bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammation, Pravastatin, and the Risk of Coronary Events After Myocardial Infarction in Patients With Average Cholesterol Levels
Authors: Ridker Paul M. , Rifai Nader , Pfeffer Marc A. , Sacks Frank M. , Moye Lemuel A. , Goldman Steven , Flaker Greg C. , Braunwald Eugene
Published: June 2012

Background
—We studied whether inflammation after myocardial infarction (MI) is a risk factor for recurrent coronary events and whether randomized treatment with pravastatin reduces that risk.

Methods and Results
—A nested case-control design was used to compare C-reactive protein (CRP) and serum amyloid A (SAA) levels in prerandomization blood samples from 391 participants in the Cholesterol and Recurrent Events (CARE) trial who subsequently developed recurrent nonfatal MI or a fatal coronary event (cases) and from an equal number of age- and sex-matched participants who remained free of these events during follow-up (control subjects). Overall, CRP and SAA were higher among cases than control subjects (for CRP
P
=0.05; for SAA
P
=0.006) such that those with levels in the highest quintile had a relative risk (RR) of recurrent events 75% higher than those with levels in the lowest quintile (for CRP RR=1.77,
P
=0.02; for SAA RR=1.74,
P
=0.02). The study group with the highest risk was that with consistent evidence of inflammation (elevation of both CRP and SAA) who were randomly assigned to placebo (RR=2.81,
P
=0.007); this risk estimate was greater than the product of the individual risks associated with inflammation or placebo assignment alone. In stratified analyses, the association between inflammation and risk was significant among those randomized to placebo (RR=2.11,
P
=0.048) but was attenuated and nonsignificant among those randomized to pravastatin (RR=1.29,
P
=0.5).

Conclusions
—Evidence of inflammation after MI is associated with increased risk of recurrent coronary events. Therapy with pravastatin may decrease this risk, an observation consistent with a nonlipid effect of this agent.
Mechanism of Mitral Regurgitation in Hypertrophic Cardiomyopathy
Authors: Schwammenthal Ehud , Nakatani Satoshi , He Shengqiu , Hopmeyer Joanne , Sagie Alex , Weyman Arthur E. , Lever Harry M. , Yoganathan Ajit P. , Thomas James D. , Levine Robert A.
Published: June 2012

Background
—In hypertrophic cardiomyopathy, a spectrum of mitral leaflet abnormalities has been related to the mechanism of mitral systolic anterior motion (SAM), which causes both subaortic obstruction and mitral regurgitation. In the individual patient, SAM and regurgitation vary in parallel; clinically, however, great interindividual differences in mitral regurgitation can occur for comparable degrees of SAM. We hypothesized that these differences relate to variations in posterior leaflet length and mobility, restricting its ability to follow the anterior leaflet (participate in SAM) and coapt effectively.

Methods and Results
—Different mitral geometries produced surgically in porcine valves were studied in vitro. Comparable degrees of SAM resulted in more severe mitral regurgitation for geometries characterized by limited posterior leaflet excursion. Mitral geometry was also analyzed in 23 patients with hypertrophic cardiomyopathy by intraoperative transesophageal echocardiography. All had typical anterior leaflet SAM with significant outflow tract gradients but considerably more variable mitral regurgitation; therefore, regurgitation did not correlate with obstruction. In contrast, mitral regurgitation correlated inversely with the length over which the leaflets coapted (
r
=−0.89), the most severe regurgitation occurring with a visible gap. Regurgitation increased with increasing mismatch of anterior to posterior leaflet length (
r
=0.77) and decreasing posterior leaflet mobility (
r
=−0.79).

Conclusions
—SAM produces greater mitral regurgitation if the posterior leaflet is limited in its ability to move anteriorly, participate in SAM, and coapt effectively. This can explain interindividual differences in regurgitation for comparable degrees of SAM. Thus, the spectrum of leaflet length and mobility that affects subaortic obstruction also influences mitral regurgitation in patients with SAM.
Simultaneous Endocardial Mapping in the Human Left Ventricle Using a Noncontact Catheter
Authors: Schilling Richard J. , Peters Nicholas S. , Davies D. Wyn
Published: June 2012

Background
—Catheter ablation of ventricular tachycardia is limited in part by difficulty in identifying suitable sites for ablation. A noncontact multielectrode array (MEA) has been developed that allows reconstruction of 3360 electrograms, using inverse-solution mathematics, that are superimposed onto a computer-simulated model of the endocardium. This study assesses the accuracy of timing and morphology of reconstructed unipolar electrograms compared with contact unipolar electrograms from the same endocardial site.

Methods and Results
—The MEA was deployed in the left ventricles of 13 patients (end-diastolic diameters, 61.7±8.4 mm [mean±SD]). We recorded contact electrograms at 76 points equatorial and 32 points nonequatorial to the MEA during sinus rhythm using a catheter-locator signal to record direction and distance from the MEA. Morphology (cross-correlation) and timing of maximum −dV/dt of contact and reconstructed electrograms were compared at different distances from the MEA center to endocardium (M-E) and from the MEA equatorial plane. For equatorial data, the M-E was 32.12±12.12 mm. The timing of reconstructed with respect to contact electrograms was −1.94±7.12 ms for M-E <34 mm and −14.16±19.29 ms at M-E >34 mm (
P
<0.001). Cross-correlation of electrograms was 0.87±0.12 (95% CI, 0.84 to 0.91) and 0.76±0.18 (95% CI, 0.69 to 0.83) for M-E <34 mm and >34 mm, respectively. Nonequatorial points were 32.33±10.81 mm (range, 16.9 to 55.6 mm) from the MEA equatorial plane; electrogram timing difference was −8.97±15.75 ms and was unrelated to this distance from the equator.

