bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypercholesterolemia Attenuates Angiogenesis but Does Not Preclude Augmentation by Angiogenic Cytokines
Authors: Van Belle Eric , Rivard Alain , Chen Donghui , Silver Marcy , Bunting Stuart , Ferrara Napoleon , Symes James F. , Bauters Christophe , Isner Jeffrey M.
Published: June 2012

Background
The impact of hyperlipidemia on collateral vessel development in vivo remains enigmatic. We sought to determine the anatomic extent and functional capacity of the collateral bed that develops in response to limb ischemia in a well characterized animal model of spontaneous hypercholesterolemia, the Watanabe heritable hyperlipidemic (WHHL) rabbit. We further characterized the impact of exogenous angiogenic cytokine administration on collateral vessel development and function in the same animal model.

Methods and Results
Weight-matched 6-month-old male homozygous WHHL (n=9) and normal New Zealand White (NZW) (n=9) rabbits underwent surgical resection of one femoral artery. Ten days later, the ischemic hindlimb was evaluated for collateral vessel formation, blood flow, and tissue damage. Collateral vasculature was less extensive among WHHL than NZW, as indicated by a significant reduction in angiographic score (0.19±0.02 versus 0.35±0.03,
P
<.001) and capillary density (46.4±4.1 versus 78.9±4.6/mm
2
,
P
<.0002). This was associated with a reduction in calf blood pressure index (9.5±3.5% versus 32.8±2.8%,
P
<.0001), arterial blood flow (7.5±0.6 versus 13.6±0.7 mL/min,
P
<.0001), and muscle perfusion index (40.1±3.2% versus 65.9±2.0%,
P
<.0001) and an increase in muscle necrosis (48.16±5.41% versus 25.90±3.83% negative 2,3,5-triphenyltetrazolium chloride staining,
P
<.004). Treatment of WHHL rabbits (n=9) with recombinant human vascular endothelial growth factor produced a statistically significant improvement in all functional as well as anatomic indices of collateral development.

Conclusions
Collateral vessel development associated with hindlimb ischemia in vivo is severely attenuated in an animal model of spontaneous hypercholesterolemia but nevertheless may be augmented by administration of angiogenic cytokines.
The Role of Nitric Oxide in Coronary Vascular Effects of Estrogen in Postmenopausal Women
Authors: Guetta Victor , Quyyumi Arshed A. , Prasad Abhiram , Panza Julio A. , Waclawiw Myron , Cannon Richard O.
Published: June 2012

Background
At physiological concentrations, 17β-estradiol selectively enhances endothelium-dependent coronary vasodilation by an unknown mechanism in postmenopausal women.

Methods and Results
To assess the contribution of nitric oxide (NO) to the vascular effects of estradiol, we measured coronary epicardial and microvascular responses to intracoronary acetylcholine (range, 3 to 300 μg/min for 2 minutes) before and after intracoronary estradiol 75 ng/min for 15 minutes in 20 estrogen-deficient women, 16 of whom had angiographic evidence of atherosclerosis or risk factors for atherosclerosis. This testing was repeated after inhibition of NO synthesis with intracoronary
N
G
-monomethyl-
l
-arginine (L-NMMA) 64 μmol/min for 5 minutes. Estradiol increased acetylcholine-stimulated coronary flow from 54±48% (mean±SD) above baseline values before estradiol infusion to 100±63% above baseline values (
P
=.007) and decreased coronary resistance from 32±21% to 46±15% below baseline values (
P
=.007) at a coronary sinus estradiol concentration of 1725±705 pmol/L (470±192 pg/mL). Estradiol also tended to lessen the severity of acetylcholine-induced epicardial coronary artery vasoconstriction from 8±11% to 3±11% below baseline values (
P
=.123). However, during L-NMMA infusion, estradiol no longer potentiated the effects of acetylcholine on coronary flow dynamics; coronary flow increased 39±46% above baseline values and coronary resistance decreased 19±30% below baseline values (both
P
<.001 versus pre–L-NMMA responses). The epicardial diameter decreased 8±11% below baseline values (
P
=.06 versus pre–L-NMMA response).

Conclusions
The effects of estradiol at physiological concentrations on endothelium-dependent coronary vasodilator responsiveness in postmenopausal women are mediated by enhanced bioavailability of NO, which may be responsible in part for the cardioprotective effects of estrogen.
Dietary Supplementation With Marine Fish Oil Improves In Vitro Small Artery Endothelial Function in Hypercholesterolemic Patients
Authors: Goode Grahame K. , Garcia Susana , Heagerty Anthony M.
Published: June 2012

Background
Marine fish oils improve vascular function, but the mechanism of benefit is unclear. We conducted a study to examine the effects of fish oils given to hypercholesterolemic patients on small artery function in vitro.

Methods and Results
In a randomized, double-blind, placebo-controlled trial, subcutaneous gluteal fat biopsies were taken from 16 hypercholesterolemic patients (serum total cholesterol, 7.97±0.16 mmol/L [mean±SEM]) and 12 age- and sex-matched control subjects (mean cholesterol, 5.11±0.34 mmol/L). Small arteries were mounted on a wire myograph for isometric tension experiments. Patients and control subjects were randomized to receive fish oil (Maxepa 5 capsules BID) or placebo for 3 months. A second biopsy was taken and the studies were repeated. Relaxation to acetylcholine was significantly improved in the hypercholesterolemic group given Maxepa but not in the placebo group (mean maximum relaxation before and after, 48±6.2% and 68.83±2.19%,
P
=.0054). The dysfunction was not restored to control values (84.3±5.2%,
P
=.0002). There was also a smaller but significant impairment in endothelium-independent relaxation provoked by sodium nitroprusside (
P
<.01). A good correlation between the increase in eicosapentanoic acid (n=3) in red cell membrane and improvement in relaxation in the hypercholesterolemic group given fish oils was seen (
r
=.781,
P
<.02).

