bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Endothelin A Receptor Blockade Causes Selective Pulmonary Vasodilation in Patients With Chronic Heart Failure
Authors: Givertz Michael M. , Colucci Wilson S. , LeJemtel Thierry H. , Gottlieb Stephen S. , Hare Joshua M. , Slawsky Mara T. , Leier Carl V. , Loh Evan , Nicklas John M. , Lewis Bruce E.
Published: June 2012

Background
—Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET
A
receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET
A
receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy.

Methods and Results
—This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21±1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure ≥15 mm Hg and a cardiac index ≤2.5 L · min
−1
· m
−2
were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure (
P
≤0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan.

Conclusions
—In patients with moderate to severe heart failure receiving conventional therapy, acute ET
A
receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure.
Active Remodeling of the Coronary Arterial Lesions in the Late Phase of Kawasaki Disease
Authors: Suzuki Atsuko , Miyagawa-Tomita Sachiko , Komatsu Keiko , Nishikawa Toshio , Sakomura Yasunari , Horie Toshinobu , Nakazawa Makoto
Published: June 2012

Background
—Remodeling of the coronary artery lesions in Kawasaki disease has been observed in longitudinal angiographic studies. However, mechanisms of such remodeling have not yet been elucidated.

Methods and Results
—We examined formalin-fixed specimens of the coronary arteries immunohistochemically by using antibodies against vascular growth factors (GFs) and their receptors in 7 children with Kawasaki disease, 9 children with no coronary disease, and 3 adults with atherosclerosis. In the thickened intima at stenotic sites and at recanalized vessels with Kawasaki disease, extensive expression of vascular GFs, such as transforming GF-β
1
, platelet-derived GF-A, and basic fibroblast GF, was observed both within and surrounding smooth muscle cells. Vascular endothelial GF was observed within smooth muscle cells. Furthermore, all of these GFs were strongly expressed in the newly formed microvessels within the intima. In the thinned media, these GFs were focally and weakly expressed. In contrast, these GFs were expressed only in the media in the control children. In cases of adult atherosclerosis, GFs were expressed diffusely in the media but focally and weakly if at all in the intima.

Conclusions
—Active remodeling of the coronary artery lesions in Kawasaki disease continues in the form of luxuriant intimal proliferation and neoangiogenesis for several years after the onset of the disease. This process is distinct from adult-onset atherosclerosis.
Estrogen Attenuates Integrin-β
3
–Dependent Adventitial Fibroblast Migration After Inhibition of Osteopontin Production in Vascular Smooth Muscle Cells
Authors: Li Guohong , Chen Yiu-Fai , Kelpke Stacey S. , Oparil Suzanne , Thompson John A.
Published: June 2012

Background
—Previous in vitro studies have suggested that estrogen attenuates the vascular injury response by modulating vascular smooth muscle cell (VSMC) expression of soluble factor(s) directing migration of adventitial fibroblasts. Previous in vivo studies have established a role for osteopontin (OPN) and its integrin receptors after vascular injury. In this study, we examined OPN expression in activated VSMCs, its modulation by estrogen, and its effects on adventitial fibroblast migration. In addition, the relative functional roles of β
1
- and β
3
-integrin–matrix interactions were examined.

Methods and Results
—Primary cultures of VSMCs and adventitial fibroblasts were derived from female Sprague-Dawley rats. Serum-activated VSMCs expressed high levels of OPN mRNA and secreted protein that was effectively inhibited by estrogen treatment (10
−7
mol/L). Compared with VSMCs, fibroblasts expressed similar levels of integrins αν and β
1
and higher levels of integrin-β
3
. Exogenous OPN (5.0 to 40 μg/mL) directed fibroblast migration in a dose-dependent fashion. Anti–β
3
-integrin antibody (F11) pretreatment markedly inhibited adventitial fibroblast migration directed by exogenous OPN or VSMC-conditioned medium in a dose-dependent manner. In contrast, anti–β
1
-integrin antibody (Ha2/5) did not affect fibroblast migration. Similarly, pretreatment with either linear or cyclic RGD peptides (10 to 1000 μmol/L) inhibited fibroblast migration directed by OPN or VSMC-conditioned medium in a dose-dependent manner.

Conclusions
—These observations suggest that estrogen indirectly attenuates integrin-β
3
–dependent adventitial fibroblast migration after inhibition of OPN expression in VSMCs.
Noninvasive In Vivo Magnetic Resonance Imaging of Experimental Coronary Artery Lesions in a Porcine Model
Authors: Worthley Stephen G. , Helft Gérard , Fuster Valentin , Fayad Zahi A. , Rodriguez Oswaldo J. , Zaman Azfar G. , Fallon John T. , Badimon Juan J.
Published: June 2012

Background
—The ability to characterize and quantify coronary artery atherosclerotic lesions accurately, reproducibly, and noninvasively may allow the stratification of risk for future acute coronary syndromes and help direct therapeutic management. MRI has been shown to accurately characterize and quantify atherosclerosis; however, because of the combination of cardiac and respiratory motion artifacts, nonlinear course, and relatively small size of the coronary arteries, these techniques have not been able to be translated to the coronary system in vivo.

