have suggested that atrioventricular junction ablation and pacemaker implantation have beneficial effects on quality of life in patients with chronic atrial fibrillation (AF).

Methods and Results
—We performed a multicenter, controlled, randomized, 12-month evaluation of the clinical effects of atrioventricular junction ablation and VVIR pacemaker (Abl+Pm) versus pharmacological (drug) treatment in 66 patients with chronic (lasting >6 months) AF who had clinically manifest heart failure and heart rate >90 bpm on 3 standard ECGs recorded at rest during stable clinical conditions on different days. Before completion of the study, withdrawals occurred in 8 patients of the drug group and in 4 patients of the Abl+Pm group. At the end of the 12 months, the 28 Abl+Pm patients who completed the study showed lower scores in palpitations (−78%;
P
=0.000) and effort dyspnea (−22%;
P
=0.05) than the 26 of the drug group. Lower scores, although not significant, were also observed for exercise intolerance (−20%), easy fatigue (−17%), chest discomfort (−50%), Living with Heart Failure Questionnaire (−14%), New York Heart Association functional classification (−4%), and Activity scale (−12%). The intrapatient comparison between enrollment and month 12 showed that in the Abl+Pm group, all variables except easy fatigue improved significantly from 14% to 82%. However, because an improvement was also observed in the drug group, the difference between the 2 groups was significant only for palpitations (
P
=0.000), effort dyspnea (
P
=0.01), exercise intolerance (
P
=0.005), easy fatigue (
P
=0.02), and chest discomfort (
P
=0.02). Cardiac performance, evaluated by means of standard echocardiogram and exercise test, did not differ significantly between the 2 groups and remained stable over time.

Conclusions
—In patients with heart failure and chronic AF, Abl+Pm treatment is effective and superior to drug therapy in controlling symptoms, although its efficacy appears to be less than that observed in uncontrolled studies because some improvement can also be expected in medically treated patients. Cardiac performance is not modified by the treatment.
Progressive Tricuspid Valve Disease in Patients With Congenitally Corrected Transposition of the Great Arteries
Authors: Prieto Lourdes R. , Hordof Allan J. , Secic Michelle , Rosenbaum Marlon S. , Gersony Welton M.
Published: June 2012

Background
—The outcome of patients with corrected transposition of the great arteries (CTGA) is variably affected by associated intracardiac defects, tricuspid valve competence, and systemic right ventricular (RV) function. The relative importance of these factors in long-term outcome has not been evaluated.

Methods and Results
—Since 1958, 40 patients with CTGA were studied to determine risk factors for poor outcome, including age, open heart surgery, tricuspid insufficiency (TI), cardiac rhythm, pulmonary overcirculation, and RV dysfunction. Follow-up ranged from 7 to 36 years (mean 20 years). Intracardiac repair was performed in 21 patients; 19 were unoperated or had closed heart procedures. For the purposes of this study the designation TI
s
refers to at least moderately severe TI as delineated by echocardiogram and/or angiography. TI
s
was the only independently significant factor for death (
P
=0.01), and in turn, only the presence of a morphologically abnormal TV predicted TI
s
(
P
=0.03). Twenty-year survival without TI
s
was 93%, but only 49% with TI
s
. Poor long-term postoperative outcome was due to TI
s
in all but 1 patient; 20-year survival rates for operated patients with and without TI
s
were 34% and 90%, respectively (
P
=0.002). Similarly, 20-year survival rates for unoperated patients with and without TI
s
were 60% and 100%, respectively, whether or not attempts to repair the TI were made (
P
=0.08).

Conclusions
—TI
s
represents the major risk factor for CTGA patients; RV dysfunction appears to be almost always secondary to long-standing TI. Decisions related to surgical interventions with or without associated lesions must be strongly influenced by the status of the tricuspid valve.
Myocardial Infarction and Use of Low-Dose Oral Contraceptives
Authors: Sidney Stephen , Siscovick David S. , Petitti Diana B. , Schwartz Stephen M. , Quesenberry Charles P. , Psaty Bruce M. , Raghunathan Trivellore E. , Kelaghan Joseph , Koepsell Thomas D.
Published: June 2012

Background
—Population-based case-control studies to assess the relationship of low-dose oral contraceptive (OC) use with myocardial infarction (MI) were performed at 2 sites in the United States (California and Washington state). The purpose of the present study was to estimate risk of MI in relation to use of low-dose OCs in a pooled analysis combining results from the 2 sites.

