bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of an Aggressive Invasive Catheterization and Revascularization Strategy on Mortality in Patients With Cardiogenic Shock in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) Trial
Authors: Berger Peter B. , Holmes David R. , Stebbins Amanda L. , Bates Eric R. , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
Although retrospective analyses have revealed an association between survival and coronary angiography and angioplasty in patients with acute myocardial infarction complicated by cardiogenic shock, the degree to which bias in the selection of patients to undergo these procedures contributes to this observation remains unclear.

Methods and Results
We studied 2200 patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial with acute myocardial infarction complicated by cardiogenic shock (systolic blood pressure <90 mm Hg for ≥1 hour) who survived ≥1 hour after the onset of shock to determine the influence of an aggressive strategy of early angiography (within 24 hours of shock onset) and coronary angioplasty or bypass surgery, if appropriate, on survival. Revascularization was not protocol mandated but was selected by the attending physicians. Shock was present on admission in 11% and developed after admission in 89% of shock patients. The 30-day mortality was 38% in the 406 patients who underwent early angiography and were referred within 24 hours for angioplasty (n=175), bypass surgery (n=36), angioplasty and bypass surgery (n=22), or neither (late or no revascularization, n=173) compared with 62% in the 1794 patients who did not (
P
=.0001). However, there were important differences in the baseline characteristics of the two groups, including younger age (63 versus 68 years,
P
=.0001), less prior infarction (19% versus 27%,
P
=.001), and a shorter time to thrombolytic therapy (2.9 versus 3.2 hours,
P
=.0001) in patients treated with an aggressive strategy. Using multivariate logistic regression analysis to adjust for differences in baseline characteristics, an aggressive strategy was independently associated with reduced 30-day mortality (odds ratio, 0.43 [confidence interval, 0.34 to 0.54],
P
=.0001).

Conclusions
An aggressive strategy of early angiography (and revascularization when appropriate) is associated with a reduction in mortality in patients with acute myocardial infarction and cardiogenic shock who receive thrombolytic therapy.
Thrombomodulin Gene Mutations Associated With Myocardial Infarction
Authors: Ireland Helen , Kunz Gabriella , Kyriakoulis Konstantinos , Stubbs Peter J. , Lane David A.
Published: June 2012

Background
Thrombomodulin is an important receptor for thrombin on the endothelial cell surface of most blood vessels, including those of the heart. Thrombin-bound thrombomodulin activates protein C, which inhibits thrombin generation by degrading factors Va and VIIIa. The aim of this study was to analyze the 5′ region of the thrombomodulin gene to determine whether mutations contribute a risk for myocardial infarction.

Methods and Results
We screened the promoter region of the thrombomodulin gene by single-stranded conformation polymorphism analysis in 104 patients with diagnosed myocardial infarction. Five mutations (three distinct) were identified (GG−9/−10AT, G−33A, and C−133A). The dinucleotide mutation GG−9/−10AT was identified in 3 individuals (2 heterozygous, 1 homozygous). Only one of the three different mutations was identified in 104 patient control subjects matched for age, sex, and race (G−33A in a single individual). All mutations identified were in close proximity to consensus sequences for transcription control elements within the thrombomodulin gene. In contrast, no difference was observed between patients and control subjects for the allelic frequency of a previously identified neutral polymorphism GCC/GTC coding for Ala/Val
455
, with 3 individuals homozygous for GTC (Val) in both groups.

Conclusions
The findings suggest that mutations in the promoter region of the thrombomodulin gene may constitute a risk for arterial thrombosis.
Morning Hypercoagulability and Hypofibrinolysis
Authors: Kapiotis Stylianos , Jilma Bernd , Quehenberger Peter , Ruzicka Katharina , Handler Sylvia , Speiser Wolfgang
Published: June 2012

Background
Diurnal fluctuations of blood coagulation and fibrinolysis activity are thought to play a role in the observed circadian variation in the frequency of onset of acute cardiovascular events. In the present study, the diurnal variations in blood coagulation and fibrinolysis activity were investigated in 10 young, healthy control subjects by use of specific molecular activation markers.

Methods and Results
The plasma levels of activated factor FVII (FVIIa), the active portion of the main coagulation activator, decreased during the day (8
am
: 2.03 ng/mL, CI 1.16 to 2.88 ng/mL; 8
pm
: 1.16 ng/mL, CI 0.81 to 1.5 ng/mL;
P
=.005), whereas FVII antigen did not change significantly. In parallel with the diurnal variations of FVIIa, we found a decrease of prothrombin fragment F
1+2
(8
am
: 0.97 nmol/L, CI 0.79 to 1.15 nmol/L; 8
pm
: 0.78 nmol/L, CI 0.64 to 0.93 nmol/L;
P
=.005), a molecular marker of intravasal thrombin generation. Evidence for a possible functional relevance of circulating FVIIa was found because this parameter was significantly correlated with prothrombin fragment F
1+2
in 72 fasting healthy individuals (
r
=.29,
P
=.011). Plasminogen activator inhibitor-1 levels decreased (8
am
: 9.9 ng/mL, CI 7.7 to 12.1 ng/mL; 8
pm
: 5.4 ng/mL, CI 3.8 to 6.9 ng/mL;
P
<.005), whereas plasmin–plasmin inhibitor complex levels, representing the degree of intravascular plasmin generation, concomitantly increased (8
am
: 235 μg/L, CI 198 to 272 μg/L; 8
pm
: 449 μg/L, CI 391 to 507 μg/L;
P
=.008).