Methods and Results
—Coronary lesions were induced in Yorkshire albino swine (n=6) with balloon angioplasty, and 4 weeks later MRI of the coronary artery lesions was performed. High-resolution in vivo images of the coronary artery wall and lesions were obtained with a double-inversion-recovery fast-spin-echo sequence in a 1.5-T MR system. There was good agreement between measurements of vessel wall thickness and area from MR images of the coronary arteries and the matched histopathology sections (n=43). The mean difference (MRI minus histopathology ± SD) for mean wall thickness was 0.26±0.18 mm, and for vessel wall area, 5.65±3.51 mm
2
. MRI was also able to visualize intralesion hematoma (sensitivity 82%, specificity 84%).

Conclusions
—Using a clinical MR system, we were able to image coronary artery lesions in vivo in an experimental porcine model. Further studies are needed to assess the ability of MRI to characterize coronary atherosclerotic lesions in vivo.
Changes in Sinus Node Function in a Rabbit Model of Heart Failure With Ventricular Arrhythmias and Sudden Death
Authors: Opthof Tobias , Coronel Ruben , Rademaker Han M. E. , Vermeulen Jessica T. , Wilms-Schopman Francien J. G. , Janse Michiel J.
Published: June 2012

Background
—Heart failure is associated with profound changes in the balance of the autonomic nervous system, such as vagal withdrawal and increased catecholamine levels. It is not known whether the intrinsic sinus node function changes during the progression of heart failure.

Methods and Results
—We implanted transmitters for Holter recording in an established rabbit model of heart failure (n=9) and observed changes in sinus cycle length and the occurrence of arrhythmias during the progression of heart failure. The in vitro sinus cycle length and the responses to acetylcholine and norepinephrine in the isolated right atria were analyzed in 12 rabbits with heart failure and in 6 control rabbits. In vivo cycle length increased in some animals and decreased in others. Sudden death occurred in 3 of 9 rabbits. These rabbits had developed a shorter cycle length than the surviving rabbits. Ventricular tachycardias developed in all but 1 rabbit. The in vitro sinus cycle length increased in heart failure. The response to acetylcholine also increased in heart failure, whereas the response to norepinephrine was unchanged.

Conclusions
—Changes in intrinsic sinus node function during the progression of heart failure cannot explain the observed decreases in heart rate variability and/or baroreflex sensitivity in this disease, because increased responsiveness to acetylcholine would be expected to cause the opposite.
Androgen Receptor Expression Is Greater in Macrophages From Male Than From Female Donors
Authors: McCrohon Jane A. , Death Alison K. , Nakhla Shirley , Jessup Wendy , Handelsman David J. , Stanley Keith K. , Celermajer David S.
Published: June 2012

Background
—Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated.

Methods and Results
—Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64±0.06 versus 0.15±0.02 amol/μg total RNA;
P
<0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (
P
=0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (n=9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109±10%, 117±3%, and 120±4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control,
P
=0.002; 95±8% for DHT with hydroxyflutamide,
P
=0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages (
P
>0.2 versus controls).

Conclusions
—Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men.
Effects of Intravenous and Intracoronary Adenosine 5′-Triphosphate as Compared With Adenosine on Coronary Flow and Pressure Dynamics
Authors: Jeremias Allen , Filardo Steven D. , Whitbourn Robert J. , Kernoff Robert S. , Yeung Alan C. , Fitzgerald Peter J. , Yock Paul G.
Published: June 2012

Background
—Measurements of Doppler derived coronary flow reserve (CFR) and pressure derived fractional flow reserve (FFR) for coronary stenosis assessment depend on the induction of maximal hyperemia. Adenosine is the most widely used pharmacological agent but is expensive and poorly tolerated by some patients.

Methods and Results
—The objective of this study was to test the equivalency of adenosine 5′-triphosphate (ATP) to adenosine in their ability to cause maximal hyperemia as compared with the hyperemic response of complete coronary occlusion in 6 canines. Intracoronary administration of either ATP or adenosine resulted in a significant increase in CFR (2.79±0.64 and 2.22±0.7 for 10 μg versus 4.65±1.22 and 4.25±0.78 for 100 μg for ATP and adenosine, respectively,
P
for trend <0.001) but not reaching the level of coronary occlusion (6.35±2.26). Additionally, FFR and CFR were measured in 35 different stenoses using ATP, adenosine, and coronary occlusion. There was an excellent linear correlation between ATP and adenosine for both CFR (
R
=0.934,
P
<0.001) and FFR (
R
=0.985,
P
<0.001). However, hyperemia with either ATP or adenosine was less than postocclusion hyperemia, resulting in significantly different reserve measurements (CFR: 1.93±0.66 and 2.08±0.81 versus 2.35±0.97,
P
<0.001; FFR: 0.62±0.24 and 0.63±0.23 versus 0.58±0.2,
P
<0.001).

Conclusions
—1) Step up in dosage of ATP and adenosine beyond currently recommended clinical doses resulted in a significant increase in coronary hyperemia; 2) ATP was equivalent to adenosine for both CFR and FFR; and 3) complete coronary occlusion yielded a better hyperemic response than either drug, indicating that maximal hyperemia was not achieved by either pharmacological stimulus.
Alcohol Potentiates Orthostatic Hypotension
Authors: Narkiewicz Krzysztof , Cooley Ryan L. , Somers Virend K.
Published: June 2012

Background
—Alcohol consumption may be linked to syncopal events. The mechanisms by which alcohol may induce syncope are unknown. Impairment of the response to orthostatic stress may be involved. Using a double-blind, randomized, placebo-controlled study, we tested the hypothesis that short-term alcohol intake causes orthostatic hypotension because of an impairment in the vasoconstrictor response to orthostatic stress.