Methods and Results
—The study included as cases women aged 18 to 44 years with incident MI who had no prior history of ischemic heart disease or cerebrovascular disease. Women in the case and control groups were interviewed in person regarding OC use and cardiovascular risk factors. The analysis included 271 MI cases and 993 controls. Compared with noncurrent users, the adjusted pooled odds ratio for MI in current OC users was 0.94 (95% CI, 0.44, 2.20) after adjustment for major risk factors and sociodemographic factors. Compared with never users, the adjusted pooled odds ratio for MI was 0.56 (0.21, 1.49) in current OC users and 0.54 (0.31, 0.95) in past OC users. Among past OC users, duration and recency of use were unrelated to MI risk as was current hormone replacement therapy. There was no evidence of interaction between OC use and age, presence of cardiovascular risk factors (hypercholesterolemia, hypertension, diabetes), obesity, or smoking.

Conclusions
—We conclude that low-dose OCs as used in these populations are safe with respect to risk of MI in women.
Induction of Early Atherosclerosis in LDL-Receptor–Deficient Mice Immunized With β
2
-Glycoprotein I
Authors: George Jacob , Afek Arnon , Gilburd Boris , Blank Miri , Levy Yair , Aron-Maor Anabel , Levkovitz Hana , Shaish Aviv , Goldberg Iris , Kopolovic Juri , Harats Dror , Shoenfeld Yehuda
Published: June 2012

Background
—Immunization with β
2
-glycoprotein I (β2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of β2GPI immunization on the progression of atherosclerosis.

Methods and Results
—In the first experiment, 3 groups of LDL receptor–deficient (LDL-RD) mice (n=15 per group) were immunized with either β2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All β2GPI-immunized mice developed high titers of anti-β2GPI antibodies as well as a specific lymph node proliferation to β2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the β2GPI-immunized mice (mean aortic lesion, 26 000±5700 μm
2
) in comparison with their ovalbumin-immunized (mean, 3000±1099 μm
2
;
P
<0.01) and nonimmunized (mean, 2250±700 μm
2
;
P
<0.01) littermates. The average lesion size in the β2GPI-immunized mice fed an atherogenic diet (mean, 98 000±8305 μm
2
) was larger than the ovalbumin-immunized mice (mean, 81 250±12 933 μm
2
;
P
=NS) or the nonimmunized controls (mean, 75 625±7281 μm
2
;
P
=NS). The atherosclerotic plaques in the β2GPI-immunized mice appeared to be more mature, and denser infiltration of CD4 lymphocytes was present in the subendothelium of the aortic sinuses from this group of mice.

Conclusions
—The results of the present study provide the first direct evidence for the proatherogenic effect of β2GPI immunization and establish a new model for immune-mediated atherosclerosis.
Enhanced Susceptibility for Acquired Torsade de Pointes Arrhythmias in the Dog With Chronic, Complete AV Block Is Related to Cardiac Hypertrophy and Electrical Remodeling
Authors: Vos M. A. , de Groot S. H. M. , Verduyn S. C. , van der Zande J. , Leunissen H. D. M. , Cleutjens J. P. M. , van Bilsen M. , Daemen M. J. A. P. , Schreuder J. J. , Allessie M. A. , Wellens H. J. J.
Published: June 2012

Background
—Chronic, complete AV block (CAVB) in the dog leads to ventricular hypertrophy, which has been described as an independent risk factor for arrhythmias. In this model, we examined (1) whether the short- and long-term electrical adaptations predispose to acquired torsade de pointes arrhythmias (TdP) and (2) the nature of the structural and functional adaptations involved.