Conclusions
Our data suggest that the diurnal changes in the plasma levels of activators and inhibitors of coagulation and fibrinolysis lead to corresponding changes in the activity state of these systems, leading to morning hypercoagulability and hypofibrinolysis.
Mobile Thromboses of the Aortic Arch Without Aortic Debris
Authors: Laperche Thierry , Laurian Claude , Roudaut Raymond , Steg P. Gabriel
Published: June 2012

Background
Atherosclerotic lesions of the aortic arch are potential sources of arterial embolism. Mobile thrombi in the aortic arch in young patients without diffuse atherosclerosis have been reported recently, but such cases remain exceptional. We describe a series of young patients with unexplained arterial embolism in whom transesophageal echocardiography detected mobile aortic arch thromboses.

Methods and Results
Transesophageal echocardiography files collected between 1991 and 1995 in French academic cardiology centers were reviewed to identify patients who fulfilled the following criteria: (1) an arterial embolic event in the preceding weeks; (2) a mobile pedunculated aortic arch thrombosis, defined as an echogenic mass protruding into the lumen of the aorta and inserted on the aortic arch; and (3) absence of obvious diffuse aortic atherosclerosis or of aortic debris on transesophageal echocardiography. Twenty-three cases were identified from 27 855 examinations. Thromboses were located on the horizontal aorta (n=4), near the ostium of the left subclavian artery (n=5), or on the concavity of the posterior segment of the aortic arch (in the isthmus) (n=14). The insertion site was a small atherosclerotic plaque in 21 patients. The remaining aortic wall always appeared normal or mildly atherosclerotic. The mean age of the patients was 45±8.4 years (range, 26 to 61 years). All patients were treated with intravenous heparin after the diagnosis of aortic arch thrombosis, and surgical removal of the thrombosis was performed in 10 patients in whom histological examination confirmed an atherosclerotic process at the site of insertion of the thrombosis. The prognosis was mainly influenced by embolic events.

Conclusions
Thromboses of the aortic arch appear to be a variant form of aortic atherosclerotic disease associated with arterial embolism in young patients.
Hemodynamic Patterns of Age-Related Changes in Blood Pressure
Authors: Franklin Stanley S. , Gustin William , Wong Nathan D. , Larson Martin G. , Weber Michael A. , Kannel William B. , Levy Daniel
Published: June 2012

Background
We attempted to characterize age-related changes in blood pressure in both normotensive and untreated hypertensive subjects in a population-based cohort from the original Framingham Heart Study and to infer underlying hemodynamic mechanisms.

Methods and Results
A total of 2036 participants were divided into four groups according to their systolic blood pressure (SBP) at biennial examination 10, 11, or 12. After excluding subjects receiving antihypertensive drug therapy, up to 30 years of data on normotensive and untreated hypertensive subjects from biennial examinations 2 through 16 were used. Regressions of blood pressure versus age within individual subjects produced slope and curvature estimates that were compared with the use of ANOVA among the four SBP groups. There was a linear rise in SBP from age 30 through 84 years and concurrent increases in diastolic blood pressure (DBP) and mean arterial pressure (MAP); after age 50 to 60 years, DBP declined, pulse pressure (PP) rose steeply, and MAP reached an asymptote. Neither the fall in DBP nor the rise in PP was influenced significantly by removal of subsequent deaths and subjects with nonfatal myocardial infarction or heart failure. Age-related linear increases in SBP, PP, and MAP, as well as the early rise and late fall in DBP, were greatest for subjects with the highest baseline SBP; this represents a divergent rather than parallel tracking pattern.

Conclusions
The late fall in DBP after age 60 years, associated with a continual rise in SBP, cannot be explained by “burned out” diastolic hypertension or by “selective survivorship” but is consistent with increased large artery stiffness. Higher SBP, left untreated, may accelerate large artery stiffness and thus perpetuate a vicious cycle.
Reoxygenation of Hypoxic Human Umbilical Vein Endothelial Cells Activates the Classic Complement Pathway
Authors: Collard Charles D. , Väkevä Antti , Büküsoglu Cüneyt , Zünd Gregor , Sperati C. John , Colgan Sean P. , Stahl Gregory L.
Published: June 2012

Background
Ischemia-reperfusion injury leads to the activation and endothelial deposition of complement. We investigated whether exposure of human umbilical vein endothelial cells (HUVECs) to hypoxia and/or reoxygenation activates complement and decreases HUVEC-surface expression of the C3 regulatory proteins CD46 and CD55.

Methods and Results
HUVECs were subjected to 0, 12, or 24 hours of hypoxia (O
2
=1%) and then reoxygenated for 3 hours (O
2
=21%) in the presence of 30% human serum. C3 deposition and HUVEC-surface expression of CD46 and CD55 were evaluated by ELISA and flow cytometry. C3 deposition on HUVECs subjected to 12 or 24 hours of hypoxia followed by 3 hours of reoxygenation was significantly greater than normoxic HUVECs. Inhibition of the classic but not the alternative complement pathway during reoxygenation attenuated C3 deposition. Western blot analysis of HUVEC lysates under reducing conditions demonstrated significantly increased iC3b deposition in hypoxic/reoxygenated HUVECs compared with normoxic HUVECs. FACS analysis confirmed iC3b deposition. HUVEC-surface expression of CD46 and CD55 increased after hypoxia and/or reoxygenation.