Methods and Results
—We examined the effects of alcohol on blood pressure, heart rate, and forearm vascular resistance (FVR) during orthostatic stress achieved by stepwise increases in lower-body negative pressure (LBNP) in 14 healthy young volunteers. During the placebo session, blood pressure did not change significantly during LBNP at −5, −10, and −20 mm Hg. A significant decrease in blood pressure was evident only at −40 mm Hg. In contrast, blood pressure fell significantly at all levels of LBNP during the alcohol session. Compared with placebo, alcohol potentiated the hypotensive responses to LBNP, particularly at −40 mm Hg, when the decrease in systolic blood pressure after alcohol intake (−14 mm Hg) was double that after placebo intake (−7 mm Hg). FVR increased with LBNP after placebo. However, after alcohol intake, FVR did not increase during LBNP despite the potentiated decrease in blood pressure. FVR responses during LBNP were reduced during alcohol compared with placebo consumption (
P
=0.04).

Conclusions
—Short-term alcohol consumption elicits hypotension during orthostatic stress because of impairment of vasoconstriction. These findings have implications for the understanding of the hemodynamic effects of alcohol and, in particular, for understanding syncopal events that occur in association with alcohol intake.
Activation of Mitochondrial ATP-Dependent Potassium Channels by Nitric Oxide
Authors: Sasaki Norihito , Sato Toshiaki , Ohler Andreas , O’Rourke Brian , Marbán Eduardo
Published: June 2012

Background
—Nitric oxide (NO) has been implicated as a mediator of “second-window” ischemic preconditioning, and mitochondrial ATP-dependent K
+
(mitoK
ATP
) channels are the likely effectors. The links between NO and mitoK
ATP
channels are unknown.

Methods and Results
—We measured mitochondrial redox potential as an index of mitoK
ATP
channel opening in rabbit ventricular myocytes. The NO donor
S
-nitroso-
N
-acetyl-
dl
-penicillamine (SNAP, 0.1 to 1 mmol/L) oxidized the mitochondrial matrix dose-dependently without activating sarcolemmal K
ATP
channels. SNAP-induced oxidation was blocked by the selective mitoK
ATP
channel blocker 5-hydroxydecanoate and by the NO scavenger 2-(4-carboxyphenyl)-4,4′,5,5′-tetramethylimidazole-1-oxyl-3-oxide. SNAP-induced mitochondrial oxidation was detectable either by photomultiplier tube recordings of flavoprotein fluorescence or by confocal imaging. SNAP also enhanced the oxidative effects of diazoxide when both agents were applied together. Exposure to 1 mmol/L 8Br-cGMP failed to mimic the effects of SNAP.

Conclusions
—NO directly activates mitoK
ATP
channels and potentiates the ability of diazoxide to open these channels. These results provide novel mechanistic links between NO-induced cardioprotection and mitoK
ATP
channels.
Relation Between Baseline and On-Treatment Lipid Parameters and First Acute Major Coronary Events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
Authors: Gotto Antonio M. , Whitney Edwin , Stein Evan A. , Shapiro Deborah R. , Clearfield Michael , Weis Stephen , Jou Jesse Y. , Langendörfer Alexandra , Beere Polly A. , Watson Douglas J. , Downs John R. , de Cani John S.
Published: June 2012

Background
—The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs.

Methods and Results
—With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed.

Conclusions
—Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.
Evaluation of Sympathetic Nerve Terminals With [
11
C]Epinephrine and [
11
C]Hydroxyephedrine and Positron Emission Tomography
Authors: Münch Götz , Nguyen Ngoc T. B. , Nekolla Stephan , Ziegler Sibylle , Muzik Otto , Chakraborty Pulak , Wieland Donald M. , Schwaiger Markus
Published: June 2012

Background
—The goal of the present study was to directly compare the new radiopharmaceutical agent [
11
C]epinephrine (EPI) with [
11
C]hydroxyephedrine (HED) through the use of PET.

Methods and Results
—Seven healthy volunteers and 10 patients were investigated after heart transplantation. PET images of both tracers were of excellent quality in the volunteers. Values for radiolabeled metabolites (measured in percent of blood activity) at 5, 20, and 60 minutes after injection were ≈35%, ≈82%, and ≈86% for EPI and ≈13%, ≈47%, and ≈78% for HED, respectively. At 35 minutes, metabolite-corrected mean myocardial retention fraction of EPI (0.235±0.022 min
−1
) was significantly greater (
P
<0.01) than that of HED (0.142±0.012 min
−1
). Corrected tracer retention fractions of both EPI and HED were significantly reduced in transplant recipients (0.055±0.004 min
−1
,
P
<0.0001; and 0.050±0.006 min
−1
,
P
<0.0001, respectively) compared with volunteers. Normalization of retention fractions of patients with transplantation within 1 year to volunteers resulted in a value (ratio expressed in percent) of 20.6±1.8% for EPI, significantly (
P
<0.03) smaller than 27.8±0.8% for HED. In patients with transplantation later than 1 year, the values were 26.0±2.9% for EPI compared with 44.2±5.6% for HED (
P
<0.014).