Conclusions
Marine fish oil significantly improved endothelial function in peripheral small arteries in hypercholesterolemia patients. This may provide a mechanism for the beneficial effects of these fatty acids in coronary heart disease.
Quantitative Overview of Randomized Trials of Amiodarone to Prevent Sudden Cardiac Death
Authors: Sim Ida , McDonald Kathryn M. , Lavori Philip W. , Norbutas Catherine M. , Hlatky Mark A.
Published: June 2012

Background
Some randomized clinical trials of amiodarone therapy to prevent sudden cardiac death have had positive results and others have had negative results, but all were relatively small. This meta-analysis aimed to pool all trials to assess the effect of amiodarone on mortality and the impact of differences in patient population and study design on trial outcomes.

Methods and Results
Fifteen randomized trials were identified, and outcome measures were combined by use of a random effects model. The effect of patient population and study design on total mortality was assessed by use of a hierarchical Bayes model. Amiodarone reduced total mortality by 19% (confidence limits, 6% to 31%;
P
<.01), with somewhat greater reductions in cardiac mortality (23%,
P
<.001) and sudden death (30%,
P
<.001). Mortality reductions were similar in trials enrolling patients after myocardial infarction (21%), with left ventricular dysfunction (22%), and after cardiac arrest (25%). There was a trend toward greater risk reduction in trials requiring evidence of ventricular ectopy (25%) than in the remaining trials (10%). The trials using placebo controls had considerably less risk reduction (10%) than trials with active controls (27%) or usual care controls (42%, posterior odds <0.02).

Conclusions
Amiodarone reduced total mortality by 10% to 19% in patients at risk of sudden cardiac death. Amiodarone reduced risk similarly in patients after myocardial infarction, with heart failure, or with clinically evident arrhythmia. The apparent inconsistencies among results of randomized trials appear to be due to small sample sizes and the type of control group used, not the type of patient enrolled.
An Airline Cardiac Arrest Program
Authors: O’Rourke Michael F. , Donaldson Eric , Geddes John S.
Published: June 2012

Background
As many as 1000 lives are lost annually from cardiac arrest in commercial aircraft. Ventricular fibrillation (VF), the most common mechanism, can be treated effectively only with prompt defibrillation, whereas the current policy of most airlines is to continue cardiopulmonary resuscitation pending aircraft diversion. The objective of this study was to assess the impact of making semiautomatic external defibrillators (AEDs) available for use on airline passengers with cardiac arrest.

Methods and Results
AEDs were installed on international Qantas aircraft and at major terminals, selected crew were trained in their use, and all crew members were trained in cardiopulmonary resuscitation. Supervision was provided by medical volunteers or (remotely) by airline physicians. During a 64-month period, AEDs were used on 109 occasions: 63 times for monitoring an acutely ill passenger and 46 times for cardiac arrest. Twenty-seven episodes of cardiac arrest occurred in aircraft, often (11 of 27 [41%]) unwitnessed, and they were usually (21 of 27 [78%]) associated with asystole or pulseless idioventricular rhythm. All 19 arrests in terminals were witnessed; VF was present in 17 (89%). Overall, defibrillation was initially successful in 21 of 23 cases (91%). Long-term survival from VF was achieved in 26% (2 of 6 in aircraft and 4 of 17 in terminals). The ability to monitor cardiac rhythm aided decisions on diversion, which was avoided in most passengers with asystole or idioventricular rhythm.

Conclusions
AEDs in aircraft and terminals, with appropriate crew training, are helpful in the management of cardiac emergencies. Survival from VF is practicable and is comparable with the most effective prehospital ambulance emergency services. Costly aircraft diversions can be avoided in clearly futile situations, enhancing the cost-effectiveness of the program.
Hibernating Myocardium
Authors: Elsässer Albrecht , Schlepper Martin , Klövekorn Wolf-Peter , Cai Wei-jun , Zimmermann René , Müller Klaus-Detlef , Strasser Rudolf , Kostin Sava , Gagel Christina , Münkel Brigitte , Schaper Wolfgang , Schaper Jutta
Published: June 2012

Background
We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply.

Methods and Results
In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, α-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3).

Conclusions
Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.
High Concentration of Thrombomodulin in Plasma Is Associated With Hemorrhage
Authors: Jansson Jan-Håkan , Boman Kurt , Brännström Mats , Nilsson Torbjörn K.
Published: June 2012

Background
The aim of this study was to prospectively test whether the risk of bleeding complications in 212 consecutive outpatients treated with oral anticoagulants could be predicted by levels of endothelium-derived hemostatic variables.

Methods and Results
All bleeding complications were recorded during 5 years of follow-up; serious bleeding was defined as intracranial bleeding or hemorrhage causing death or necessitating hospitalization. The relationships of bleeding complications and plasma concentrations of tissue plasminogen activator, von Willebrand factor, and thrombomodulin, plasminogen activator inhibitor activity, and other possible risk factors were studied.