Conclusions
We conclude that (1) hypoxia and reoxygenation of HUVECs significantly increases iC3b deposition on HUVECs, (2) C3 deposition after hypoxia and reoxygenation is largely mediated by the classic complement pathway, and (3) HUVEC-surface expression of CD46 and CD55 increases after hypoxia and reoxygenation. These data demonstrate that hypoxia and reoxygenation of human endothelial cells activates the classic complement pathway despite an increase in complement C3 regulatory proteins.
Prospective Evaluation of Dietary and Other Predictors of Fatal Stroke in Shanghai, China
Authors: Ross Ronald K. , Yuan Jian-Min , Henderson Brian E. , Park Jinha , Gao Yu-Tang , Yu Mimi C.
Published: June 2012

Background
Although a number of risk factors for fatal stroke are well established in Western populations, this is less true for Asian countries, many of which have stroke mortality rates that are historically high. In a prospective study in Shanghai, China, we determined whether the same factors predict risk for fatal stroke as in the West. We also studied a number of potential dietary associations, particularly those with dietary antioxidants because these have been suggested to reduce atherogenesis.

Methods and Results
Between 1986 and 1989, 18 244 men aged 45 to 64 years living in four geographically defined areas of Shanghai, China were recruited to participate in a prospective study of diet and cancer. All participants completed an in-person, structured interview and provided blood and urine samples. As of March 1994, fatal stroke accounted for 245 of the 980 observed deaths. The most important risk factor for stroke mortality was a history of hypertension (multivariate relative risk, 4.5; 95% confidence interval, 3.3, 6.2). Cigarette smoking was not strongly associated with risk, and alcohol consumption increased risk only in the extreme categories of lifetime consumption. Educational level was strongly, inversely associated with fatal stroke, and this could not be explained by adjustment for any other risk factors. No macronutrient was associated with risk, including total energy, fat consumption, or any component of fat. There also were no significant inverse associations for stroke mortality with several micronutrients of interest, including vitamin C, carotene, vitamin E, riboflavin, or calcium.

Conclusions
Our data demonstrate that hypertension is by far the most important contributor to stroke mortality in Shanghai and that among dietary factors, only alcohol consumption shows any evidence whatsoever of being a risk factor.
First Chronic Platelet Glycoprotein IIb/IIIa Integrin Blockade
Authors: Simpfendorfer Conrad , Kottke-Marchant Kandice , Lowrie Marsha , Anders Robert J. , Burns Daniel M. , Miller Dave P. , Cove Christopher S. , DeFranco Anthony C. , Ellis Stephen G. , Moliterno David J. , Raymond Russell E. , Sutton Joseph M. , Topol Eric J.
Published: June 2012

Background
Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy.

Methods and Results
Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding.

Conclusions
Xemilofiban, an orally active glycoprotein IIb/IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.
Endothelial Dysfunction Is Associated With Cholesterol Levels in the High Normal Range in Humans
Authors: Steinberg Helmut O. , Bayazeed Basel , Hook Ginger , Johnson Ann , Cronin Jessica , Baron Alain D.
Published: June 2012

Background
The purpose of this study was to test the hypothesis that cholesterol levels in the high normal range are associated with impaired endothelium-dependent vasodilation.

Methods and Results
We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP) in normal volunteers exhibiting a wide range of total cholesterol levels within the normal range (<75th percentile). LBF increased in a dose-dependent fashion in response to the femoral artery infusions of MCh and SNP (
P
<.001). LBF responses to MCh were significantly blunted (
P
<.001) in subjects with high normal cholesterol (195±6 mg/dL, n=13) compared with subjects with low normal cholesterol (146±5 mg/dL, n=20). Maximal endothelium-dependent vasodilation in the high normal group was decreased by nearly 50% compared with the low normal group (146±13% versus 268±34%,
P
<.01). There was a negative correlation between total cholesterol levels and maximal endothelium-dependent vasodilation (total cholestero,l
r
=−.41,
P
<.02; LDL cholesterol,
r
=−.42,
P
<.02). On the other hand, LBF responses to the endothelium-independent vasodilator SNP did not differ between groups.

Conclusions
These data suggest that an inverse and continuous relationship exists between the prevailing cholesterol level and endothelium-dependent vasodilation. Moreover, cholesterol levels even in the normal range may be associated with endothelial dysfunction, thus potentially contributing to the increased risk of macrovascular disease conferred by cholesterol elevations.
Estimating Effectiveness of Cardiac Arrest Interventions
Authors: Valenzuela Terence D. , Roe Denise J. , Cretin Shan , Spaite Daniel W. , Larsen Mary P.
Published: June 2012

Background
The study objective was to develop a simple, generalizable predictive model for survival after out-of-hospital cardiac arrest due to ventricular fibrillation.

Methods and Results
Logistic regression analysis of two retrospective series (n=205 and n=1667, respectively) of out-of-hospital cardiac arrests was performed on data sets from a Southwestern city (population, 415 000; area, 406 km
2
) and a Northwestern county (population, 1 038 000; area, 1399 km
2
). Both are served by similar two-tiered emergency response systems. All arrests were witnessed and occurred before the arrival of emergency responders, and the initial cardiac rhythm observed was ventricular fibrillation. The main outcome measure was survival to hospital discharge. Patient age, initiation of CPR by bystanders, interval from collapse to CPR, interval from collapse to defibrillation, bystander CPR/collapse-to-CPR interval interaction, and collapse-to-CPR/collapse-to-defibrillation interval interaction were significantly associated with survival. There was not a significant difference between observed survival rates at the two sites after control for significant predictors. A simplified predictive model retaining only collapse to CPR and collapse to defibrillation intervals performed comparably to the more complicated explanatory model.