Conclusions
—Both tracers showed high selectivity for neuronal uptake in the heart, with a significant reduction in tracer retention in transplant recipients compared with volunteers. Compared with HED, EPI showed greater retention in volunteers and a lower retention ratio in transplant recipients, suggesting that EPI may be the superior tracer with higher sensitivity to neuronal abnormalities. Because EPI reflects neuronal uptake, metabolism, and storage, it may be more suitable for the study of neuronal integrity than HED, which primarily traces uptake-1 capacity.
Soluble Complement Receptor-1 Protects Heart, Lung, and Cardiac Myofilament Function From Cardiopulmonary Bypass Damage
Authors: Chai Paul J. , Nassar Rashid , Oakeley Annette E. , Craig Damian M. , Quick George , Jaggers James , Sanders Stephen P. , Ungerleider Ross M. , Anderson Page A. W.
Published: June 2012

Background
—Host defense system activation occurs with cardiopulmonary bypass (CPB) and is thought to contribute to the pathophysiological consequences of CPB. Complement inhibition effects on the post-CPB syndrome were tested with soluble complement receptor-1 (sCR1).

Methods and Results
—Twenty neonatal pigs (weight 1.8 to 2.8 kg) were randomized to control and sCR1-treated groups. LV pressure and volume, left atrial pressure, pulmonary artery pressure and flow, and respiratory system compliance and resistance were measured. Preload recruitable stroke work, isovolumic diastolic relaxation time constant (τ), and pulmonary vascular resistance were determined. Pre-CPB measures were not statistically significantly different between the 2 groups. After CPB, preload recruitable stroke work was significantly higher in the sCR1 group (n=5, 46.8±3.2×10
3
vs n=6, 34.3±3.7×10
3
erg/cm
3
,
P
=0.042); τ was significantly lower in the sCR1 group (26.4±1.5, 42.4±6.6 ms,
P
=0.003); pulmonary vascular resistance was significantly lower in the sCR1 group (5860±1360 vs 12 170±1200 dyn · s/cm
5
,
P
=0.009); arterial P
o
2
in 100% F
io
2
was significantly higher in the sCR1 group (406±63 vs 148±33 mm Hg,
P
=0.01); lung compliance and airway resistance did not differ significantly. The post-CPB Hill coefficient of atrial myocardium was higher in the sCR1 group (2.88±0.29 vs 1.88±0.16,
P
=0.023).

Conclusions
—sCR1 meaningfully moderates the post-CPB syndrome, supporting the hypothesis that complement activation contributes to this syndrome.
Antihypertensive Effect of 0.1-Hz Blood Pressure Oscillations to the Kidney
Authors: Nafz Benno , Stegemann Jens , Bestle Morton H. , Richter Nadja , Seeliger Erdmann , Schimke Ingolf , Reinhardt H. Wolfgang , Persson Pontus B.
Published: June 2012

Background
—Physiological blood pressure (BP) fluctuations with frequencies >0.1 Hz can override renal blood flow autoregulation. The influence of such immediate changes in renal perfusion pressure (RPP) on daily BP regulation, eg, via shear stress–stimulated liberation of renal endothelial NO, however, is unknown. Thus, we studied the effects of such RPP oscillations on renal function and on systemic BP during the onset of renal hypertension.

Methods and Results
—Seven beagles (randomly assigned to each of the following protocols) were chronically instrumented for the measurement of systemic BP, RPP, and renal excretory function. An inflatable cuff was used to reduce and to oscillate RPP over 24 hours in the freely moving dog. Reducing RPP to 87±2 mm Hg diminished excretion of sodium and water and doubled plasma renin activity (PRA, n=7,
P
<0.01) but had no significant effect on urinary nitrate excretion (n=6), a marker of NO generation. Superimposing 0.1-Hz oscillations (±10 mm Hg) onto the reduced RPP blunted hypertension, returned fluid excretion almost to control levels, and doubled renal sodium elimination. Nitrate excretion peaked at 8 hours, only to return to control values shortly thereafter. PRA, conversely, was significantly reduced during the last third of the experimental protocols.

Conclusions
—BP fluctuations transiently stimulate NO liberation and induce a reduction in PRA, which enhances 24-hour sodium and water excretion and markedly attenuates the acute development of renovascular hypertension.
Antiarrhythmic Efficacy of Dipyridamole in Treatment of Reperfusion Arrhythmias
Authors: Yoshida Yukihiko , Hirai Makoto , Yamada Takumi , Tsuji Yukiomi , Kondo Takahisa , Inden Yasuya , Akahoshi Makoto , Murakami Yoshimasa , Tsuda Makoto , Tsuboi Naoya , Hirayama Haruo , Okamoto Mitsuhiro , Ito Teruo , Saito Hidehiko , Toyama Junji
Published: June 2012

Background
—Intracellular calcium overload is believed to play an important role in development of reperfusion arrhythmias. Dipyridamole, an inhibitor of cellular uptake of adenosine, may prevent or terminate reperfusion arrhythmias by reducing intracellular calcium overload.