Twenty-two patients suffered from bleeding complications during anticoagulant treatment; in 14 patients, these were serious. We found that the numbers both of serious hemorrhages and of total hemorrhages were significantly associated with increased levels of thrombomodulin. The number of bleeding episodes increased exponentially through quartiles one to four of the thrombomodulin distribution.

Conclusions
Thrombomodulin concentrations in plasma are related to the risk of hemorrhage in patients treated with oral anticoagulants.
Adrenergic Control of the Force-Frequency and Relaxation-Frequency Relations in Patients With Hypertrophic Cardiomyopathy
Authors: Izawa Hideo , Yokota Mitsuhiro , Takeichi Yasushi , Inagaki Masafumi , Nagata Kohzo , Iwase Mitsunori , Sobue Toshikazu
Published: June 2012

Background
Exercise-induced enhancement of the force-frequency and relaxation-frequency relations has been studied in conscious animals but not in intact diseased human hearts.

Methods and Results
We evaluated left ventricular (LV) isovolumic contraction (dP/dt
max
) and relaxation (τ) during atrial pacing and dynamic exercise in 13 patients with nonobstructive hypertrophic cardiomyopathy (HCM) and 7 control subjects to investigate the influence of exercise on the force-frequency and relaxation-frequency relations. Group A consisted of 6 patients in whom the heart rate (HR)–dP/dt
max
relation was markedly enhanced during exercise (88±30%) compared with during pacing (34±15%). Group B consisted of 7 patients in whom the HR-dP/dt
max
relation showed similar enhancement during exercise (28±7%) and atrial pacing (28±11%). There was no difference in the HR-τ (derivative method [TD] and pressure half-time method [T
1/2
]) relation between pacing and exercise in groups A and B. Both the mean maximal wall thickness and the hypertrophy score in group B were greater than in group A (27±5 versus 19±2 mm and 7±1 versus 5±1 points, respectively; both
P
<.01). There was no difference in the LV peak systolic pressure, end-diastolic pressure, or the plasma level of catecholamines at baseline, at 50 W of exercise, and at peak pacing between groups A and B. The HR-dP/dt
max
relation in the control group was markedly enhanced during exercise (80±27%) compared with during pacing (32±14%). The HR-τ relation in the control group was enhanced during exercise (TD, 35±9%; T
1/2
, 34±8%) compared with during pacing (TD, 12±7%; T
1/2
, 14±7%).

Conclusions
Exercise-induced enhancement of the relaxation-frequency relation was inhibited in all HCM patients, regardless of the degree of LV hypertrophy. The patients without exercise-induced enhancement of the force-frequency relation had more severe LV hypertrophy than the patients with the enhancement, indicating that the adrenergic control of the force-frequency relation may, at least in part, depend on the severity of LV hypertrophy or the stage of HCM.
Development of Decompensated Dilated Cardiomyopathy Is Associated With Decreased Gene Expression and Activity of the Milrinone-Sensitive cAMP Phosphodiesterase
PDE3A
Authors: Smith Carolyn J. , Huang Raymond , Sun Dong , Ricketts Sidonnie , Hoegler Carl , Ding Jia-Zhen , Moggio Richard A. , Hintze Thomas H.
Published: June 2012

Background
Phosphodiesterase III (PDE3) inhibitors are inotropic agents used to treat congestive heart failure (CHF) and are less effective in patients with severe CHF. Little is known about relative changes in PDE3 activity or gene expression during the evolution of cardiomyopathy.

Methods and Results
In the present study, we evaluated temporal changes in
PDE3A
gene expression before and after pacing-induced CHF in nine mongrel dogs. Three weeks of left ventricular (LV) pacing produced LV end-diastolic pressures of 15±1.7 mm Hg, whereas overt CHF at 4 to 5 weeks was associated with LV end-diastolic pressures of 24±1.7 mm Hg; prepacing values were 6.6±0.6 mm Hg. Total RNA isolated from LV tissues was analyzed on Northern blots; 10 unpaced normal hearts served as tissue controls. Signals for
PDE3A
mRNAs (7, 8, and 10 kb) or
PDE4D
(7.6 kb) were normalized against glyceraldehyde-3-phosphate dehydrogenase (
GAPDH
) or ribosomal 18S RNA. Before the onset of CHF,
PDE3A
/
GAPDH
ratios were not different between the control and 3-week paced groups. In contrast, all
PDE3A
/
GAPDH
ratios were selectively reduced by 52%, and
PDE3A
/18S was reduced by 70% (
P
<.05) in CHF;
PDE4D
/
GAPDH
(or 18S) was unchanged. LV tissues from four control and four CHF dogs were also processed to isolate cytosolic and microsomal membrane protein for cAMP PDE3 activity assays. CHF was associated with a significant 54% reduction (
P
<.05) in microsomal but not cytosolic PDE3 activity.

Conclusions
Selective downregulation of
PDE3A
may account in part for the ineffectiveness of milrinone in the treatment of severe CHF.
Comparison of Polarized and Depolarized Arrest in the Isolated Rat Heart for Long-term Preservation
Authors: Snabaitis A. K. , Shattock M. J. , Chambers D. J.
Published: June 2012

Background
Hypothermic hyperkalemic cardioplegic solutions are currently used for donor heart preservation. Hyperkalemia-induced depolarization of the resting membrane potential (E
m
) may predispose the heart to Na
+
and Ca
2+
loading via voltage-dependent “window currents,” thereby exacerbating injury and limiting the safe storage duration. Alternatively, maintaining the resting E
m
with a polarizing solution may reduce ionic movements and improve postischemic recovery; we investigated this concept with the reversible sodium channel blocker tetrodotoxin (TTX) to determine (1) whether polarized arrest was more efficacious than depolarized arrest during hypothermic long-term myocardial preservation and (2) whether TTX induces and maintains polarized arrest.