Conclusions
The effectiveness of prehospital interventions for out-of-hospital cardiac arrest may be estimated from their influence on collapse to CPR and collapse to defibrillation intervals. A model derived from combined data from two geographically distinct populations did not identify site as a predictor of survival if clinically relevant predictor variables were controlled for. This model can be generalized to other US populations and used to project the local effectiveness of interventions to improve cardiac arrest survival.
Upregulation of Angiotensin-Converting Enzyme During the Healing Process After Injury at the Site of Percutaneous Transluminal Coronary Angioplasty in Humans
Authors: Ohishi Mitsuru , Ueda Makiko , Rakugi Hiromi , Okamura Atsunori , Naruko Takahiko , Becker Anton E. , Hiwada Kunio , Kamitani Atsushi , Kamide Kei , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Background
Balloon injury models in rat have shown enhanced expression of ACE in the developing neointima. However, neointimal lesions in human coronary arteries are complex due to atherosclerosis and different types of wall laceration. This study was designed to investigate whether ACE is present in the neointima of humans, including patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA).

Methods and Results
Thirty-seven sites with angioplasty injury, obtained at autopsy, were studied using immunocytochemical techniques. Sites with injury limited to a fibrous plaque and those with injury extending into the media (<2 months after PTCA) showed fibrocellular repair tissue composed mainly of smooth muscle cells that were distinctly positive for ACE. In cellular reactions at the site of injury limited to the atheromatous plaque (<2 months after PTCA), the expression of ACE appeared first in accumulated macrophages; once smooth muscle cells appeared in the repair tissue, they also expressed ACE. At a later stage (3 months after PTCA), the number of cells with ACE expression decreased markedly; from 7 months on, ACE was no longer expressed within the repair tissue. Basically, there were no differences with regard to ACE expression during the healing process after PTCA between segments with and those without angiographic evidence of restenosis.

Conclusions
These results show that PTCA injury in humans results in upregulation of ACE at sites of active repair and, therefore, ACE could play an important role as one of the mediators of the healing process after PTCA.
Coronary Endothelial Dysfunction in Humans Is Associated With Myocardial Perfusion Defects
Authors: Hasdai David , Gibbons Raymond J. , Holmes David R. , Higano Stuart T. , Lerman Amir
Published: June 2012

Background
Coronary endothelial dysfunction may occur in patients with minimally obstructive coronary artery disease and angina, and potentially may cause myocardial ischemia.

Methods and Results
Coronary endothelium-dependent vasodilation was examined in patients with angina and <50% coronary artery diameter (CAD) stenosis by selectively infusing acetylcholine (10
−6
mol/L to 10
−4
mol/L) into the left anterior descending coronary artery (LAD). Percent change in CAD (%ΔCAD) was measured by quantitative coronary angiography, and percent change in coronary blood flow (%ΔCBF) was calculated using intracoronary flow Doppler. Coronary endothelium-independent vasodilation was examined using intracoronary adenosine and nitroglycerin.
99m
Tc sestamibi was injected intravenously just prior to the infusion of the highest dose of acetylcholine. Patients were divided blindly into three groups: Perfusion defects in non-LAD territory (group 1, n=6), no perfusion defects (group 2, n=7), and perfusion defects in the LAD territory (group 3, n=7). All patients had intact endothelium-independent vasodilation. In group 1, perfusion defects outside the LAD territory reflected an increase in %ΔCAD and %ΔCBF by 24±5% and 241±46% in the LAD. In group 2, %ΔCAD decreased by 26±5%, but %ΔCBF increased by 54±17%. In group 3, perfusion defects were within the LAD territory, reflecting a decrease in %ΔCAD and %ΔCBF by 35±5% and 51±14%, respectively.

Conclusions
This study demonstrates that coronary endothelial dysfunction in humans may be temporally associated with myocardial perfusion defects and supports a role for the coronary epicardial and microcirculation endothelium in regulating myocardial perfusion. Myocardial ischemia may occur in humans with impaired endothelium-dependent coronary flow reserve of the coronary epicardial and microcirculation.
Activation of the Complement System During and After Cardiopulmonary Bypass Surgery
Authors: Bruins Peter , Velthuis Henk te , Yazdanbakhsh Aria P. , Jansen Piet G. M. , van Hardevelt Fred W. J. , de Beaumont Eddy M. F. H. , Wildevuur Charles R. H. , Eijsman León , Trouwborst Ad , Hack C. Erik
Published: June 2012

Background
Complement activation during cardiopulmonary bypass (CPB) surgery is considered to result from interaction of blood with the extracorporeal circuit. We investigated whether additional mechanisms may contribute to complement activation during and after CPB and, in particular, focused on a possible role of the acute-phase protein C–reactive protein (CRP).

Methods and Results
In 19 patients enrolled for myocardial revascularization, perioperative and postoperative levels of complement activation products, interleukin-6 (IL-6), CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo, were measured and related to clinical symptoms. A biphasic activation of complement was observed. The ratio between the areas under the curve of perioperative and postoperative C3b/c and C4b/c were 3:2 and 1:46, respectively. IL-6 levels reached a maximum at 6 hours post-surgery. CRP levels peaked on the second postoperative day. Each complement-CRP complex had peak levels on the second or third postoperative day. By multivariate analysis, maximum levels of CRP on the second postoperative day were mainly explained by C4b/c levels after protamine administration, leukocyte count on the second postoperative day, and preoperative levels of CRP. Peak levels of C4b/c after protamine administration (
P
=.0073) and on the second postoperative day correlated with the occurrence of arrhythmia on the same day (
P
=.0065).