Methods and Results
—First, we tested for a preventive effect of dipyridamole. Sixty-one patients who underwent primary PTCA for treatment of acute anterior wall myocardial infarction were enrolled in this prospective study. Patients were divided into dipyridamole (DP) and nondipyridamole (non-DP) groups. The 2 groups had similar baseline characteristics. In the DP group, dipyridamole 0.5 mg/kg was infused intravenously for 3 minutes immediately before reperfusion during primary PTCA. Arrhythmias after reperfusion were analyzed from continuous ECG recordings. None of the patients in the DP group (n=23) had accelerated idioventricular rhythms (AIVR) or ventricular tachycardia (VT). In contrast, 7 (18.4%) had AIVR and 3 (7.9%) had VT in the non-DP group (n=38;
P
<0.01). Second, we tested for a termination effect of dipyridamole. Dipyridamole 0.5 mg/kg was infused intravenously while continuous ECG recordings were obtained in 9 patients who had either sustained AIVR (n=7) or sustained VT (n=2) after reperfusion of occluded coronary artery. Arrhythmias were terminated in all patients.

Conclusions
—These results indicate that administration of dipyridamole can prevent and terminate reperfusion arrhythmias such as AIVR and VT. cAMP-mediated triggered activity may, at least in part, be responsible for reperfusion-induced AIVR and VT.
Exaggerated Renal Vasoconstriction During Exercise in Heart Failure Patients
Authors: Middlekauff Holly R. , Nitzsche Egbert U. , Hoh Carl K. , Hamilton Michele A. , Fonarow Gregg C. , Hage Antoine , Moriguchi Jaime D.
Published: June 2012

Background
—During static exercise in normal healthy humans, reflex renal cortical vasoconstriction occurs. Muscle metaboreceptors contribute importantly to this reflex renal vasoconstriction. In patients with heart failure, in whom renal vascular tone is already increased at rest, it is unknown whether there is further reflex renal vasoconstriction during exercise.

Methods and Results
—Thirty-nine heart failure patients (NYHA functional class III and IV) and 38 age-matched control subjects (controls) were studied. Renal blood flow was measured by dynamic positron emission tomography. Graded handgrip exercise and posthandgrip ischemic arrest were used to clarify the reflex mechanisms involved. During sustained handgrip (30% maximum voluntary contraction), peak renal vasoconstriction was significantly increased in heart failure patients compared with controls (70±13 versus 42±1 U,
P
=0.02). Renal vasoconstriction returned to baseline in normal humans by 2 to 5 minutes but remained significantly increased in heart failure patients at 2 to 5 minutes and had returned to baseline at 20 minutes. In contrast, during posthandgrip circulatory arrest, which isolates muscle metaboreceptors, peak renal vasoconstriction was not greater in heart failure patients than in normal controls. In fact, the increase in renal vasoconstriction was blunted in heart failure patients compared with controls (20±5 versus 30±2 U,
P
=0.05).

Conclusions
—During sustained handgrip exercise in heart failure, both the magnitude and duration of reflex renal vasoconstriction are exaggerated in heart failure patients compared with normal healthy humans. The contribution of the muscle metaboreceptors to reflex renal vasoconstriction is blunted in heart failure patients compared with normal controls.
Study on the Relationship Between Plasma Nitrite and Nitrate Level and Salt Sensitivity in Human Hypertension
Authors: Fujiwara Naoto , Osanai Tomohiro , Kamada Takaatsu , Katoh Takeshi , Takahashi Koki , Okumura Ken
Published: June 2012

Background
—High salt intake suppresses the effect of nitric oxide (NO) in the peripheral resistance vessels in animal models. We tested the hypothesis that the modulation of endogenous NO is related to salt sensitivity in human hypertension.

Methods and Results
—Inpatients with essential hypertension (n=24) were maintained on a normal-salt diet (12 g/d NaCl) for 3 days, a low-salt diet (2 g), a high-salt diet (20 to 23 g), and a low-salt diet for 7 days. Normotensive subjects (n=16) were maintained on the first 2 salt diets. The hypertensive patients whose average 24-hour blood pressure was increased by >5% by salt loading were assigned to group 1 (n=8) and the others to group 2 (n=16). Nitrate plus nitrite (NO
x
) was measured by the Griess method, and asymmetrical dimethylarginine (ADMA) by high-performance liquid chromatography. The plasma NO
x
level during the normal-salt diet was lower in group 1 than in group 2 and the normotensive group. After salt loading, the plasma NO
x
level was decreased and reversed after the second salt restriction. Plasma ADMA level was increased after salt loading and decreased after salt restriction. The change in plasma NO
x
level was correlated inversely with those in blood pressure (
r
=−0.59,
P
=0.0007) and plasma ADMA level (
r
=−0.64,
P
=0.003) after salt loading and restriction.

Conclusions
—Modulation of NO synthesis by salt intake may be involved in a mechanism for salt sensitivity in human hypertension, presumably via the change in ADMA.
Interleukin-10 Inhibits Intimal Hyperplasia After Angioplasty or Stent Implantation in Hypercholesterolemic Rabbits
Authors: Feldman Laurent J. , Aguirre Luc , Ziol Marianne , Bridou Jean-Pierre , Nevo Nathalie , Michel Jean-Baptiste , Steg P. Gabriel
Published: June 2012

Background
—Intimal hyperplasia after stent implantation is the main cause of in-stent restenosis. Activated monocytes play a key role in intimal growth. The anti-inflammatory cytokine interleukin-10 (IL-10) is a potent monocyte deactivator, endogenously produced in the atherosclerotic plaque. We tested the hypothesis that exogenous IL-10 may limit postangioplasty intimal hyperplasia after balloon angioplasty or stenting.