Methods and Results
The isolated crystalloid-perfused working rat heart preparation was used in this study. Preliminary studies determined an optimal TTX concentration of 22 μmol/L and an optimal storage temperature of 7.5°C. To compare depolarized and polarized arrest, hearts were arrested with either Krebs-Henseleit (KH) buffer (control), KH buffer containing 16 mmol/L K
+
, or KH buffer containing 22 μmol/L TTX and then stored at 7.5°C for 5 hours. Postischemic recovery of aortic flow was 13±4%, 38±2%, and 48±3%* (*
P
<.05 versus control and 16 mmol/L K
+
), respectively. When conventional 3 mol/L KCl-filled intracellular microelectrodes were used, E
m
gradually depolarized during control unprotected ischemia to ≈−55 mV before reperfusion, whereas arrest with 16 mmol/L K
+
caused rapid depolarization to ≈−50 mV, where it remained throughout the 5-hour storage period. In contrast, in 22 μmol/L TTX-arrested hearts, E
m
remained more polarized, at ≈−70 mV, for the entire ischemic period.

Conclusions
Blockade of cardiac sodium channels by TTX during ischemia maintained polarized arrest, which was more protective than depolarized arrest, possibly because of reduced ionic imbalance.
Coronary Angioscopic Findings in the Infarct-Related Vessel Within 1 Month of Acute Myocardial Infarction
Authors: Van Belle Eric , Lablanche Jean-Marc , Bauters Christophe , Renaud Nathalie , McFadden Eugène P. , Bertrand Michel E.
Published: June 2012

Background
—Limited angioscopic information is available on the natural history of infarct-related plaque after myocardial infarction (MI), in particular the effect of thrombolysis.

Methods and Results
—We studied with angioscopy the morphological characteristics of the infarct-related lesion in 56 patients between 24 hours and 4 weeks after MI. Forty of these patients were initially treated with a thrombolytic agent. Most lesions were complex (complex+ulcerated shape=54%). The predominant color of the plaque was yellow in 79% of cases; only 6% were uniformly white. Angioscopically visible thrombus was found in 77% of cases. Despite angioscopic evidence of instability, only 7% of the patients had post-MI angina. During the 1-month time window since the occurrence of MI, there was no significant difference in the angioscopic appearance of the plaque except for a slight increase in uniformly white plaques (
P
=.07). The use of a thrombolytic agent at the onset of MI was associated with a reduction in thrombus size and less protruding thrombi (
P
=.02) but not with a decreased frequency of plaque containing thrombi. Furthermore, a trend for more frequently ulcerated plaques (45% versus 16%,
P
=.06) was associated with the use of a thrombolytic agent.

Conclusions
—These results suggest that healing of the infarct-related lesion requires more than 1 month and that an “unstable” yellow plaque with adherent thrombus is common during that period. This finding may partly explain the unique behavior of recent infarct-related lesions, which are more prone to occlude than other lesions.
Functional Changes in Aging Polymorphonuclear Leukocytes
Authors: Tanji-Matsuba Kayoko , van Eeden Stephan F. , Saito Yuji , Okazawa Mitsushi , Klut Maria E. , Hayashi Shizu , Hogg James C.
Published: June 2012

Background
—Previous studies from our laboratory have shown that the expression of L-selectin on polymorphonuclear neutrophils (PMN) decreases as the cell ages in the circulation and that these older PMN have more fragmented DNA and show morphological features of apoptosis.

Methods and Results
—The present study was designed to compare the functional capabilities of PMN expressing low levels of L-selectin (L-selectin
low
) and the total population of PMN they were isolated from (L-selectin
mixed
). The results show no difference of the baseline filamentous actin (F-actin) content between PMN expressing low and high levels of L-selectin. However, the ability of L-selectin
low
PMN to assemble F-actin was impaired after stimulation by
n
-formyl-
l
-methionyl-
l
-leucyl-
l
-phenylalanine (fMLP) (1 nmol/L fMLP:
P
<.02, 10 nmol/L fMLP:
P
<.01). The ability of L-selectin
low
PMN to change shape when stimulated (10 nmol/L fMLP) was also decreased (
P
<.05). Filtration studies showed no difference in baseline deformability between L-selectin
low
and L-selectin
mixed
leukocytes, but the L-selectin
low
cells showed a decreased ability to stiffen after fMLP stimulation (
P
<.05). L-selectin
low
cells demonstrated a decreased ability to migrate toward a chemoattractant (1, 3, and 10 nmol/L fMLP) (
P
<.004) but have an enhanced ability to upregulate CD18 (
P
<.00002) and produce hydrogen peroxide (
P
<.00004).

Conclusions
—We conclude that PMN undergo substantial functional changes as they age in the circulation.
Cholesterol Reduction Yields Clinical Benefit
Authors: Gould A. Lawrence , Rossouw Jacques E. , Santanello Nancy C. , Heyse Joseph F. , Furberg Curt D.
Published: June 2012

Background
—We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors (“statins”) on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering.