Conclusions
Cardiac surgery with CPB causes a biphasic complement activation. The first phase occurs during CPB and results from the interaction of blood with the extracorporeal circuit. The second phase, which occurs during the first 5 days after surgery, involves CRP, is related to baseline CRP levels, and is associated with clinical symptoms such as arrhythmia.
Na
+
/H
+
Exchanger Activity Does Not Contribute to Protection by Ischemic Preconditioning in the Isolated Rat Heart
Authors: Shipolini Alex R. , Yokoyama Hiroyuki , Galiñanes Manuel , Edmondson Stephen J. , Hearse David J. , Avkiran Metin
Published: June 2012

Background
Despite evidence that pharmacological inhibition of the Na
+
/H
+
exchanger (NHE) is cardioprotective, activation of NHE has been proposed as a protective mechanism of ischemic preconditioning (PC).

Methods and Results
In isolated rat ventricular myocytes (n=8 to 11 per group) loaded with the fluorescent pH indicator C-SNARF-1, we showed that HOE-642 (HOE) was a potent inhibitor of the sarcolemmal NHE (80% inhibition at 1 μmol/L); such inhibition was readily reversible by washout of the drug. We confirmed that 1 μmol/L HOE produces significant and reversible inhibition of NHE activity in isolated rat hearts as well (n=4), and in this model, we tested (n=8 per group) whether the presence of the drug during (1) the prolonged period of ischemia (40 or 60 minutes) or (2) the preceding brief periods of PC ischemia (3 minutes plus 5 minutes) modulates the protective efficacy of PC. In protocol 1, HOE was infused for 5 minutes immediately before the prolonged ischemic period. With 40 minutes of prolonged ischemia, the postischemic recovery of left ventricular developed pressure (LVDP) was 15±2% in controls and was improved to 45±7% with HOE (
P
<.05), 55±5% with PC (
P
<.05), and 68±2% with PC+HOE (
P
<.05 versus all groups). When the prolonged ischemic period was extended to 60 minutes, an additive effect of PC and HOE was readily apparent and LVDP recovery with PC+HOE (66±2%) was almost double that observed with HOE (37±4%) or PC (34±5%) alone (
P
<.05). In protocol 2, HOE was infused for 3 minutes immediately before each episode of PC ischemia and was subsequently washed out before a 40-minute prolonged ischemic period (HOE+PC). LVDP recovery was 34±4% in controls and was improved to 57±2% with PC (
P
<.05) and 55±3% with HOE+PC (
P
<.05). Improved recovery of LVDP was matched by reduced creatine kinase leakage in all cases.

Conclusions
Because coadministration of HOE (at a concentration sufficient to inhibit NHE activity) did not reduce the efficacy of PC in either protocol, we conclude that NHE activity does not contribute to the cardioprotective actions of PC. On the contrary, NHE inhibition during the prolonged ischemic period may enhance the protection afforded by PC.
Hemodynamic Evaluation of the Heart With a Nonfluoroscopic Electromechanical Mapping Technique
Authors: Gepstein Lior , Hayam Gal , Shpun Shlomo , Ben-Haim Shlomo A.
Published: June 2012

Background
Clinical cardiac volumetric measurement techniques are essential for assessing cardiac performance but produce significant inaccuracies in extrapolation of the volume of a three-dimensional (3D) object from two-dimensional images and lack the ability to associate cardiac electrical and mechanical activities. In this study, we tested the accuracy of cardiac volumetric measurements using a new catheter-based system.

Methods and Results
The system uses magnetic technology to accurately locate a special catheter at a frequency of 125 Hz and is currently used in the field of electrophysiology, in which activation maps are superimposed on the 3D geometry of the cardiac chamber. The mapping procedure is based on sequentially acquiring the location of the tip and local electrogram while in contact with the endocardium. The 3D geometry of the chamber is reconstructed in real time, and its volume could be calculated at every time step (8 ms). The volumetric measurements of the system were found to be highly accurate for simple phantoms (mean±SEM deviation, 2.3±1.1%), left ventricular casts (9.6±1.3%), and a dynamic test jig. In addition, left ventricular volumes of 12 swine were measured. Intraobserver and interobserver variabilities were found to be minimal (ejection fraction, 6.5±1.9% and 7.1±2.0%; stroke volume, 4.5±1.0% and 11.3±2.4%). Comparison with the thermodilution method for measuring stroke volume showed an average deviation of 8.1±2.2%. Typical pressure-volume loops were also obtained.

Conclusions
The new mapping image provides, for the first time, simultaneous information regarding cardiac mechanics, hemodynamics, and electrical properties. Furthermore, all this information is achieved without the use of fluoroscopy, contrast medium, or complicated image processing.
Rapid Assessment of Platelet Function With a Modified Whole-Blood Aggregometer in Percutaneous Transluminal Coronary Angioplasty Patients Receiving Anti-GP IIb/IIIa Therapy
Authors: Mascelli Mary A. , Worley Seth , Veriabo Nicholas J. , Lance Ellen T. , Mack Sabina , Schaible Tom , Weisman Harlan F. , Jordan Robert E.
Published: June 2012

Background
The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (c7E3 Fab, ReoPro) is approved for use in high-risk percutaneous transluminal coronary angioplasty (PTCA). At present, no “point of care” exists for measuring pharmacological GP IIb/IIIa blockade. To address this need, the Chrono-log Whole Blood Aggregometer, which measures platelet aggregation by electrical impedance, was adapted to test platelet function at the bedside.