Methods and Results
—We determined (1) endocardial right (RV) and left (LV) ventricular APD, ΔAPD (LV APD−RV APD), presence of EADs at 0 weeks (acute: AAVB), and CAVB (6 weeks) and inducibility of TdP by pacing and
d
-sotalol (n=10); (2) steady-state and dynamic LV hemodynamics at 0 and 6 weeks (n=6); (3) plasma neurohumoral levels in time (n=7); (4) structural parameters of the LV and RV of CAVB dogs (n=6) compared with sinus rhythm (SR) dogs (n=6); and (5) expression of ventricular mRNA atrial natriuretic factor (ANF) in CAVB (n=4) and SR (n=4) dogs. Compared with AAVB, CAVB led to nonhomogeneous prolongation of LV and RV APD and different sensitivity for
d
-sotalol, leading to EADs (4 of 14 versus 9 of 18,
P
<0.05), increased ΔAPD (45±30 versus 125±60 ms,
P
<0.05), and induction of TdP in most dogs (0% versus 60%,
P
<0.05). CAVB led to biventricular hypertrophy, whereas LV function was similar in AAVB and CAVB. The neurohumoral levels were transiently elevated. The LV and RV collagen and the capillary/fiber ratio remained normal, whereas ventricular ANF mRNA was not detectable.

Conclusions
—The electrical remodeling occurring after CAVB predisposes the heart to acquired TdP, whereas the structural changes (hypertrophy) are successfully aimed at maintaining cardiac function.
Activated Platelets Induce Monocyte Chemotactic Protein-1 Secretion and Surface Expression of Intercellular Adhesion Molecule-1 on Endothelial Cells
Authors: Gawaz Meinrad , Neumann Franz-Josef , Dickfeld Timm , Koch Werner , Laugwitz Karl-Ludwig , Adelsberger Helmut , Langenbrink Kirsten , Page Sharon , Neumeier Dieter , Schömig Albert , Brand Korbinian
Published: June 2012

Background
—Platelet/endothelium interaction plays an important role in the pathophysiology of inflammation and atherosclerosis. The role of platelets for monocyte chemotactic protein-1 (MCP-1) secretion and surface expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells has been assessed.

Methods and Results
—Monolayers of human umbilical vein endothelial cells were incubated with nonstimulated or ADP-activated platelets for 6 hours, and secretion of MCP-1 and surface expression of ICAM-1 were determined by ELISA and flow cytometry, respectively. In the presence of ADP-activated platelets, both MCP-1 secretion and ICAM-1 surface expression were significantly increased compared with nonstimulated platelets (
P
<0.02). Activation of the transcription factor nuclear factor-κB (NF-κB) determined by electrophoretic mobility shift assay and κB-dependent transcriptional activity was enhanced in the presence of activated platelets. In addition, ADP-activated platelets induced MCP-1 and ICAM-1 promoter–dependent transcription. Liposomal transfection of a double-stranded κB phosphorothioate oligonucleotide, but not of the mutated form, inhibited MCP-1 secretion and surface expression of ICAM-1 on activated endothelium (
P
<0.05).

Conclusions
—The present study indicates that activated platelets modulate chemotactic (MCP-1) and adhesive (ICAM-1) properties of endothelial cells via an NF-κB–dependent mechanism. Platelet-induced activation of the NF-κB system might contribute to early inflammatory events in atherogenesis.
Clinical Effects of β-Adrenergic Blockade in Chronic Heart Failure
Authors: Lechat Philippe , Packer Milton , Chalon Stephan , Cucherat Michel , Arab Tarek , Boissel Jean-Pierre
Published: June 2012

Background
—β-Blockers have improved symptoms and reduced the risk of cardiovascular events in studies of patients with heart failure, but it is unclear which end points are most sensitive to the therapeutic effects of these drugs.

Methods and Results
—We combined the results of all 18 published double-blind, placebo-controlled, parallel-group trials of β-blockers in heart failure. From this combined database of 3023 patients, we evaluated the strength of evidence supporting an effect of treatment on left ventricular ejection fraction, NYHA functional class, hospitalizations for heart failure, and death. β-Blockers exerted their most persuasive effects on ejection fraction and on the combined risk of death and hospitalization for heart failure. β-Blockade increased the ejection fraction by 29% (
P
<10
−9
) and reduced the combined risk of death or hospitalization for heart failure by 37% (
P
<0.001). Both effects remained significant even if >90% of the trials were eliminated from the analysis or if a large number of trials with a neutral result were added to the analysis. In contrast, the effect of β-blockade on NYHA functional class was of borderline significance (
P
=0.04) and disappeared with the addition or removal of only 1 moderate-size study. Although β-blockade reduced all-cause mortality by 32% (
P
=0.003), this effect was only moderately robust and varied according to the type of β-blocker tested, ie, the reduction of mortality risk was greater for nonselective β-blockers than for β
1
-selective agents (49% versus 18%,
P
=0.049). However, selective and nonselective β-blockers did not differ in their effects on other measures of clinical efficacy.