Methods and Results
—We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (
P
<.001), and total mortality risk would be reduced by 11% (
P
<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk.

Conclusions
—Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.
Increased Levels of Soluble P-Selectin in Hypercholesterolemic Patients
Authors: Davı̀ Giovanni , Romano Mario , Mezzetti Andrea , Procopio Antonio , Iacobelli Stefano , Antidormi Teresa , Bucciarelli Tonino , Alessandrini Paola , Cuccurullo Franco , Bon Gabriele Bittolo
Published: June 2012

Background
—Hypercholesterolemia is considered a major risk factor for the development of atherosclerosis. Enhanced lipid peroxidation and persistent platelet activation can be observed in vivo in hypercholesterolemic patients and may have pathophysiological implications in the occurrence of cardiovascular events. P-selectin may play an important role in the pathogenesis of multicellular events, including atherosclerosis. We studied the impact of hypercholesterolemia and oxidative stress on plasma levels of P-selectin.

Methods and Results
—Plasma levels of P-selectin were measured by means of an enzyme immunoassay in 20 hypercholesterolemic patients with no clinical evidence of cardiovascular disease and in 20 sex- and age-matched normocholesterolemic subjects. Hypercholesterolemic patients had higher levels of P-selectin compared with that of control subjects (98±61 versus 56±14 ng/mL;
P
=.001). They also displayed increased von Willebrand Factor (vWF) levels (176±22 versus 119±12%;
P
=.0001). A direct correlation was observed between P-selectin and LDL cholesterol levels (ρ=.453). Administration of vitamin E (600 mg/d for 2 weeks) to hypercholesterolemic patients significantly reduced plasma P-selectin (40%), and an inverse correlation was observed between vitamin E and P-selectin plasma levels (ρ=−.446).

Conclusions
—Hypercholesterolemia is associated with elevated plasmatic P-selectin. Altered oxidative processes leading to endothelial dysfunction and persistent platelet activation may contribute to increased soluble P-selectin levels. P-selectin may be proposed as a marker of endothelial dysfunction in hypercholesterolemic patients.
Prognostic Importance of Emotional Support for Elderly Patients Hospitalized With Heart Failure
Authors: Krumholz Harlan M. , Butler Javed , Miller Jeremy , Vaccarino Viola , Williams Christianna S. , Mendes de Leon Carlos F. , Seeman Teresa E. , Kasl Stanislav V. , Berkman Lisa F.
Published: June 2012

Background
—Several studies have indicated that a variety of social relationships are important predictors of morbidity and mortality in patients with coronary artery disease, but little attention has been focused on the prognostic importance of these factors in the growing population of elderly patients with heart failure. To address this issue, we sought to determine whether emotional support is associated with fatal and nonfatal cardiovascular events in elderly patients hospitalized with heart failure.

Methods and Results
—We reviewed the medical records of 292 subjects aged ≥65 years who were hospitalized with clinical heart failure and were part of the New Haven, Conn, cohort of the Established Population for the Epidemiologic Study of the Elderly, a longitudinal, community-based study of aging that included a comprehensive assessment of psychosocial support. In the unadjusted analysis, lack of emotional support was significantly associated with the 1-year risk of fatal and nonfatal cardiovascular outcomes [odds ratio, 2.4; 95% confidence interval, 1.1 to 4.9]. After adjustment for demographic factors, clinical severity, comorbidity and functional status, social ties, and instrumental support, the absence of emotional support remained associated with a significantly higher risk (odds ratio, 3.2; 95% confidence interval, 1.4 to 7.8). The test for interaction between emotional support and sex was significant (
P
=.01). In the fully adjusted model, the odds ratio for women was 8.2 (95% confidence interval, 2.5 to 27.2) compared with 1.0 (95% confidence interval, 0.3 to 3.3) for men.

Conclusions
—Among elderly patients hospitalized with clinical heart failure, the absence of emotional support, measured before admission, is a strong, independent predictor of the occurrence of fatal and nonfatal cardiovascular events in the year after admission. In this cohort, the association is restricted to women.
Significance of Paroxysmal Atrial Fibrillation Complicating Acute Myocardial Infarction in the Thrombolytic Era
Authors: Eldar Michael , Canetti Menachem , Rotstein Zeev , Boyko Valentina , Gottlieb Shmuel , Kaplinsky Elieser , Behar Solomon
Published: June 2012

Background
—Paroxysmal atrial fibrillation (PAF) is considered a frequent complication of acute myocardial infarction (AMI), associated with increased in-hospital and long-term mortality rates. This notion is based on data collected before thrombolysis and additional modern methods of treatment became widely available, and no information is available on the significance of PAF in the general population with AMI in the thrombolytic era. The aim of the present study was to define the incidence, associated clinical parameters, and short- and long-term prognostic significance of PAF in patients with AMI in the thrombolytic era.