Conclusions
—This noncontact mapping system accurately reconstructs endocardial unipolar electrograms from the human left ventricle. At M-E distances >34 mm, timing accuracy of reconstruction decreases.
Somatic Gene Transfer of Human ApoA-I Inhibits Atherosclerosis Progression in Mouse Models
Authors: Benoit Patrick , Emmanuel Florence , Caillaud Jean Michel , Bassinet Laurent , Castro Graciela , Gallix Pierre , Fruchart Jean Charles , Branellec Didier , Denèfle Patrice , Duverger Nicolas
Published: June 2012

Background
—Apolipoprotein (apo) A-I is the major component of HDL, and it displays antiatherogenic properties.

Methods and Results
—The human apoA-I gene has been transferred into different mouse models by use of a recombinant adenovirus under the control of an RSV-LTR promoter (AV RSV apoA-I). Administration of AV RSV apoA-I to C57BL/6 mice resulted in moderate expression of human apoA-I for 3 weeks, leading to a transient elevation (40% at day 11 after injection) of HDL cholesterol concentration. In contrast, administration of AV RSV apoA-I to human apoA-I–transgenic mice induced a large increase of human apoA-I and HDL cholesterol concentrations (300% and 360%, respectively, at day 14 after injection) for 10 weeks, indicating that an immune response to the transgene was one major hurdle for long-term duration of expression. Recombinant adenovirus expressing human apolipoprotein A-I (AV RSV apoA-I) was also injected into human apoA-I–transgenic/apoE-deficient mice, which are prone to develop atherosclerosis. Over a 6-week period, overexpression of human apoA-I inhibited fatty streak lesion formation by 56% in comparison with control.

Conclusions
—Somatic gene transfer of human apoA-I prevents the development of atherosclerosis in the mouse model.
Age-Dependent Impairment of Angiogenesis
Authors: Rivard Alain , Fabre Jean-Etienne , Silver Marcy , Chen Dongfen , Murohara Toyoaki , Kearney Marianne , Magner Meredith , Asahara Takayuki , Isner Jeffrey M.
Published: June 2012

Background
—The effect of aging on angiogenesis in ischemic vascular disease has not been studied. Accordingly, we investigated the hypothesis that angiogenesis is impaired as a function of age.

Methods and Results
—Forty days after the resection of 1 femoral artery, collateral vessel development was significantly impaired in old (aged 4 to 5 years; n=7) versus young (aged 6 to 8 months; n=6) New Zealand White (NZW) rabbits on the basis of reduced hindlimb perfusion (ischemic: normal blood pressure ratio=0.58±0.05 versus 0.77±0.06;
P
<0.005), reduced number of angiographically visible vessels (angiographic score=0.48±0.05 versus 0.70±0.05;
P
<0.01), and lower capillary density in the ischemic limb (130.3±5.8/mm
2
versus 171.4±9.5/mm
2
;
P
<0.001). Angiogenesis was also impaired in old (aged 2 years) versus young (aged 12 weeks) mice as shown by reduced hindlimb perfusion (measured by laser Doppler imaging) and lower capillary density (353.0±14.3/mm
2
versus 713.3±63.4/mm
2
;
P
<0.01). Impaired angiogenesis in old animals was the result of impaired endothelial function (lower basal NO release and decreased vasodilation in response to acetylcholine) and a lower expression of vascular endothelial growth factor (VEGF) in ischemic tissues (by Northern blot, Western blot, and immunohistochemistry). When recombinant VEGF protein was administered to young and old rabbits, both groups exhibited a significant and similar increase in blood pressure ratio, angiographic score, and capillary density.

Conclusions
—Angiogenesis responsible for collateral development in limb ischemia is impaired with aging; responsible mechanisms include age-related endothelial dysfunction and reduced VEGF expression. Advanced age, however, does not preclude augmentation of collateral vessel development in response to exogenous angiogenic cytokines.
Pathology of Acute and Chronic Coronary Stenting in Humans
Authors: Farb Andrew , Sangiorgi Giuseppe , Carter Andrew J. , Walley Virginia M. , Edwards William D. , Schwartz Robert S. , Virmani Renu
Published: June 2012

Background
—Despite the increasing use of stents, few reports have described human coronary artery morphology early and late after stenting.

Methods and Results
—Histology was performed on 55 stents in 35 coronary vessels (32 native arteries and 3 vein grafts) from 32 patients. The mean duration of stent placement was 39±82 days. Fibrin, platelets, and neutrophils were associated with stent struts ≤11 days after deployment. In stents implanted for ≤3 days, only 3% of struts in contact with fibrous plaque had >20 associated inflammatory cells compared with 44% of struts embedded in a lipid core and 36% of struts in contact with damaged media (
P
<0.001). Neointimal growth determined late histological success, and increased neointimal growth correlated with increased stent size relative to the proximal reference lumen area. Neointimal thickness was greater for struts associated with medial damage than struts in contact with plaque (
P
<0.0001) or intact media (
P
<0.0001). When matched for time since treatment, neointimal cell density in stented arteries was similar to that in unstented arteries that had undergone balloon angioplasty and showed similar proteoglycan deposition.

Conclusions
—Morphology after coronary stenting demonstrates early thrombus formation and acute inflammation followed by neointimal growth. Medial injury and lipid core penetration by struts result in increased inflammation. Neointima increases as the ratio of stent area to reference lumen area increases. Deployment strategies that reduce medial damage and avoid stent oversizing may lower the frequency of in-stent restenosis.
Relation of Weight and Rate of Increase in Weight During Childhood and Adolescence to Body Size, Blood Pressure, Fasting Insulin, and Lipids in Young Adults
Authors: Sinaiko Alan R. , Donahue Richard P. , Jacobs David R. , Prineas Ronald J.
Published: June 2012

Background
—Weight gain is of concern during early development because adult obesity and its cardiovascular consequences appear to have their origins during childhood. Insulin resistance is known to be related to obesity. Thus, weight gain beginning in childhood may influence the development of insulin-induced cardiovascular risk during adulthood.