Methods and Results
—Hypercholesterolemic rabbits were treated with recombinant human IL-10 (rhuIL-10) for 3 days after balloon angioplasty or 28 days after stent implantation. High IL-10 serum levels and intense deactivation of circulating monocytic cells, assessed by inhibition of IL-1β release by lipopolysaccharide-stimulated whole blood, were detected for at least 8 hours after rhuIL-10 intravenous injection (ELISA). Morphometric analyses, performed 28 days after injury, indicated that rhuIL-10 reduced intimal growth by ≈50% after balloon angioplasty or stenting, resulting in more preserved lumen in stented arteries. Moreover, rhuIL-10 reduced macrophage infiltration by 67% and proliferative activity by 81% in the intima and the media. No toxic effect was detected except minor changes in blood cell count.

Conclusions
—The anti-inflammatory cytokine rhuIL-10 reduces postinjury intimal hyperplasia. The potent attenuation of in-stent intimal growth by rhuIL-10 and its favorable toxicity profile suggest that rhuIL-10 may be useful in the prevention of in-stent restenosis.
Persistent Changes in Myocardial Glucose Metabolism In Vivo During Reperfusion of a Limited-Duration Coronary Occlusion
Authors: McNulty Patrick H. , Jagasia Dinesh , Cline Gary W. , Ng Chin K. , Whiting Jennifer M. , Garg Pradeep , Shulman Gerald I. , Soufer Robert
Published: June 2012

Background
—Rapid reperfusion of an occluded coronary artery salvages regional mechanical function, but this benefit may not be realized for hours or days because of postischemic stunning. Recovery from stunning is incompletely understood but may involve adaptive changes in heart glucose metabolism.

Methods and Results
—To examine whether reversible coronary occlusion produces sustained changes in regional glucose metabolism in vivo, we performed a 20-minute left coronary artery occlusion followed by 24 hours of open-artery reperfusion in intact rats. Coronary occlusion produced stunning of the anterolateral left ventricle that resolved over 24 hours. When examined at 24 hours, reperfused regions were fully contractile and viable by vital staining and microscopy but demonstrated 25% reduction in blood flow and 50% increased uptake of circulating glucose, as estimated by in vivo [
13
N]NH
3
and [
18
F]fluorodeoxyglucose (FDG) tracer uptake. Reperfused regions had largely inactive glycogen synthase, low rates of glycogen synthesis, and persistent 50% glycogen depletion but increased flux of plasma [1-
13
C]glucose into myocardial [3-
13
C]alanine, indicating preferential shunting of imported glucose away from storage and into glycolysis.

Conclusions
—Sustained increases in regional glycolytic consumption of circulating glucose occur during reperfusion of a limited-duration coronary occlusion. This suggests a role for glycolytic ATP in the recovery from postischemic stunning in vivo. Furthermore, [
13
N]NH
3
/FDG regional mismatch may constitute a clinically accessible late metabolic signature of regional myocardial ischemia.
Resistance to Endotoxin Shock in Transgenic Mice Overexpressing Endothelial Nitric Oxide Synthase
Authors: Yamashita Tomoya , Kawashima Seinosuke , Ohashi Yoshitaka , Ozaki Masaori , Ueyama Tomomi , Ishida Tatsuro , Inoue Nobutaka , Hirata Ken-ichi , Akita Hozuka , Yokoyama Mitsuhiro
Published: June 2012

Background
—Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice.

Methods and Results
—LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97±3 to 59±3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84±4 to 71±4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in the lungs were significantly lower in Tg mice than in control mice. LPS-induced pulmonary leukocyte infiltration and increases in lung water content were also significantly attenuated in Tg mice. Histological examination revealed that lung injury after LPS injection was milder in Tg mice. Furthermore, Tg mice exhibited enhanced survival from LPS-induced septic shock compared with control mice.

Conclusions
—Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.
Asymptomatic Peripheral Arterial Disease Is Independently Associated With Impaired Lower Extremity Functioning
Authors: McDermott Mary McGrae , Fried Linda , Simonsick Eleanor , Ling Shari , Guralnik Jack M.
Published: June 2012

Background
—We report the implications of asymptomatic lower extremity peripheral arterial disease (PAD) for lower extremity functioning among participants in the Women’s Health and Aging Study, an observational study of disabled women ≥65 years of age living in and around Baltimore.

Methods and Results
—The ankle brachial index (ABI) and measures of upper and lower extremity functioning were measured among study participants. Of 933 women with ABI ≤1.50, 328 (35%) had an ABI <0.90, consistent with PAD. Sixty-three percent of PAD participants had no exertional leg pain. Among participants without exertional leg pain, lower ABI levels were associated with slower walking velocity, poorer standing balance score, slower time to arise 5 times consecutively from a seated position, and fewer blocks walked per week, adjusting for age, sex, race, cigarette smoking, and comorbidities. ABI was not associated independently with measures of upper extremity functioning.