Methods and Results
—A prospective, nationwide survey was conducted of 2866 consecutive patients admitted with AMI in all 25 coronary care units in Israel during January/February 1992, 1994, and 1996 (thrombolytic era [TE]). The data were compared with a previous Israeli study of 5803 patients with AMI hospitalized in 1981 through 1983 (prethrombolytic era [PTE]). Patients in the TE with PAF were older and had a worse risk profile than those without PAF. PAF in the TE was independently associated with increased 30-day (odds ratio, 1.32; 95% confidence interval, 0.92 to 1.87) and 1-year (relative risk, 1.33; 95% confidence interval, 1.05 to 1.68) mortality rates. The incidence of PAF (8.9% and 9.9%) and the 30-day (25.1% and 27.6%) and 1-year (38.4% and 42.5%) mortality rates of patients with PAF were similar in the TE and PTE, although PAF in the TE occurred in older and sicker patients than those in the PTE. After adjustment for conventional risk factors, PAF was associated with significantly lower 30-day (odds ratio, 0.64; 95% confidence interval, 0.44 to 0.94) and 1-year (relative risk, 0.69; 95% confidence interval, 0.54 to 0.88) mortality rates compared with the PTE.

Conclusions
—Patients with AMI who develop PAF in the TE have significantly worse short- and long-term prognoses than patients without PAF, mostly due to their worse risk profile. After adjustment for confounding factors, patients with PAF in the TE have a better overall outcome than counterparts in the PTE, probably reflecting the better management of patients with AMI in the TE.
Quantitative Evaluation of Global and Regional Left Ventricular Diastolic Function With Color Kinesis
Authors: Vignon Philippe , Mor-Avi Victor , Weinert Lynn , Koch Rick , Spencer Kirk T. , Lang Roberto M.
Published: June 2012

Background
—Diastolic wall motion asynchrony is a major determinant of impaired left ventricular (LV) filling in patients with concentric hypertrophy and coronary artery disease. We evaluated the ability of Color Kinesis, a new echocardiographic technique that color-encodes endocardial motion, to quantitatively assess global and regional LV filling properties.

Methods and Results
—Color Kinesis images and mitral and pulmonary vein flow Doppler data were acquired in 29 patients with LV hypertrophy and 29 age-matched control subjects. In addition, Color Kinesis data were correlated to coronary angiographic findings in 15 patients with suspected coronary artery disease. Segmental analysis of Color Kinesis images was used to obtain time histograms of regional diastolic fractional area change, wherein early and late peaks (peaks 1 and 2) reflected rapid LV filling and atrial contraction, respectively. Regional mean LV filling time and filling curves were used to objectively identify diastolic endocardial motion asynchrony in patients with LV hypertrophy and coronary artery disease. None of the mitral and pulmonary vein Doppler indices differentiated patients with normalized mitral Doppler profile (n=13) from control subjects, whereas reduced peak1/peak2 ratio and prolonged mean filling time indicated augmented contribution of atrial contraction toward LV filling (
P
<.05). In 22 of 25 patients with LV hypertrophy and preserved systolic function and in all patients with coronary artery disease, delayed diastolic endocardial motion was observed in at least one segment.

Conclusions
—Analysis of Color Kinesis images provides objective assessment of global and regional LV filling properties and allows identification of both diastolic dysfunction in patients with normalized Doppler indices and wall motion asynchrony.
Serum Cholesterol Distribution and Coronary Heart Disease Risk
Authors: Jousilahti Pekka , Vartiainen Erkki , Pekkanen Juha , Tuomilehto Jaakko , Sundvall Jouko , Puska Pekka
Published: June 2012

Background
—The purpose of the present study was to assess the implications of cholesterol distribution and its change on coronary heart disease (CHD) mortality and disease prevention at a population level.

Methods and Results
—In five independent risk factor surveys (1972, 1977, 1982, 1987, and 1992) in eastern Finland, serum cholesterol was measured in 27 721 randomly selected men and women aged 30 to 59 years. The association between cholesterol level and CHD risk and the prediction of the effect of different prevention strategies was estimated by use of logistic regression models. The entire cholesterol distribution of the population shifted markedly toward lower levels between 1972 and 1992. The proportion of subjects with a very high cholesterol level (≥8.0 mmol/L), also decreased markedly, from 16% to 3%. The risk of CHD death among subjects with cholesterol ≥8.0 mmol/L was ≈5-fold that of those individuals having cholesterol <5.0 mmol/L. Nevertheless, because CHD risk increases continuously as serum cholesterol increases, and because the number of people having only slightly or moderately increased serum cholesterol was large, most CHD deaths occurred among them. A 10% reduction in cholesterol levels in the entire population would subsequently reduce CHD mortality by 20%, as much as an effective treatment as a 25% decrease in serum cholesterol among all subjects with cholesterol >6.5 mmol/L and four times more than similar treatment of all subjects with cholesterol ≥8.0 mmol/L.

Conclusions
—The community-based population strategy in cardiovascular disease prevention was effective in decreasing cholesterol levels among the entire population, including the subjects with the highest cholesterol values. The balanced application of both high-risk and population strategies is needed for the effective prevention of CHD.
Use of Reperfusion Therapy for Acute Myocardial Infarction in the United States
Authors: Barron Hal V. , Bowlby Laura J. , Breen Tim , Rogers William J. , Canto John G. , Zhang Yuan , Tiefenbrunn Alan J. , Weaver W. Douglas
Published: June 2012

Background
—There is clear evidence that reperfusion therapy improves survival in selected patients with an acute myocardial infarction. However, several studies have suggested that many patients with an acute myocardial infarction do not receive this therapy. Whether this underutilization occurs in patients appropriate for such therapy remains unclear.