Methods and Results
—We monitored 679 individuals from 7.7±0.1 years of age with repeated measures of height, weight, and systolic blood pressure (SBP) until 23.6±0.2 years of age, when blood samples were obtained for measurements of insulin and lipids. Initial childhood weight, body mass index (BMI), and height were significantly correlated with young adult weight, BMI, and height and with fasting insulin, lipids, and SBP. The increases in weight and BMI but not height during childhood were significantly related to the young adult levels of insulin, lipids, and SBP.

Conclusions
—These data suggest that weight gain in excess of normal growth during childhood is a determinant of adult cardiovascular risk. The finding in multiple linear regression analysis that weight gain during childhood rather than the childhood weight at 7.7 years of age is significantly related to young adult risk factors suggests that a reduction in weight gain could reduce subsequent levels of cardiovascular risk.
Aldosterone, Not Estradiol, Is the Physiological Agonist for Rapid Increases in cAMP in Vascular Smooth Muscle Cells
Authors: Christ Michael , Günther Andreas , Heck Marina , Schmidt Bernhard M. W. , Falkenstein Elisabeth , Wehling Martin
Published: June 2012

Background
—Steroid-induced gene regulation in the endocrine tissues and vascular wall is achieved through the interaction of specific receptor proteins and promoters of target genes. In addition to these delayed steroid actions, rapid effects of steroids have been reported in various tissues that were clearly incompatible with the classic theory of genomic steroid action.

Methods and Results
—Because high doses of 17β-estradiol have been shown to modulate intracellular cAMP levels in vascular smooth muscle cells, steroid-induced stimulation of adenylate cyclase stimulation and phosphorylation of cAMP response element binding protein was investigated in porcine coronary artery vascular smooth muscle cells. Aldosterone induces a ≈1.5- to 2.5-fold increase in intracellular cAMP levels (EC
50
≈0.01 to 0.1 nmol/L) within 1 minute, whereas 17β-estradiol and hydrocortisone act only at supraphysiological concentrations (10 μmol/L). Aldosterone-induced changes in intracellular cAMP are calcium dependent; they are not blocked by inhibitors of mineralocorticoid receptors, transcription, or protein synthesis. In addition, aldosterone induces a time-dependent phosphorylation of cAMP response element binding protein with potential transcriptional importance.

Conclusions
—A nongenomic modulation of vascular smooth muscle cells by aldosterone is consistent with the data that aldosterone, not estrogen, is the physiological stimulus for cAMP.
Cellular and Ionic Basis for T-Wave Alternans Under Long-QT Conditions
Authors: Shimizu Wataru , Antzelevitch Charles
Published: June 2012

Background
—T-wave alternans (TWA), an ECG phenomenon characterized by beat-to-beat alternation of the morphology, amplitude, and/or polarity of the T wave, is commonly observed in the acquired and congenital long-QT syndromes (LQTS). This study examines the cellular and ionic basis for TWA induced by rapid pacing under conditions mimicking the LQT3 form of the congenital LQTS in an arterially perfused canine left ventricular wedge preparation.

Methods and Results
—Transmembrane action potentials from epicardial, M, and endocardial cells and 6 to 8 intramural unipolar electrograms were simultaneously recorded together with a transmural ECG and isometric tension development. In the presence of sea anemone toxin (ATX-II; 20 nmol/L), an increase in pacing rate (from a cycle length [CL] of 500 to 400 to 250 ms) produced a wide spectrum of T-wave and mechanical alternans. Acceleration to CLs of 400 to 300 ms produced mild to moderate TWA principally due to beat-to-beat alternation of repolarization of cells in the M region. Transmural dispersion of repolarization during alternans was exaggerated during alternate beats. Acceleration to CLs of 300 to 250 ms caused more pronounced beat-to-beat alternation of action potential duration (APD) of the M cell, resulting in a reversal of repolarization sequence across the ventricular wall, leading to alternation in the polarity of the T wave. The peak of the negative T waves coincided with repolarization of the M region, whereas the end of the negative T wave coincided with the repolarization of epicardium. In almost all cases, electrical alternans was concordant with mechanical alternans. Torsade de pointes occurred after an abrupt acceleration of CL, which was associated with marked TWA. Both ryanodine and low [Ca
2+
]
o
completely suppressed alternans of the T wave, APD, and contraction, suggesting a critical role for intracellular Ca
2+
cycling in the maintenance of TWA.

Conclusions
—Our results suggest that TWA observed at rapid rates under long-QT conditions is largely the result of alternation of the M-cell APD, leading to exaggeration of transmural dispersion of repolarization during alternate beats, and thus the potential for development of torsade de pointes. Our data also suggest that unlike transient forms of TWA that damp out quickly and depend on electrical restitution factors, the steady-state electrical and mechanical alternans demonstrated in this study appears to be largely the result of beat-to-beat alternans of [Ca
2+
]
i
.
Endothelial Cytotoxicity Mediated by Serum Antibodies to Heat Shock Proteins of
Escherichia coli
and
Chlamydia pneumoniae
Authors: Mayr Manuel , Metzler Bernhard , Kiechl Stefan , Willeit Johann , Schett Georg , Xu Qingbo , Wick Georg
Published: June 2012

Background
—Growing evidence suggests that an immunological reaction against heat shock proteins (HSPs) may be involved in atherogenesis. Because HSPs show a high degree of amino acid sequence homology between different species, from prokaryotes to humans, we investigated the possibility of “antigenic mimicry” caused by an immunological cross-reaction between microorganisms and autoantigens.