Conclusions
—These analyses indicate that there is persuasive evidence supporting a favorable effect of β-blockade on ejection fraction and the combined risk of death and hospitalization for heart failure. In contrast, the effect of these drugs on other end points requires additional study.
Molecular Basis of Transient Outward Potassium Current Downregulation in Human Heart Failure
Authors: Kääb S. , Dixon J. , Duc J. , Ashen D. , Näbauer M. , Beuckelmann D. J. , Steinbeck G. , McKinnon D. , Tomaselli G. F.
Published: June 2012

Background
—Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world. A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K
+
currents—prominently, the Ca
2+
-independent transient outward current (
I
to
). The mechanism for the reduction of
I
to
in heart failure is unknown. The K
+
channel α-subunit Kv4.3, a homolog of the
Drosophila Shal
family, is most likely to encode all or part of the native cardiac
I
to
in humans.

Methods and Results
—We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and
I
to
in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak
I
to
density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied (
HERG
, Kv1.4, Kir2.1, Kvβ1.3, and the α1C subunit of the Ca
2+
channel). mRNAs encoding Kv1.2, Kv1.5, and Kv2.1 were found in low abundance in human ventricle.

Conclusions
—These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac
I
to
in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.
Central Vagotonic Effects of Atropine Modulate Spectral Oscillations of Sympathetic Nerve Activity
Authors: Montano Nicola , Cogliati Chiara , Porta Alberto , Pagani Massimo , Malliani Alberto , Narkiewicz Krzysztof , Abboud Francois M. , Birkett Clay , Somers Virend K.
Published: June 2012

Background
—Low-dose atropine causes bradycardia either by acting on the sinoatrial node or by its effects on central muscarinic receptors increasing vagal activity. Any central muscarinic effects of high-dose atropine on RR interval are masked by peripheral muscarinic blockade at the sinoatrial node, which causes tachycardia. Effects of central parasympathetic activation on sympathetic activity are not known.

Methods and Results
—Using power spectral analysis of RR interval, intra-arterial blood pressure, respiration, and muscle sympathetic nerve activity (MSNA), we examined the effects of both low (2 μg/kg IV) and high (15 μg/kg IV) doses of atropine. After low-dose atropine, RR increased by 9±1% (
P
<0.0001), the low-frequency (LF) component (in normalized units, NU) of RR variability decreased by −32±8%, and the high-frequency (HF)
NU
component increased (+74±19%); hence, LF/HF of RR variability fell by 52±10% (all
P
<0.01). Although overall MSNA did not change, LF
NU
of MSNA decreased (−15±5%), HF
NU
of MSNA increased (+31±3%), and LF/HF of MSNA fell (−41±8%) (all
P
<0.01). After high-dose atropine, LF
NU
of MSNA decreased (−17±12%), HF
NU
of MSNA increased (+22±3%), and LF/HF of MSNA fell (−51±21%) (all
P
<0.02).

Conclusions
—Increasing central parasympathetic activity with low-dose atropine is associated with an increase in the HF and a decrease in the LF oscillations of both RR interval and MSNA variability. High-dose atropine similarly induces an increase in the HF and a decrease in the LF components of MSNA variability. Thus, central parasympathetic activation is able to modulate the oscillatory characteristics of sympathetic nerve traffic to peripheral blood vessels.
Increased Carotid Artery Intimal-Medial Thickness in Asymptomatic Older Subjects With Exercise-Induced Myocardial Ischemia
Authors: Nagai Yoji , Metter E. Jeffrey , Earley Christopher J. , Kemper Mary K. , Becker Lewis C. , Lakatta Edward G. , Fleg Jerome L.
Published: June 2012

Background
—Previous studies have shown an association between symptomatic coronary artery disease (CAD) and increased intimal-medial thickness of the common carotid artery (CCA IMT), a purported index of atherosclerosis. This study determines whether CCA IMT is increased in asymptomatic older subjects with an ischemic ST-segment response to treadmill exercise.