Methods and Results
—We examined the use of reperfusion therapy in patients with an acute myocardial infarction hospitalized at 1470 hospitals participating in the National Registry of Myocardial Infarction 2. We identified 84 663 patients who were eligible for reperfusion therapy as defined by diagnostic changes on the initial 12-lead ECG, presentation to the hospital within 6 hours from symptom onset, and no contraindications to thrombolytic therapy. Twenty-four percent of these eligible patients did not receive any form of reperfusion therapy (7.5% of all patients). When multivariate analyses were used, left bundle-branch block (odds ratio [OR]=0.22; 95% CI=0.20 to 0.24), lack of chest pain at presentation (OR=0.22; 95% CI=0.21 to 0.24), age >75 years (OR=0.40, 95% CI=0.36 to 0.43), female sex (OR=0.88, 95% CI=0.83 to 0.92), and various preexisting cardiovascular conditions were independent predictors that the patient would not receive reperfusion therapy.

Conclusions
—Reperfusion therapy may be underutilized in the United States. Increased use of reperfusion therapy could potentially reduce the unnecessarily high mortality rates observed in women, the elderly, and other patient groups with the highest risk of death from an acute myocardial infarction.
Effects of Quinidine and Verapamil on Human Cardiovascular α
1
-Adrenoceptors
Authors: Shibata Katsushi , Hirasawa Akira , Foglar Rudolf , Ogawa Satoshi , Tsujimoto Gozoh
Published: June 2012

Background
—The antiarrhythmic drugs quinidine and verapamil are known to block α
1
-adrenoceptors (α
1
ARs). α
1
ARs are a heterogeneous family of three subtypes (α
1A
, α
1B
, and α
1D
), and little is known about the effects of quinidine and verapamil on the different human α
1
AR subtypes.

Methods and Results
—Reverse transcriptase–polymerase chain reaction showed that all α
1
AR subtypes are expressed in both human heart (atrium and ventricle) and the mesenteric artery. Pharmacological profiles of quinidine and verapamil actions on the α
1
AR subtypes were characterized with Chinese hamster ovary cells stably expressing cloned human α
1
AR subtypes. Radioligand binding studies showed that quinidine and verapamil had high affinities for all α
1
AR subtypes. Also, both drugs synergistically inhibited α
1
AR-mediated inositol 1,4,5-triphosphate production at the clinical effective concentration range (1 μmol/L quinidine and 0.1 μmol/L verapamil).

Conclusions
—The results show that all α
1
AR subtypes are expressed in the human cardiovascular system and that quinidine and verapamil may have a potent, synergistic inhibitory effect on the α
1
ARs. Clinically observed hypotension after quinidine plus verapamil can be explained by their synergistic inhibitory effects on human α
1
ARs.
Blood Viscosity and Elevated Carotid Intima-Media Thickness in Men and Women
Authors: Lee Amanda J. , Mowbray Philip I. , Lowe Gordon D.O. , Rumley Ann , Fowkes F. Gerald R. , Allan Paul L.
Published: June 2012

Background
—Several hemostatic and rheological factors have been associated with incident cardiovascular events. However, there have been no reports on the relationship of rheological factors with early atherosclerosis and very few on hemostatic factors. We therefore studied the relationship between these factors and carotid intima-media thickness (IMT).

Methods and Results
—The Edinburgh Artery Study measured fibrinogen, tissue plasminogen activator (tPA), fibrin
d
-dimer, von Willebrand factor (vWF), blood and plasma viscosities, and hematocrit as part of its baseline examination during 1988–1989. At the 5-year follow-up, valid measurements of IMT had been recorded in 1106 men and women 60 to 80 years old. In men, blood viscosity (
P
≤.001) and its major determinants, plasma viscosity, fibrinogen (both
P
≤.01), and hematocrit (
P
≤.05), were all linearly related to IMT. Furthermore, blood viscosity, fibrinogen (both
P
≤.01), and plasma viscosity (
P
≤.05) remained significantly associated on multivariate analysis. Correcting blood viscosity to a standard hematocrit of 45% had little effect on its association. In men, there was a significantly increased risk of having an IMT above versus below the upper quartile of its distribution (1.05 mm) for SD increases in blood viscosity (
P
≤.01), fibrinogen, corrected blood viscosity, and plasma viscosity (all
P
≤.05). With the exception of plasma viscosity, these risks were unaffected by adjustment for other common cardiovascular risk factors. No significant associations were found between any of the hemorheological factors and IMT in women or for tPA, fibrin
d
-dimer, or vWF in either sex.

Conclusions
—These findings suggest that in men, blood viscosity and its major determinants are associated not only with incident cardiovascular events but also with the early stages of atherosclerosis. This may be one explanation for the link between rheological factors and events.
Association of Virulent
Helicobacter pylori
Strains With Ischemic Heart Disease
Authors: Pasceri Vincenzo , Cammarota Giovanni , Patti Giuseppe , Cuoco Lucio , Gasbarrini Antonio , Grillo Rita L. , Fedeli Giuseppe , Gasbarrini Giovanni , Maseri Attilio
Published: June 2012

Background
—Previous studies have reported an association between chronic
Helicobacter pylori
infection and ischemic heart disease. However, it is not clear whether this association is really due to the virulence of the bacterium or is merely the result of confounding factors (in particular, age and social class).