Methods and Results
—Serum antibodies against the
Escherichia coli
HSP (GroEL) and the 60-kDa chlamydial HSP (cHSP60) from subjects with atherosclerosis were purified by use of affinity chromatography. Western blot analyses and competitive ELISAs confirmed the cross-reaction of the eluted antibodies with human HSP60 and the bacterial counterparts. The cytotoxicity of anti-GroEL and anti-cHSP60 antibodies was determined on human endothelial cells labeled with
51
Cr. A significant difference (40% versus 8%) was observed in the specific
51
Cr release of heat-treated (42°C for 30 minutes) and untreated cells, respectively, in the presence of these anti-HSP antibodies and complement. This effect was blocked by addition of 100 μg/mL recombinant GroEL. In addition, seropositivity against specific non-HSP60
Chlamydia pneumoniae
antigens is more prominent among high–anti-HSP titer sera than low-titer sera.

Conclusions
—Serum antibodies against HSP65/60 cross-react with human HSP60, cHSP60, and GroEL; correlate with the presence of antibodies to
C pneumoniae
and endotoxin; and mediate endothelial cytotoxicity. These findings suggest that humoral immune reactions to bacterial HSPs, such as cHSP60 and GroEL, may play an important role in the process of vascular endothelial injury, which is believed to be a key event in the pathogenesis of atherosclerosis.
Effects of Intracoronary β-Radiation Therapy After Coronary Angioplasty
Authors: Meerkin David , Tardif Jean-Claude , Crocker Ian R. , Arsenault Andre , Joyal Michel , Lucier Guylaine , King Spencer B. , Williams David O. , Serruys Patrick W. , Bonan Raoul
Published: June 2012

Background
—Endovascular radiation is emerging as a potential solution for the prevention and treatment of restenosis. Its effects on the morphology of unstented vessels cannot be determined by angiography and therefore require the use of intravascular ultrasound.

Methods and Results
—Through a 5F noncentered catheter for delivery of a
90
Sr/Y source train, 12, 14, or 16 Gy at 2 mm was delivered to native coronary arteries after successful balloon angioplasty in 30 patients. Four patients required stent deployment in the first week. Quantitative coronary angiography and IVUS were performed during the initial procedure and at 6-month follow-up. Binary angiographic restenosis was present in 3 of 30 patients, with target lesion and vessel revascularization performed in 3 and 5 patients, respectively. Angiographic late loss was −0.02±0.60 mm, with a −0.09±0.46 loss index. IVUS demonstrated no significant reduction in lumen area (from 5.69±1.72 mm
2
after treatment to 6.04±2.63 mm
2
at follow-up), with no significant change in external elastic membrane area (13.71±4.54 to 14.22±4.71 mm
2
) over the 6-month follow-up. Wall area was 8.01±3.85 mm
2
after radiation therapy and 8.19±3.44 mm
2
at follow-up (
P
=NS). No significant differences were noted between the different dose groups.

Conclusions
—β-Radiation therapy resulted in a low restenosis rate with negligible late loss by angiography. By IVUS, β-radiation was shown to inhibit neointima formation, with no reduction of total vessel area at 6-month follow-up.
Hydrogen Peroxide, Potassium Currents, and Membrane Potential in Human Endothelial Cells
Authors: Bychkov Rostislav , Pieper Knud , Ried Christian , Milosheva Marianna , Bychkov Eugen , Luft Friedrich C. , Haller Hermann
Published: June 2012

Background
—Hydrogen peroxide (H
2
O
2
) and reactive oxygen species are implicated in inflammation, ischemia-reperfusion injury, and atherosclerosis. The role of ion channels has not been previously explored.

Methods and Results
—K
+
currents and membrane potential were recorded in endothelial cells by voltage- and current-clamp techniques. H
2
O
2
elicited both hyperpolarization and depolarization of the membrane potential in a concentration-dependent manner. Low H
2
O
2
concentrations (0.01 to 0.25 μmol/L) inhibited the inward-rectifying K
+
current (K
IR
). Whole-cell K
+
current analysis revealed that H
2
O
2
(1 mmol/L) applied to the bath solution increased the Ca
2+
-dependent K
+
current (K
Ca
) amplitude. H
2
O
2
increased K
Ca
current in outside-out patches in a Ca
2+
-free solution. When catalase (5000 μ/mL) was added to the bath solution, the outward-rectifying K
+
current amplitude was restored. In contrast, superoxide dismutase (1000 u/mL) had only a small effect on the H
2
O
2
-induced K
+
current changes. Next, we measured whole-cell K
+
currents and redox potentials simultaneously with a novel redox potential-sensitive electrode. The H
2
O
2
-mediated K
Ca
current increase was accompanied by a whole-cell redox potential decrease.

Conclusions
—H
2
O
2
elicited both hyperpolarization and depolarization of the membrane potential through 2 different mechanisms. Low H
2
O
2
concentrations inhibited inward-rectifying K
+
currents, whereas higher H
2
O
2
concentrations increased the amplitude of the outward K
+
current. We suggest that reactive oxygen species generated locally increases the K
Ca
current amplitude, whereas low H
2
O
2
concentrations inhibit K
IR
via intracellular messengers.
Angiogenesis Inhibitors Endostatin or TNP-470 Reduce Intimal Neovascularization and Plaque Growth in Apolipoprotein E–Deficient Mice
Authors: Moulton Karen S. , Heller Eric , Konerding Moritz A. , Flynn Evelyn , Palinski Wulf , Folkman Judah
Published: June 2012

Background
—Neovascularization within the intima of human atherosclerotic lesions is well described, but its role in the progression of atherosclerosis is unknown. In this report, we first demonstrate that intimal vessels occur in advanced lesions of apolipoprotein E–deficient (apoE −/−) mice. To test the hypothesis that intimal vessels promote atherosclerosis, we investigated the effect of angiogenesis inhibitors on plaque growth in apoE −/− mice.