Conclusions
—Asymptomatic PAD is common and is independently associated with impaired lower extremity functioning. In addition to preventing cardiovascular morbidity and death, further study is warranted to identify effective interventions to improve functioning among the growing number of men and women with asymptomatic PAD.
Coronary Artery Flow Velocity Is Related To Lumen Area and Regional Left Ventricular Mass
Authors: Anderson H. Vernon , Stokes Michael J. , Leon Miltiadis , Abu-Halawa Subhi A. , Stuart Yvonne , Kirkeeide Richard L.
Published: June 2012

Background
—Coronary flow velocity varies widely between individuals, even at rest. Because of this variation, indices with less apparent deviation, such as the ratio of hyperemic to resting velocity (coronary flow reserve), have been more commonly studied. We tested the hypothesis that the flow continuity principle could be used to model resting coronary flow, and we examined the resulting velocity relationship.

Methods and Results
—We studied coronary velocity in 59 patients using a Doppler wire to measure resting and hyperemic average peak velocities in the left anterior descending artery. Quantitative techniques were used to calculate lumen cross-sectional area and the lengths of all distal coronary branches. Branch lengths were used to estimate regional left ventricular mass. We then calculated the ratio of lumen area to regional mass (A/m). Regional perfusion was estimated from the double product of heart rate and systolic blood pressure. Resting velocity (V) varied inversely with A/m ratio [V=46.5/(A/m);
r
=0.68,
P
<0.001]. Disease in the left anterior descending artery was categorized as none or luminal irregularities only (n=22), mild (n=15), or moderate (n=22). The A/m ratio declined across these groups (8.7±4.0, 8.5±6.2, and 5.6±3.0 mm
2
/100 g, respectively;
P
<0.04), and the resting average peak velocity increased (27±16, 33±11, and 37±20 cm/s, respectively;
P
=0.06).

Conclusions
—Resting coronary artery flow velocity is inversely related to the ratio of lumen area to regional left ventricular mass. Higher resting velocities are found when insufficient lumen size exists for the distal myocardial bed, as occurs with diffuse mild or moderate coronary atherosclerosis.
Vitamin E Reduces the Uptake of Oxidized LDL by Inhibiting CD36 Scavenger Receptor Expression in Cultured Aortic Smooth Muscle Cells
Authors: Ricciarelli Roberta , Zingg Jean-Marc , Azzi Angelo
Published: June 2012

Background
—Vitamin E is well known as an antioxidant, and numerous studies suggest that it has a preventive role in atherosclerosis, although the mechanism of action still remains unclear.

Methods and Results
—The original aim of this study was to establish whether α-tocopherol (the most active form of vitamin E) acts at the earliest events on the cascade of atherosclerosis progression, that of oxidized LDL (oxLDL) uptake and foam-cell formation. We show here that the CD36 scavenger receptor (a specific receptor for oxLDL) is expressed in cultured human aortic smooth muscle cells (SMCs). Treatment of SMCs and HL-60 macrophages with α-tocopherol (50 μmol/L, a physiological concentration) downregulates CD36 expression by reducing its promoter activity. Furthermore, we find that α-tocopherol treatment of SMCs leads to a reduction of oxLDL uptake.

Conclusions
—This study indicates that CD36 is expressed in cultured human SMCs. In these cells, CD36 transports oxLDL into the cytosol. α-Tocopherol inhibits oxLDL uptake by a mechanism involving downregulation of CD36 mRNA and protein expression. Therefore, the beneficial effect of α-tocopherol against atherosclerosis can be explained, at least in part, by its effect of lowering the uptake of oxidized lipoproteins, with consequent reduction of foam cell formation.
Tissue Endothelin-Converting Enzyme Activity Correlates With Cardiovascular Risk Factors in Coronary Artery Disease
Authors: Ruschitzka Frank , Moehrlen Ueli , Quaschning Thomas , Lachat Mario , Noll Georg , Shaw Sidney , Yang Zhihong , Teupser Daniel , Subkowski Thomas , Turina Marko I. , Lüscher Thomas F.
Published: June 2012

Background
—Endothelin-converting enzymes (ECEs) are the key enzymes in endothelin-1 (ET-1) generation. However, their pathophysiological role in patients with cardiovascular disease remains elusive.

Methods and Results
—Vascular reactivity to big endothelin-1 (bigET-1; 10
−
9
to 10
−
7
mol/L) and ET-1 (10
−
9
to 10
−
7
mol/L) were examined in the internal mammary artery (IMA, n=33) and saphenous vein (SV, n=27) of patients with coronary artery disease with identified cardiovascular risk factors. Vascular ECE activity was determined by conversion of exogenously added bigET-1 to ET-1. Tissue contents of bigET-1 and ET-1 were measured by radioimmunoassay. In addition, the effects of LDL and oxidized LDL on ECE-1 protein levels were determined by Western blot analysis in human IMA endothelial cells. In the IMA, vascular ECE activity showed an inverse correlation with serum LDL levels (
r
=−0.76;
P
<0.01) and systolic and diastolic blood pressure and a positive correlation with fibrinogen (
r
=0.58;
P
<0.05). In the SV, fibrinogen was the only parameter to be correlated with vascular ECE activity. Vascular tissue content of bigET-1 was attenuated in the IMA of patients with hyperfibrinogenemia but increased in patients with elevated systolic blood pressure and increased serum LDL levels (
P
<0.05). Most interestingly, LDL and oxidized LDL downregulated ECE-1 protein levels in human IMA endothelial cells (
P
<0.05).