Methods and Results
—We assessed the prevalence of infection by
Helicobacter pylori
and by strains bearing the cytotoxin-associated gene-A (CagA), a strong virulence factor, in 88 patients with ischemic heart disease (age, 57±8 years; 74 men) and in 88 age- and sex-matched controls (age, 57±8 years; 74 men) with similar social background. Prevalence of
Helicobacter
infection was significantly higher in patients than in controls (62% versus 40%;
P
=.004), with an odds ratio of 2.8 (95% CI, 1.3 to 7.4;
P
<.001) adjusted for age, sex, main cardiovascular risk factors, and social class. Patients with ischemic heart disease also had a higher prevalence of CagA-positive strains (43% versus 17%;
P
=.0002), with an adjusted odds ratio of 3.8 (95% CI, 1.6 to 9.1;
P
<.001). Conversely, prevalence of CagA-negative strains was similar in patients and controls (19% versus 23%), with an adjusted odds ratio of 0.8 (95% CI, 0.4 to 1.4).

Conclusions
—The association between
Helicobacter pylori
and ischemic heart disease seems to be due to a higher prevalence of more virulent
Helicobacter
strains in patients. These results support the hypothesis that
Helicobacter pylori
may influence atherogenesis through low-grade, persistent inflammatory stimulation.
Obesity and Risk of Adverse Outcomes Associated With Coronary Artery Bypass Surgery
Authors: Birkmeyer Nancy J. O. , Charlesworth David C. , Hernandez Felix , Leavitt Bruce J. , Marrin Charles A. S. , Morton Jeremy R. , Olmstead Elaine M. , O’Connor Gerald T.
Published: June 2012

Background
—Obesity is frequently cited as a risk factor for adverse outcomes of major surgery. The results of prior studies of the relationship between obesity and risk of adverse outcomes of coronary artery bypass grafting (CABG) have been contradictory because of insufficient power to assess relatively infrequent outcomes or data to adjust for confounding factors.

Methods and Results
—Data on patient age, sex, height, weight, medical history, current clinical status, and treatment factors were assessed prospectively among 11 101 consecutive patients undergoing CABG. Body mass index (BMI) was used as the measure of obesity and was categorized as nonobese (1st to 74th percentiles), obese (75th to 94th percentiles), or severely obese (95th to 100th percentiles). Adverse outcomes occurring in-hospital, including mortality, intraoperative/postoperative cerebrovascular accident (CVA), postoperative bleeding, and sternal wound infection, were defined prospectively. Associations between obesity and postoperative outcomes were assessed by use of logistic regression to adjust for potentially confounding variables. Although obesity was not associated with increased mortality (adjusted odds ratio [OR], 1.16;
P
=.261) or postoperative CVA (adjusted OR, 1.06;
P
=.765), risks of sternal wound infection were substantially increased in the obese (adjusted OR, 2.10; confidence interval [CI], 1.45 to 3.06;
P
<.001) and severely obese (adjusted OR, 2.74; CI, 1.49 to 5.02;
P
=.001). On the other hand, rates of postoperative bleeding were significantly lower in the obese (adjusted OR, 0.66; CI, 0.49 to 0.90;
P
=.009) and severely obese (adjusted OR, 0.40; CI, 0.20 to 0.81;
P
=.011).

Conclusions
—With the exception of sternal wound infection, the perception among clinicians that obesity predisposes to various postoperative complications with CABG is not supported by these data. Further work is needed to understand the apparent protective effect of obesity on risks of postoperative bleeding.
Acute Hyperglycemia Attenuates Endothelium-Dependent Vasodilation in Humans In Vivo
Authors: Williams Stephen B. , Goldfine Allison B. , Timimi Farris K. , Ting Henry H. , Roddy Mary-Anne , Simonson Donald C. , Creager Mark A.
Published: June 2012

Background
—Endothelial function is impaired in patients with diabetes mellitus. However, the factors contributing to this defect are currently unknown. Hyperglycemia attenuates endothelium-dependent relaxation in normal rabbit arteries in vitro and rat arterioles in vivo. Accordingly, this study examined the effect of acute hyperglycemia on endothelium-dependent vasodilation in nondiabetic humans in vivo.

Methods and Results
—Endothelium-dependent vasodilation was assessed through brachial artery infusion of methacholine chloride both before and during 6 hours of local hyperglycemia (300 mg/dL) achieved by intra-arterial infusion of 50% dextrose. Forearm blood flow was determined by plethysmography. In a group of 10 subjects, there was a trend toward attenuated methacholine-mediated vasodilation during hyperglycemia compared with euglycemia (
P
=.07 by ANOVA; maximal response, 13.3±2.8 versus 14.7±1.5 mL · min
−1
· 100 mL
−1
, respectively). In these subjects, the systemic serum insulin levels increased significantly during the dextrose infusion (
P
<.001). To eliminate the confounding vasoactive effects of insulin, the protocol was repeated during systemic infusion of octreotide (30 ng · kg
−1
· min
−1
) to inhibit pancreatic secretion of insulin. In these subjects (n=10), hyperglycemia significantly attenuated the forearm blood flow response to methacholine (
P
<.01 by ANOVA; maximal response, 16.9±2.5 before versus 12.7±1.8 mL · min
−1
· 100 mL
−1
during hyperglycemia). Methacholine-mediated vasodilation was not attenuated by an equimolar infusion of mannitol (
P
>.40), nor did hyperglycemia reduce endothelium-independent vasodilation to verapamil (
P
>.50).

Conclusions
—Acute hyperglycemia impairs endothelium-dependent vasodilation in healthy humans in vivo. This finding suggests that elevated glucose may contribute to the endothelial dysfunction observed in patients with diabetes mellitus.