Methods and Results
GP IIb/IIIa receptor blockade, impedance (5 μg/mL collagen), and turbidimetric aggregation (5 and 20 μmol/L ADP) measurements were obtained on 14 PTCA patients who received the standard bolus plus a 12-hour infusion of abciximab. During abciximab administration, mean GP IIb/IIIa receptor blockade was >91%, and both impedance and turbidimetric aggregation were inhibited by ≥90%. At 12 hours after abciximab treatment, the mean inhibition of turbidimetric platelet aggregation to 5 and 20 μmol/L ADP was 65±20% and 49±14%, respectively, and inhibition of impedance aggregation was 69±12%. GP IIb/IIIa receptor blockade was 67±8%. At 36 hours after abciximab treatment (n=8), the mean inhibition of turbidimetric platelet aggregation to 5 and 20 μmol/L ADP was 44±21% and 30±14%, respectively, whereas impedance aggregation was inhibited by 60±14%. GP IIb/IIIa receptor blockade was 57±7%.

Conclusions
During and at 12 hours after abciximab therapy, impedance and turbidimetric platelet aggregation to 5 μmol/L ADP were comparable and closely correlated with GP IIb/IIIa receptor blockade. However, at 36 hours after abciximab treatment, impedance platelet aggregation more closely paralleled GP IIb/IIIa receptor blockade and indicated a slower recovery of platelet function than turbidimetric aggregometry.
Aggregating Human Platelets Stimulate the Expression of Thrombin Receptors in Cultured Vascular Smooth Muscle Cells via the Release of Transforming Growth Factor-β
1
and Platelet-Derived Growth Factor
AB
Authors: Schini-Kerth Valérie B. , Bassus Steffen , Fisslthaler Beate , Kirchmaier Carl M. , Busse Rudi
Published: June 2012

Background
Thrombin and the thrombin receptor have been implicated in the proliferation of vascular smooth muscle cells (VSMCs) observed after angioplasty and in atherosclerosis. Because thrombin receptor activation is an irreversible proteolytic event, the marked upregulation of the smooth muscle cell thrombin receptor after vascular injury may account for the maintained mitogenic activity of thrombin. The present study was designed to determine whether aggregating platelets stimulate thrombin receptor expression in cultured VSMCs and, if so, to identify the mediators.

Methods and Results
Thrombin receptor expression was assessed by Northern and Western blot analyses and functionally by measuring the release of 6-keto prostaglandin F
1α
. Platelet-derived products (PDPs) released by aggregating human platelets enhanced thrombin receptor mRNA levels in a time- and concentration-dependent manner, an effect that was potentiated by transient acidification of PDPs, which release bioactive transforming growth factor (TGF)-β
1
, and that was slightly inhibited by ketanserin. Among several factors known to be released by aggregating platelets, only TGF-β
1
, platelet-derived growth factor
AB
(PDGF
AB
), and serotonin mimicked the PDP effect. The level of membrane thrombin receptor protein was increased in TGF-β
1
–treated VSMCs. Pretreatment of VSMCs with either acidified PDP, or TGF-β
1
increased the α-thrombin–stimulated release of 6-keto prostaglandin F
1α
. This effect was blunted by incubating acidified PDP with either a TGF-β–or a PDGF-neutralizing antibody.

Conclusions
Aggregating human platelets stimulate the expression of thrombin receptors in VSMCs through the release of TGF-β
1
, PDGF
AB
, and, to a lesser extent, serotonin. The upregulation of the thrombin receptor by products released by aggregating platelets may sustain the mitogenic activity of thrombin in the vascular wall at sites of injury.
Angiotensin Type 2 Receptors Are Reexpressed by Cardiac Fibroblasts From Failing Myopathic Hamster Hearts and Inhibit Cell Growth and Fibrillar Collagen Metabolism
Authors: Ohkubo Naohiko , Matsubara Hiroaki , Nozawa Yoshihisa , Mori Yasukiyo , Murasawa Satoshi , Kijima Kazuhisa , Maruyama Katsuya , Masaki Hiroya , Tsutumi Yoshiaki , Shibazaki Yoshinobu , Iwasaka Toshiji , Inada Mitsuo
Published: June 2012

Background
Angiotensin (Ang) II type 1 receptor (AT
1
-R) induces cardiomyocyte hypertrophy and fibroblast proliferation, whereas the physiological role of AT
2
-R in cardiac remodeling remains poorly defined.

Methods and Results
Using Bio14.6 cardiomyopathic (CM) hamsters, we found that AT
2
-R sites were increased by 153% during heart failure compared with F1B controls. AT
1
-R numbers were increased by 72% in the hypertrophy stage and then decreased to the control level during heart failure. Such differential regulation of AT
2
-R and AT
1
-R during heart failure was consistent with changes in the respective mRNA levels. Autoradiography and immunocytochemistry revealed that both AT
2
-R and AT
1
-R are localized at higher densities in fibroblasts present in fibrous regions. Surrounding myocardium predominantly expressed AT
1
-R, but the level of expression was less than that in fibrous regions. Cardiac fibroblasts isolated from CM hearts during heart failure but not from control hamsters expressed AT
2
-R (30 fmol/mg protein). Using the cardiac fibroblasts expressing AT
2
-R, we found that Ang II stimulated net collagenous protein production by 48% and pretreatment with an AT
2
-R antagonist, PD123319, evoked a further elevation (83%). Ang II–induced synthesis of fibronectin and collagen type I were enhanced by 40% and 53%, respectively, by pretreatment with PD123319. Ang II–induced DNA synthesis (assessed by [
3
H]thymidine uptake) was significantly increased by PD123319, and the AT
2
-R agonist CGP42112A reduced the serum-stimulated increase in cell numbers by 23%. Treatment with an AT
1
-R antagonist, TCV116, for 20 weeks inhibited progression of interstitial fibrosis by 28%, whereas with 44-week PD123319 treatment but not 20-week treatment, the extent of the fibrous region was increased significantly, by 29%.