Conclusions
—These data demonstrate, for the first time, that vascular ECE activity is (1) inversely correlated with serum LDL levels and blood pressure and (2) positively associated with fibrinogen in human vascular tissue. Hence, ECE-1 activity may modulate cardiovascular risk in patients with coronary artery disease.
Management of Patients With Acute Coronary Syndromes in the United States by Platelet Glycoprotein IIb/IIIa Inhibition
Authors: Lincoff A. Michael , Harrington Robert A. , Califf Robert M. , Hochman Judith S. , Guerci Alan D. , Ohman E. Magnus , Pepine Carl J. , Kopecky Steven L. , Kleiman Neal S. , Pacchiana Cynthia M. , Berdan Lisa G. , Kitt Michael M. , Simoons Maarten L. , Topol Eric J.
Published: June 2012

Background
—A multinational, randomized, placebo-controlled trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, PURSUIT) demonstrated that the platelet glycoprotein IIb/IIIa receptor antagonist eptifibatide reduced the incidence of death or myocardial infarction among patients with acute ischemic syndromes without ST-segment elevation. Because of expected differences in practice patterns, a prospectively planned analysis of outcomes as a function of regions of the world was performed. The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States.

Methods and Results
—Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase–MB elevation were eligible for enrollment. Of the 10 948 patients randomized worldwide, 4035 were enrolled within the United States. Patients were allocated to placebo or eptifibatide infusion for up to 72 to 96 hours. Other medical therapies and revascularization strategies were at the discretion of the treating physician. Eptifibatide reduced the rate of the primary end point of death or myocardial infarction by 30 days from 15.4% to 11.9% (
P
=0.003) among patients in the United States. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%;
P
=0.004). Bleeding events were more common in patients receiving eptifibatide but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the United States than elsewhere in the world.

Conclusions
—Platelet glycoprotein IIb/IIIa receptor blockade with eptifibatide reduces the incidence of death or myocardial infarction among patients treated for acute ischemic syndromes without ST-segment elevation within the United States.
Evidence for Antigen-Driven T-Cell Response in Unstable Angina
Authors: Caligiuri Giuseppina , Paulsson Gabrielle , Nicoletti Antonino , Maseri Attilio , Hansson Göran K.
Published: June 2012

Background
—Activation of T cells and macrophages has been associated with unstable angina (UA), but whether this reflects specific immune responses remains unclear.

Methods and Results
—We analyzed the repertoire and the length of complementarity-determining region 3 of the T-cell receptor (TCR) β-chain variable (BV) gene segments of activated lymphocytes in 23 patients with UA, 13 patients with chronic stable angina (CSA), and 6 normal control subjects. We also tested the proliferation of systemic T cells in response to autologous coronary plaque proteins, oxidized LDL, and
Chlamydia pneumoniae
as candidate antigens, in vitro. The activated T cell–TCRBV repertoire was perturbed in 13 (57%) of 23 UA patients versus 3 (23%) of 13 CSA patients (
P
=0.016) and was restricted to 6 (28%) of 21 expanded TCRBV families; all were significantly higher in UA than in CSA patients. At least one monotypic or oligotypic activated TCRBV population was found in 15 (65%) of 23 UA patients and in 3 (23%) of 13 CSA patients (
P
<0.001). Finally, T cells from UA patients, but not from CSA patients or normal control subjects, proliferated in response to autologous proteins from coronary culprit lesions and/or to oxidized LDL.

Conclusions
—Our findings suggest that the T-cell response observed in UA patients is antigen-driven and directed to antigens contained in the culprit coronary atherosclerotic plaques.
Evidence of Improving Prognosis in Heart Failure
Authors: MacIntyre K. , Capewell S. , Stewart S. , Chalmers J.W.T. , Boyd J. , Finlayson A. , Redpath A. , Pell J.P. , McMurray J.J.V.
Published: June 2012

Background
—Contemporary survival in unselected patients with heart failure and the population impact of newer therapies have not been widely studied. Therefore, we have documented case-fatality rates (CFRs) over a recent 10-year period.

Methods and Results
—In Scotland, all hospitalizations and deaths are captured on a single database. We have studied case fatality in all patients admitted with a principal diagnosis of heart failure from 1986 to 1995. A total of 66 547 patients (47% male) were studied. Median age was 72 years in men and 78 years in women. Crude CFRs at 30 days and at 1, 5, and 10 years were 19.9%, 44.5%, 76.5%, and 87.6%, respectively. Median survival was 1.47 years in men and 1.39 years in women (2.47 and 2.36 years, respectively, in those surviving 30 days). Age had a powerful effect on survival, and sex, comorbidity, and deprivation had modest effects. One-year CF was 24.2% in those aged <55 years and 58.1% in those aged >84 years. After adjustment, 30-day CFRs fell between 1986 and 1995, by 26% (95% CI 15 to 35,
P
<0.0001) in men and 17% (95% CI 6 to 26,
P
<0.0001) in women. Longer term CFRs fell by 18% (95% CI 13 to 24,
P
<0.0001) in men and 15% (95% CI 10 to 20,
P
<0.0001) in women. Median survival increased from 1.23 to 1.64 years.

Conclusions
—Heart failure CF is much higher in the general population than in clinical trials, especially in the elderly. Although survival has increased significantly over the last decade, there is still much room for improvement.