Methods and Results
—ApoE −/− mice were fed a 0.15% cholesterol diet. At age 20 weeks, mice were divided into 3 groups and treated for 16 weeks as follows: group 1, recombinant mouse endostatin, 20 mg · kg
−1
· d
−1
; group 2, fumagillin analogue TNP-470, 30 mg/kg every other day; and group 3, control animals that received a similar volume of buffer. Average cholesterol levels were similar in all groups. Plaque areas were quantified at the aortic origin. Median plaque area before treatment was 0.250 mm
2
(range, 0.170 to 0.348; n=10). Median plaque areas were 0.321 (0.238 to 0.412; n=10), 0.402 (0.248 to 0.533; n=15), and 0.751 mm
2
(0.503 to 0.838; n=12) for the endostatin, TNP-470, and control groups, respectively (
P
≤0.0001). Therefore, endostatin and TNP-470 inhibited plaque growth during the treatment period by 85% and 70%. Intimal smooth muscle cell contents of plaques from control and treated mice were similar.

Conclusions
—Prolonged treatment with either angiogenesis inhibitor reduced plaque growth and intimal neovascularization in apoE −/− mice. Although the mechanism of plaque inhibition induced by these agents is not established, these results suggest that intimal neovascularization may promote plaque development.
Local Inhibition of Tissue Factor Reduces the Thrombogenicity of Disrupted Human Atherosclerotic Plaques
Authors: Badimon Juan Jose , Lettino Maddalena , Toschi Vincenzo , Fuster Valentin , Berrozpe Maria , Chesebro James H. , Badimon Lina
Published: June 2012

Background
—Plaque disruption and subsequent thrombus formation lead to acute coronary syndromes and progression of atherosclerotic disease. Tissue factor (TF) appears to mediate plaque thrombogenicity. Tissue factor pathway inhibitor (TFPI) is the major physiological inhibitor of TF. This study analyzes the role of TF on thrombogenicity of disrupted human atherosclerotic plaques and the therapeutic possibilities of its specific inhibition.

Methods and Results
—Human atherosclerotic and normal arterial segments were exposed to heparinized blood at flow conditions modeling medium-grade coronary stenosis in the Badimon perfusion chamber. The antithrombotic effects of the specific inhibition of plaque TF was assessed by reduction in the deposition of radiolabeled platelets and fibrin(ogen) and immunohistochemical analysis of perfused arteries. TF activity was inhibited by both recombinant TFPI and a polyclonal antibody against human TF. Human lipid-rich plaques were more thrombogenic than less advanced atherosclerotic plaques. Specific inhibition of TF activity reduced plaque thrombogenicity, inhibiting both platelet and fibrin(ogen) deposition (580 versus 194 platelets×10
6
/cm
2
;
P
<0.01, and 652 versus 172×10
12
molecules of Fg/cm
2
;
P
<0.05, respectively) and thrombosis (immunohistochemistry).

Conclusions
—This study documents the key role of TF activity in acute arterial thrombosis after atherosclerotic plaque disruption and provides evidence of the benefit of blocking plaque TF activity. Therefore the inhibition of the TF pathway opens a new therapeutic strategy in the prevention of acute coronary thrombosis after plaque disruption.
Endothelium-Dependent and -Independent Perfusion Reserve and the Effect of
l
-arginine on Myocardial Perfusion in Patients With Syndrome X
Authors: Bøttcher Morten , Bøtker Hans Erik , Sonne Helle , Nielsen Torsten Toftegaard , Czernin Johannes
Published: June 2012

Background
—Impaired vasodilatation capacity in patients with angina pectoris and a normal coronary arteriogram (syndrome X [SX]) has been reported. Most studies report on the response in epicardial vessels. This does not necessarily reflect compromised myocardial microcirculation. Lack of the NO precursor
l
-arginine has been suggested as a possible cause.

Methods and Results
—Myocardial blood flow (MBF) was measured, using PET, at rest (MBF-rest) and during intravenous dipyridamole (MBF-DIP) in 25 women (mean age 53±7 years) with SX. Thirty healthy volunteers served as controls. One group (A) consisted of 15 age-matched female volunteers (54±10 years). The other control group consisted of 15 young healthy women (B; 24±5 years). In 12 SX patients, MBF-rest and MBF during cold pressor testing were also measured after infusion of L-arginine (6.7 g/min for 45 minutes). The increase in MBF after cold pressor testing was similar in the SX group compared with controls.
l
-arginine did not affect MBF-rest (0.83±0.14 versus 0.89±0.13 mL · g
−1
· min
−1
) or MBF after cold pressor test (0.95±0.10 versus 1.03±0.17 mL · g
−1
min
−1
). In contrast, the hyperemic response to DIP was blunted compared with the group A controls (1.68±0.49 versus 2.34±0.45 mL · g
−1
· min
−1
,
P
<0.05); this resulted in a significant reduction of the coronary flow reserve in SX patients relative to controls (2.03±0.53 versus 2.96±0.63 mL · g
−1
· min
−1
,
P
<0.01).