Conclusions
These findings demonstrate that AT
2
-R is reexpressed by cardiac fibroblasts present in fibrous regions in failing CM hearts and that the increased AT
2
-R exerts an anti–AT
1
-R action on the progression of interstitial fibrosis during cardiac remodeling by inhibiting both fibrillar collagen metabolism and growth of cardiac fibroblasts.
Functional Mechanisms Underlying Tachycardia-Induced Sustained Atrial Fibrillation in a Chronic Dog Model
Authors: Gaspo Rania , Bosch Ralph F. , Talajic Mario , Nattel Stanley
Published: June 2012

Background
Rapid atrial activation causes electrical remodeling that promotes atrial fibrillation (AF), but underlying mechanisms are incompletely understood. We applied epicardial mapping to evaluate atrial electrophysiology and AF duration in dogs subjected to rapid atrial pacing (400/min).

Methods and Results
Dogs paced for 1 (P1, n=7), 7 (P7, n=13), or 42 (P42, n=7) days were compared with sham dogs (P0, n=13). Atrial pacing progressively increased AF duration. Atrial effective refractory period (ERP) and ERP accommodation to rate were significantly decreased by pacing, with near-maximal changes within 7 days. Atrial conduction velocity decreased more slowly, with maximum changes at 42 days, contributing to increases in AF duration after ERP stabilized. Stepwise multilinear regression indicated that both wavelength (
P
=.02) and duration of pacing (
P
=.0001) were independent determinants of changes in AF duration. Mean atrial fibrillation cycle length (AFCL) at 112 recording sites decreased with increased duration of rapid pacing (
P
<.001), and the SD of AFCL increased progressively (
P
<.0001), together accounting for 72% of the variance in AF duration. Increases in AFCL variability were due to regionally determined differences in AFCL changes caused by rapid pacing. The number of zones of reactivation per cycle of AF increased as AF became more sustained, consistent with multiple-wavelet reentry.

Conclusions
Rapid atrial activation causes time-dependent decreases in ERP, conduction velocity, and wavelength, which, along with increased regional heterogeneity, provide a substrate for AF. The conduction abnormalities and increased regional heterogeneity previously noted in patients with AF may be a consequence, as well as a cause, of the tachyarrhythmia.
Prognostic Influence of Increased Fibrinogen and C-Reactive Protein Levels in Unstable Coronary Artery Disease
Authors: Toss H. , Lindahl B. , Siegbahn A. , Wallentin L. , Group for the FRISC Study
Published: June 2012

Background
The prognostic influences of fibrinogen and C-reactive protein levels and their relations to myocardial damage in unstable coronary artery syndromes have not been well described.

Methods and Results
Fibrinogen and C-reactive protein were determined at inclusion and related to outcome after 5 months in 965 patients with unstable angina or non–Q-wave myocardial infarction randomized to 5 weeks with low-molecular-weight heparin or placebo. The probabilities of death were 1.6%, 4.6%, and 6.9% (
P
=.005) and the probabilities of death and/or myocardial infarction were 9.3%, 14.2%, and 19.1% (
P
=.002), respectively, in patients stratified by tertiles of fibrinogen (<3.38, 3.38 to 3.99, and ≥4.0 g/L). The probabilities of death were 2.2%, 3.6%, and 7.5% (
P
=.003) after stratification of patient data by tertiles of C-reactive protein level (<2, 2 to 10, and >10 mg/L). In logistic multiple regression analysis, increased fibrinogen levels were independently associated with the incidence of death and/or myocardial infarction (
P
=.013), and elevated C-reactive protein level was associated with the incidence of death (
P
=.012). The increased relative risk of subsequent death or myocardial infarction in individuals with an elevated fibrinogen level was consistent in most subgroups evaluated; although significantly so only in patients with signs of myocardial damage.

Conclusions
Increased levels of both fibrinogen and C-reactive protein are associated with a worse outcome in patients with unstable coronary artery disease. The increased risk associated with elevated fibrinogen levels is independent of, and additive to, the prognostic influence of myocardial damage.
Circulating Adhesion Molecules VCAM-1, ICAM-1, and E-selectin in Carotid Atherosclerosis and Incident Coronary Heart Disease Cases
Authors: Hwang Shih-Jen , Ballantyne Christie M. , Sharrett A. Richey , Smith Louis C. , Davis Clarence E. , Gotto Antonio M. , Boerwinkle Eric
Published: June 2012

Background
Recruitment of circulating leukocytes at sites of atherosclerosis is mediated through a family of adhesion molecules. The function of circulating forms of these adhesion molecules remains unknown, but their levels may serve as molecular markers of subclinical coronary heart disease (CHD).