Methods and Results
—CCA IMT was measured by B-mode ultrasound in community-dwelling volunteers from the Baltimore Longitudinal Study of Aging, including 397 healthy subjects (age, 58.5±15.8 years) with normal ECG responses to maximum treadmill exercise, 72 asymptomatic subjects (age, 66.1±13.4 years) with exercise-induced horizontal or downsloping ST-segment depression ≥1 mm, and 38 subjects (age, 77.4±7.8 years) with clinically manifest CAD as diagnosed by medical history and resting ECG. Forty-three subjects with abnormal exercise ECGs also underwent exercise thallium scintigraphy. Exercise-induced ST-segment depression was associated with increased IMT (
P
<0.0001) independent of age and manifest CAD. After adjustment for age, IMT values progressively increased from healthy subjects to asymptomatic subjects with positive exercise ECG alone to those with concordant positive ECG and thallium scintigraphic findings who had virtually identical IMT to subjects with manifest CAD. Each 0.1-mm increase in IMT was associated with a 1.91-fold (95% CI, 1.46 to 2.50;
P
<0.0001) increased risk for concordant positive exercise tests or manifest CAD, independent of other significant predictors of CAD.

Conclusions
—CCA IMT is increased in older subjects with asymptomatic myocardial ischemia as evidenced by exercise ECG alone or in combination with thallium scan. Carotid ultrasound may help to identify asymptomatic individuals with CAD.
Noninvasive In Vivo High-Resolution Magnetic Resonance Imaging of Atherosclerotic Lesions in Genetically Engineered Mice
Authors: Fayad Zahi A. , Fallon John T. , Shinnar Meir , Wehrli Suzanne , Dansky Hayes M. , Poon Michael , Badimon Juan J. , Charlton Sherri A. , Fisher Edward A. , Breslow Jan L. , Fuster Valentin
Published: June 2012

Background
—The pathogenesis of atherosclerosis is currently being investigated in genetically engineered small animals. Methods to follow the time course of the developing pathology and/or the responses to therapy in vivo are limited.

Methods and Results
—To address this problem, we developed a noninvasive MR microscopy technique to study in vivo atherosclerotic lesions (without a priori knowledge of the lesion location or lesion type) in live apolipoprotein E–knockout (apoE-KO) mice. The spatial resolution was 0.0012 to 0.005 mm
3
. The lumen and wall of the abdominal aorta and iliac arteries were identified on all images in apoE-KO (n=8) and wild-type (n=5) mice on chow diet. Images obtained with MR were compared with corresponding cross-sectional histopathology (n=58). MR accurately determined wall area in comparison to histopathology (slope=1.0,
r
=0.86). In addition, atherosclerotic lesions were characterized in terms of lesion shape and type. Lesion type was graded by MR according to morphological appearance/severity and by histopathology according to the AHA classification. There was excellent agreement between MR and histopathology in grading of lesion shape and type (slope=0.97,
r
=0.91 for lesion shape; slope=0.64,
r
=0.90 for lesion type).

Conclusions
—The combination of high-resolution MR microscopy and genetically engineered animals is a powerful tool to investigate serially and noninvasively the progression and regression of atherosclerotic lesions in an intact animal model and should greatly enhance basic studies of atherosclerotic disease.
Use of a Prognostic Treadmill Score in Identifying Diagnostic Coronary Disease Subgroups
Authors: Shaw Leslee J. , Peterson Eric D. , Shaw Linda K. , Kesler Karen L. , DeLong Elizabeth R. , Harrell Frank E. , Muhlbaier Lawrence H. , Mark Daniel B.
Published: June 2012

Background
—Exercise testing is useful in the assessment of symptomatic patients for diagnosis of significant or extensive coronary disease and to predict their future risk of cardiac events. The Duke treadmill score (DTS) is a composite index that was designed to provide survival estimates based on results from the exercise test, including ST-segment depression, chest pain, and exercise duration. However, its usefulness for providing diagnostic estimates has yet to be determined.

Methods and Results
—A logistic regression model was used to predict significant (≥75% stenosis) and severe (3-vessel or left main) coronary artery disease, and a Cox regression analysis was used to predict cardiac survival. After adjustment for baseline clinical risk, the DTS was effectively diagnostic for significant (
P
<0.0001) and severe (
P
<0.0001) coronary artery disease. For low-risk patients (score ≥+5), 60% had no coronary stenosis ≥75% and 16% had single-vessel ≥75% stenosis. By comparison, 74% of high-risk patients (score <−11) had 3-vessel or left main coronary disease. Five-year mortality was 3%, 10%, and 35% for low-, moderate-, and high-risk DTS groups (
P
<0.0001).