Conclusions
—In patients with SX, the microcirculatory response to cold, reflecting the endothelium function, is normal and unaltered by intravenous
l
-arginine. This suggests preserved microcirculatory endothelial function. However, a markedly attenuated hyperemic flow and flow reserve after DIP suggest a dysfunction of the adenosine-mediated endothelium-independent vasodilatation at the microcirculatory level in these patients.
Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium
Authors: Pieske Burkert , Beyermann Beate , Breu Volker , Löffler Bernd M. , Schlotthauer Klaus , Maier Lars S. , Schmidt-Schweda Stephan , Just Hanjörg , Hasenfuss Gerd
Published: June 2012

Background
—An activated endothelin (ET) system may be of pathophysiological relevance in human heart failure. We characterized the functional effects of ET-1, ET receptors, and ET-1 peptide concentration in left ventricular myocardium from 10 nonfailing hearts (NF) and 27 hearts in end-stage failure due to idiopathic dilative cardiomyopathy (DCM).

Methods and Results
—Inotropic effects were characterized in isolated muscle strips (1 Hz; 37°C). ET-1 0.0001 to 0.3 μmol/L significantly (
P
<0.05) increased twitch force by maximally 59±10% in NF and by 36±11% in DCM (
P
<0.05 versus NF). Preincubation with propranolol 1 μmol/L and prazosin 0.1 μmol/L did not affect the response to ET-1, but the mixed ET receptor antagonist bosentan and the ET
A
receptor antagonist BQ-123 shifted the concentration-response curves for ET-1 rightward. The ET
B
receptor agonist sarafotoxin S6c 0.001 to 0.3 μmol/L had no functional effects. The inotropic response to ET-1 was not associated with increased intracellular Ca
2+
transients, as assessed in aequorin-loaded muscle strips. ET receptor density (B
max
; radioligand binding) was 62.5±12.5 fmol/mg protein in NF and 122.4±24.3 fmol/mg protein in DCM (
P
<0.05 versus NF). The increase in B
max
in DCM resulted from an increase in ET
A
receptors without change in ET
B
receptors. ET-1 peptide concentration (radioimmunoassay) was higher in DCM than in NF (14 447±2232 versus 4541±1340 pg/mg protein,
P
<0.05).

Conclusions
—ET-1 exerts inotropic effects in human myocardium through ET
A
receptor–mediated increases in myofibrillar Ca
2+
responsiveness. In DCM, functional effects of ET-1 are attenuated, but ET
A
receptor density and ET-1 peptide concentration are increased, indicating an activated local cardiac ET system and possibly a reduced postreceptor signaling efficiency.
Myocardial Lactate Metabolism in Fetal and Newborn Lambs
Authors: Bartelds Beatrijs , Knoester Hennie , Beaufort-Krol Gertie C. M. , Smid Gioia B. , Takens Janny , Zijlstra Willem G. , Heymans Hugo S. A. , Kuipers Jaap R. G.
Published: June 2012

Background
—Around birth, myocardial substrate supply changes from carbohydrates before birth to primarily fatty acids after birth. Parallel to these changes, the myocardium is expected to switch from the use of primarily lactate before birth to fatty acids thereafter. However, myocardial lactate uptake and oxidation around birth has not been measured in vivo.

Methods and Results
—We measured myocardial lactate uptake, oxidation, and release with infusion of [1-
13
C]lactate and myocardial flux of fatty acids and glucose in chronically instrumented fetal and newborn (1 to 15 days) lambs. Myocardial lactate oxidation was the same in newborn (81.7±14.7 μmol · min
−1
· 100 g
−1
, n=11) as in fetal lambs (60.7±26.7 μmol · min
−1
· 100 g
−1
, n=7). Lactate uptake was also the same in newborn as in fetal lambs. Lactate uptake was higher than lactate flux, indicating lactate release simultaneously with uptake. In the newborn lambs, lactate uptake declined with age. Lactate uptake was strongly related to lactate supply, whereas lactate oxidation was not. The supply of fatty acids or glucose did not interfere with lactate uptake, but the flux of fatty acids was inversely related to lactate oxidation.

Conclusions
—We show that lactate is an important energy source for the myocardium before birth as well as in the first 2 weeks after birth in lambs. We also show that there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose, probably at the level of pyruvate dehydrogenase.
Evidence for a New Pathophysiological Mechanism for Coronary Artery Disease Regression
Authors: Zambon Alberto , Hokanson John E. , Brown B. Greg , Brunzell John D.
Published: June 2012

Background
—Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy.

Methods and Results
—Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels ≥125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%;
P
<0.01) and niacin-colestipol therapy (10.3%;
P
<0.01), whereas HL decreased in both groups (−14% [
P
<0.01] and −17% [
P
<0.01] with lovastatin-colestipol and niacin-colestipol, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (
P
<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (
P
<0.01), followed by reduction in apolipoprotein Bl (5% of variance;
P
<0.05).

Conclusions
—These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.
Predicting Sudden Death in the Population
Authors: Jouven Xavier , Desnos Michel , Guerot Claude , Ducimetière Pierre
Published: June 2012

Background
—Sudden death was found to share the same set of usual risk factors as coronary events and therefore could not be specifically predicted in the population. It appears, however, that parental history of sudden death has not been investigated yet as a risk factor for sudden death. Therefore, we assessed risk factors, including parental sudden death, associated with the occurrence of sudden death in a long-term cohort study.

Methods and Results
—We included 7746 men employed by the city of Paris who were 43 to 52 years of age in 1967 to 1972 in the Paris Prospective Study I. Each subject underwent a physical examination and an ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers who paid particular attention to family medical history. Men with known ischemic cardiac disease were further excluded from analysis. For 95.5% of the men, vital status was obtained from specific inquiries until retirement, then by death certificates. Resting heart rate, systolic or diastolic blood pressure, tobacco consumption, body mass index, diabetes status, serum cholesterol, and parental history of sudden death were independent factors associated with sudden death during follow-up (23 years on average). When adjusted for confounding variables, including parental history of myocardial infarction, relative risk of sudden death associated with parental sudden death was 1.80 (95% CI, 1.11 to 2.88).