Methods and Results
To determine the ability of circulating vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intercellular adhesion molecule-1 (ICAM-1) to serve as molecular markers of atherosclerosis and predictors of incident CHD, we studied 204 patients with incident CHD, 272 patients with carotid artery atherosclerosis (CAA), and 316 control subjects from the large, biracial Atherosclerosis Risk In Communities (ARIC) study. Levels of VCAM-1 were not significantly different among the patients with incident CHD, those with CAA, and control subjects. Higher levels of E-selectin and ICAM-1 were observed for the patients with CHD (means [ng/mL]: E-selectin, 38.4; ICAM-1, 288.7) and those with CAA (E-selectin, 41.5; ICAM-1, 283.6) compared with the control subjects (E-selectin, 32.8; ICAM-1, 244.2), but the distributions were not notably different between the patients with CHD and CAA. Results of logistic regression analyses indicated that the relationship of ICAM-1 and E-selectin with CHD and CAA was independent of other known CHD risk factors and was most pronounced in the highest quartile. The odds of CHD and CAA were 5.53 (95% CI, 2.51–12.21) and 2.64 (95% CI, 1.40–5.01), respectively, for those with levels of ICAM-1 in the highest quartile compared with those in the lowest quartile. Odds of CAA were 2.03 (95% CI, 1.14–3.62) for those with levels of E-selectin in the highest quartile compared with those in the lowest quartile.

Conclusions
These data indicate that plasma levels of ICAM-1 and E-selectin may serve as molecular markers for atherosclerosis and the development of CHD.
Reduction of Serum Cholesterol in Postmenopausal Women With Previous Myocardial Infarction and Cholesterol Malabsorption Induced by Dietary Sitostanol Ester Margarine
Authors: Gylling Helena , Radhakrishnan Rajaratnam , Miettinen Tatu A.
Published: June 2012

Background
Reduction of serum cholesterol decreases mortality in primary and especially in secondary prevention. We investigated how effectively postmenopausal women with a previous myocardial infarction reduced their serum cholesterol with dietary means by using sitostanol ester rapeseed oil margarine, alone and in combination with statins, and to what extent cholesterol metabolism was affected.

Methods and Results
The first study group consisted of 22 randomly chosen women with angiographically documented coronary artery disease. Baseline studies on home diet were followed by double-blind, randomized, cross-over studies on margarine without and with sitostanol (3 g/d) ester for 7 weeks in random order. A second group of 10 women on simvastatin consumed sitostanol ester margarine for 12 weeks. Sitostanol ester margarine lowered serum total cholesterol by 13% (
P
<.05) and LDL cholesterol by 20% (
P
<.01). Sitostanol ester margarine reduced total cholesterol in all patients, LDL cholesterol <2.6 mmol/L (<100 mg/dL) in 32%, and <3.4 mmol/L (<133 mg/dL) in 73% versus none and 27% during the home diet (
P
<.01 for both). Combined with simvastatin, sitostanol still reduced total and LDL cholesterol by 11±3% and 16±5% (
P
<.01 for both). Sitostanol reduced absorption (−45%), increased fecal elimination (+45% as neutral sterols), and stimulated synthesis (+39%) of cholesterol. High cholestanol and plant sterol (high cholesterol absorption) and low baseline precursor sterol proportions (low cholesterol synthesis) predicted high decreases in serum cholesterol.

Conclusions
Dietary use of sitostanol ester margarine normalizes LDL cholesterol in about one third of women with previous myocardial infarction, especially in those with high baseline absorption and low synthesis of cholesterol, and in combination with statins reduces the needed drug dose.
Sphygmomanometrically Determined Pulse Pressure Is a Powerful Independent Predictor of Recurrent Events After Myocardial Infarction in Patients With Impaired Left Ventricular Function
Authors: Mitchell Gary F. , Moyé Lemuel A. , Braunwald Eugene , Rouleau Jean-Lucien , Bernstein Victoria , Geltman Edward M. , Flaker Greg C. , Pfeffer Marc A. , Investigators for the SAVE
Published: June 2012

Background
There is increasing evidence of a link between conduit vessel stiffness and cardiovascular events, although the association has never been tested in a large post–myocardial infarction patient population.

Methods and Results
We evaluated the relationship between baseline pulse pressure, measured by sphygmomanometry 3 to 16 days after myocardial infarction, and subsequent adverse clinical events in the 2231 patients enrolled in the SAVE Trial. Increased pulse pressure was associated with increased age, left ventricular ejection fraction, female sex, history of prior infarction, diabetes, and hypertension and use of digoxin and calcium channel blockers. Over a 42-month period, there were 503 deaths, 422 cardiovascular deaths, and 303 myocardial infarctions. Pulse pressure was significantly related to each of these end points as a univariate predictor. In a multivariate analysis, pulse pressure remained a significant predictor of total mortality (relative risk, 1.08 per 10 mm Hg increment in pulse pressure; 95% CI, 1.00 to 1.17;
P
<.05) and recurrent myocardial infarction (relative risk, 1.12; 95% CI, 1.01 to 1.23;
P
<.05) after control for age; left ventricular ejection fraction; mean arterial pressure; sex; treatment arm (captopril or placebo); smoking history; history of prior myocardial infarction, diabetes, or hypertension; and treatment with β-blockers, calcium channel blockers, digoxin, aspirin, or thrombolytic therapy.

Conclusions
These data provide strong evidence for a link between pulse pressure, which is related to conduit vessel stiffness, and subsequent cardiovascular events after myocardial infarction in patients with left ventricular dysfunction.