Conclusions
—The composite DTS provides accurate diagnostic and prognostic information for the evaluation of symptomatic patients evaluated for clinically suspected ischemic heart disease.
Atrioverter: An Implantable Device for the Treatment of Atrial Fibrillation
Authors: Wellens Hein J. J. , Lau Chu-Pak , Lüderitz Berndt , Akhtar Masood , Waldo Albert L. , Camm A. John , Timmermans Carl , Tse Hung-Fat , Jung Werner , Jordaens Luc , Ayers Gregory
Published: June 2012

Background
—During atrial fibrillation, electrophysiological changes occur in atrial tissue that favor the maintenance of the arrhythmia and facilitate recurrence after conversion to sinus rhythm. An implantable defibrillator connected to right atrial and coronary sinus defibrillation leads allows prompt restoration of sinus rhythm by a low-energy shock. The safety and efficacy of this system, called the Atrioverter, were evaluated in a prospective, multicenter study.

Methods and Results
—The study included 51 patients with recurrent atrial fibrillation who had not responded to antiarrhythmic drugs, were in New York Heart Association Heart failure class I or II, and were at low risk for ventricular arrhythmias. The atrial defibrillation threshold had to be ≤240 V during preimplant testing. Atrial fibrillation detection, R-wave shock synchronization, and defibrillation threshold were tested at implantation and during follow-up. Shock termination of spontaneous episodes of atrial fibrillation was performed under physician observation. Results are given after a minimum of 3 months of follow-up. During a follow-up of 72 to 613 days (mean, 259±138 days), 96% of 227 spontaneous episodes of atrial fibrillation in 41 patients were successfully converted to sinus rhythm by the Atrioverter. In 27% of episodes, several shocks were required because of early recurrence of atrial fibrillation. Shocks did not induce ventricular arrhythmias. Most patients received antiarrhythmic medication during follow-up. In 4 patients, the Atrioverter was removed: in 1 because of infection, in 1 because of cardiac tamponade, and in 1 because of frequent episodes of atrial fibrillation requiring His bundle ablation.

Conclusions
—With the Atrioverter, prompt and safe restoration of sinus rhythm is possible in patients with recurrent atrial fibrillation.
Nuclear Factor-κB Is Selectively and Markedly Activated in Humans With Unstable Angina Pectoris
Authors: Ritchie Michael E.
Published: June 2012

Background
—Nuclear factor-κB (NF-κB) resides inactive in the cytoplasm of lymphocytes, monocytes, endothelial cells, and smooth muscle cells, where, after stimulation, it transcriptionally activates interleukins, interferon, tumor necrosis factor-α, and adhesion molecules. Because acute inflammation may play a role in coronary artery plaque rupture, it was hypothesized that NF-κB activation correlated with coronary artery disease (CAD) activity.

Methods and Results
—Evidence of NF-κB activation in the circulation of 102 consecutive patients without an acute myocardial infarction who were undergoing cardiac catheterization was determined. Of these, 19 had unstable angina (USA) and were within 24 hours of the last episode of chest pain. The remaining 83 were being evaluated for stable angina (53), valvular heart disease (8), atypical chest pain (12), or congestive heart failure (10). Evidence of NF-κB activation was determined by electromobility shift assays (EMSAs) with the NF-κB binding-site–specific probe and nuclear proteins isolated from the buffy coat of blood obtained at the beginning of the procedure. Specificity of this DNA-protein interaction was confirmed by competition and supershift EMSAs. Analyses showed that 17 of 19 patients with USA had marked activation of NF-κB. Despite a significant number of patients with severe CAD (69%), only 2 of the 83 without USA showed marked NF-κB activation. A lack of NF-κB activation was not due to a lack of functional cell/protein because NF-κB was appropriately activated by lipopolysaccharide ex vivo in all patients. NF-κB activation was not a nonspecific response of all transcription factors because neither Sp1 or Oct1 was activated in patients with activated NF-κB. There was no relationship between drugs used, hemodynamic status, or other clinical characteristics and state of NF-κB activation.

Conclusions
—These data show that NF-κB is specifically and significantly activated in unstable angina pectoris and is not affected by severity of CAD or medical therapy. Furthermore, because NF-κB is activated before a clinical event, it may be mechanistically involved in the plaque disruption that produces acute coronary artery syndromes.