Conclusions
—Parental sudden death is an independent risk factor for sudden death in middle-aged men. The existence of familial risk factors for sudden death may help provide better identification of subjects at high risk of and early prevention of sudden death.
Angiotensin-Converting Enzyme Inhibitor Ramiprilat Interferes With the Sequestration of the B
2
Kinin Receptor Within the Plasma Membrane of Native Endothelial Cells
Authors: Benzing Thomas , Fleming Ingrid , Blaukat Andree , Müller-Esterl Werner , Busse Rudi
Published: June 2012

Background
—ACE (kininase II) inhibitors have been shown to exert their beneficial cardiovascular effects via the inhibition of both angiotensin II formation and bradykinin breakdown. Because recent evidence suggests that ACE inhibitors may also interfere with B
2
kinin receptor signaling and thus enhance the vascular response to bradykinin, we examined whether the distribution of B
2
kinin receptors within the plasma membrane of native endothelial cells is affected by an ACE inhibitor.

Methods and Results
—Localization of the B
2
kinin receptor in membranes prepared from native porcine aortic endothelial cells was evaluated by means of specific [
3
H]bradykinin binding and immunoprecipitation of the B
2
receptor from isolated membranes. Effects of bradykinin and ramiprilat on intracellular signaling were determined by monitoring the activation of the extracellularly regulated kinases Erk1 and Erk2 as well as [Ca
2+
]
i
increases in fura 2–loaded endothelial cells. Stimulation of native endothelial cells with bradykinin 100 nmol/L resulted in the time-dependent sequestration of the B
2
receptor to caveolin-rich (CR) membranes, which was maximal after 5 minutes. Pretreatment with ramiprilat 100 nmol/L for 15 minutes significantly attenuated the recovery of B
2
kinin receptors in CR membranes while increasing that from membranes lacking caveolin. This effect was not due to the inhibition of bradykinin degradation, because no effect was seen in the presence of an inhibitory concentration of the synthetic ACE substrate hippuryl-
l
-histidyl-
l
-leucine. Ramiprilat also decreased [
3
H]bradykinin binding to CR membranes when applied either before or after bradykinin stimulation. Moreover, ramiprilat resulted in reactivation of the B
2
receptor in bradykinin-stimulated cells and induced a second peak in [Ca
2+
]
i
and reactivation of Erk1/2.

Conclusions
—The ACE inhibitor ramiprilat interferes with the targeting of the B
2
kinin receptor to CR membrane domains in native endothelial cells. Therefore, effects other than the inhibition of kininase II may account for the effects of ramiprilat and other ACE inhibitors on the vascular system.
Comparison of Myocardial Perfusion Imaging and Cardiac Troponin I in Patients Admitted to the Emergency Department With Chest Pain
Authors: Kontos Michael C. , Jesse Robert L. , Anderson F. Philip , Schmidt Kristin L. , Ornato Joseph P. , Tatum James L.
Published: June 2012

Background
—Identification of patients with acute coronary syndromes (ACS) among those who present to emergency departments with possible myocardial ischemia is difficult. Myocardial perfusion imaging with
99m
Tc sestamibi and measurement of serum cardiac troponin I (cTnI) both can identify patients with ACS.

Methods and Results
—Patients considered at low to moderate risk for ACS underwent gated single-photon emission CT sestamibi imaging and serial myocardial marker measurements of creatine kinase–MB, total creatine kinase activity, and cTnI over 8 hours. Positive perfusion imaging was defined as a perfusion defect with associated abnormalities in wall motion or thickening. cTnI ≥2.0 ng/mL was considered abnormal. Among the 620 patients studied, 59 (9%) had myocardial infarction and 81 (13%) had significant coronary disease; of these patients, 58 underwent revascularization. Perfusion imaging was positive in 241 patients (39%), initial cTnI was positive in 37 (6%), and cTnI was ≥2.0 ng/mL in 74 (12%). Sensitivity for detecting myocardial infarction was not significantly different between perfusion imaging (92%) and cTnI (90%), and both were significantly higher than the initial cTnI (39%). Sensitivity for predicting revascularization or significant coronary disease was significantly higher for perfusion imaging than for serial cTnI, although specificity for all end points was significantly lower. Lowering the cutoff value of cTnI to 1.0 ng/mL did not significantly change the results.

Conclusions
—Early perfusion imaging and serial cTnI have comparable sensitivities for identifying myocardial infarction. Perfusion imaging identified more patients who underwent revascularization or who had significant coronary disease, but it had lower specificity. The 2 tests can provide complementary information for identifying patients at risk for ACS.
Increasing Levels of Interleukin (IL)-1Ra and IL-6 During the First 2 Days of Hospitalization in Unstable Angina Are Associated With Increased Risk of In-Hospital Coronary Events
Authors: Biasucci Luigi M. , Liuzzo Giovanna , Fantuzzi Giamila , Caligiuri Giuseppina , Rebuzzi Antonio G. , Ginnetti Francesca , Dinarello Charles A. , Maseri Attilio
Published: June 2012

Background
—A growing body of evidence suggests a role for inflammation in acute coronary syndromes. The aim of this study was to assess the role of proinflammatory cytokines, their time course, and their association with prognosis in unstable angina.

Methods and Results
—We studied 43 patients aged 62±8 years admitted to our coronary care unit for Braunwald class IIIB unstable angina. In each patient, serum levels of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6) (which represent sensitive markers of biologically active IL-1β and tumor necrosis factor-α levels, respectively), and troponin T were measured at entry and 48 hours after admission. Troponin T–positive patients were excluded. Patients were divided a posteriori into 2 groups according to their in-hospital outcome: group 1 comprised 17 patients with an uneventful course, and group 2 comprised 26 patients with a complicated in-hospital course. In group 1, mean IL-1Ra decreased at 48 hours by 12%, and IL-6 diminished at 48 hours by 13%. In group 2, IL-1Ra and IL-6 entry levels were higher than in group 1 and increased respectively by 37% and 57% at 48 hours (
P
<0.01).

Conclusions
—These findings indicate that although they receive the same medical therapy as patients who do not experience an in-hospital event, patients with unstable angina and with complicated in-hospital courses have higher cytokine levels on admission. A fall in IL-1Ra and IL-6 48 hours after admission was associated with an uneventful course and their increase with a complicated hospital course. These findings may suggest novel therapeutic approaches to patients with unstable angina.
Reduced Sodium Pump α
1
, α
3
, and β
1
-Isoform Protein Levels and Na
+
,K
+
-ATPase Activity but Unchanged Na
+
-Ca
2+
Exchanger Protein Levels in Human Heart Failure
Authors: Schwinger Robert H. G. , Wang Jiangnan , Frank Konrad , Müller-Ehmsen Jochen , Brixius Klara , McDonough Alicia A. , Erdmann Erland
Published: June 2012

Background
−Cardiac glycosides initiate an increase in force of contraction by inhibiting the sarcolemmal sodium pump (Na
+
,K
+
-ATPase), thereby decreasing Ca
2+
extrusion by the Na
+
-Ca
2+
exchanger, which increases the cellular content of Ca
2+
. In patients with heart failure the sensitivity toward cardiac glycosides is enhanced.

Methods and Results
−Because the inotropic effect of cardiac glycosides may be a function of the sodium pump and Na
+
-Ca
2+
exchanger (NCE) expression levels, the present study aimed to investigate protein expression of both transporters (immunoblot with specific antibodies against the sodium pump catalytic α
1
-, α
2
-, α
3
-, and glycoprotein β
1
-isoforms and against NCE) in left ventricle from failing (heart transplantations, New York Heart Association class IV, n=21) compared with nonfailing (donor hearts, NF, n=22) human myocardium. The density of
3
H-ouabain–binding sites (B
max
) and the Na
+
,K
+
-ATPase activity were also measured. In NYHA class IV, protein levels of Na
+
,K
+
-ATPase α
1
- (0.62±0.06 of control), α
3
- (0.70±0.09), and β
1
- (0.61±0.04) but not α
2
-isoforms were significantly reduced (
P
<0.01), whereas levels of NCE (0.92±0.13 of control) and calsequestrin (0.98±0.06) remained unchanged. Both Na
+
,K
+
-ATPase activity (NF: 1.9±0.29; NYHA class IV: 1.1±0.17 μmol ATP/min per milligram of protein) and the
3
H-ouabain binding sites (B
max
NF: 15.9±1.9 pmol/mg protein; NYHA class IV: 9.7±1.5) were reduced in NYHA class IV and correlated significantly to each other (
r
2
=0.73;
P
<0.0001), as did β
1
-subunit expression. In left ventricular papillary muscle strips from NYHA class IV compared with nonfailing tissue the Na
+
-channel modulator BDF 9198 exerted an increase in force of contraction with unchanged effectiveness but enhanced potency.

Conclusions
−The enhanced sensitivity of failing human myocardium toward cardiac glycosides may be, at least in part, attributed to a reduced protein expression and activity of the sarcolemmal Na
+
,K
+
-ATPase without a change in Na
+
-Ca
2+
exchanger protein expression.
Expression of Endothelin-1, Endothelin-Converting Enzyme, and Endothelin Receptors in Chronic Heart Failure
Authors: Zolk Oliver , Quattek Jessika , Sitzler Gerhard , Schrader Thomas , Nickenig Georg , Schnabel Petra , Shimada Kohei , Takahashi Masaaki , Böhm Michael
Published: June 2012

Background
—Elevated plasma levels of endothelin (ET)-1 have been reported in association with heart diseases, including heart failure. Furthermore, it has been suggested that ET-1 acts as a local autocrine/paracrine factor with biological activities such as vasoconstriction, mitogenesis, and inotropic effects on the heart. This study investigated alterations of ET-1, ET receptor, and endothelin-converting enzyme (ECE) expression in left ventricular myocardium from patients with end-stage heart failure.

Methods and Results
—mRNA concentrations of ET
A
and ET
B
receptors, prepro-ET-1 (ppET-1), and ECE in left ventricles from nonfailing donors hearts (NF) and from patients with end-stage chronic heart failure (NYHA functional class IV) due to dilated cardiomyopathy (DCM) were compared by use of a competitive reverse transcription–polymerase chain reaction technique. There was no significant difference in mRNA expression for ppET-1, ECE-1, and ET
A
receptors, whereas a significant reduction of ET
B
-receptor mRNA was observed in DCM hearts.
125
I-labeled ET-1 radioligand binding studies demonstrated a significant downregulation of ET
B
receptors, whereas ET
A
-receptor density was increased in membranes from DCM hearts. Phosphoramidon-sensitive ECE activity and immunodetectable amounts of ECE protein in left ventricular membrane preparations did not differ between NF and DCM hearts. Finally, immunoreactive ET-1 concentrations were increased in DCM hearts.

Conclusions
—The present study demonstrates changes in the ET-receptor expression pattern in favor of the ET
A
receptor in human end-stage heart failure. Furthermore, activation of the cardiac ET system with increased tissue ET-1 concentrations in the failing myocardium is observed. This is more likely due to decreased clearance than to increased synthesis, because ppET-1 gene expression and ECE activity are unchanged.