bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive Assessment of Myocardial Viability by Positron Emission Tomography With
11
C Acetate in Patients With Old Myocardial Infarction
Authors: Hata Tatsuhiko , Nohara Ryuji , Fujita Masatoshi , Hosokawa Ryohei , Lee Linsetsu , Kudo Takashi , Tadamura Eiji , Tamaki Nagara , Konishi Junji , Sasayama Shigetake
Published: June 2012

Background
When patients with severely depressed left ventricular function are treated, it is crucial to know in advance how much functional recovery is expected from coronary revascularization.

Methods and Results
We compared the results of
11
C acetate positron emission tomography (PET) with dobutamine infusion with changes in regional wall motion evaluated by left ventriculography in 28 patients with old Q-wave anterior myocardial infarctions. Dysfunctional but viable myocardium (group A, n=13) was separated from nonviable myocardium (group B, n=15) by echocardiographic assessments of regional wall motion before and after successful coronary revascularization.
11
C acetate PET was performed to characterize normalized myocardial blood flow and oxidative metabolism (the clearance rate constant, k mono). While the baseline k monos of the infarct areas of the two groups were different with overlap, the responses to dobutamine infusion were directionally different. In addition, relative perfusion by
11
C acetate PET could predict recovery of left ventricular function as well as or better than dobutamine
11
C acetate kinetics. The extent of the increase in k monos of the infarct area with dobutamine infusion correlated well (
P
<.01) with the degree of the increase in the percentage of systolic segment shortening in the infarct area (left ventriculography) after coronary revascularization.

Conclusions
11
C acetate PET with dobutamine infusion can predict not only the reversibility of dysfunctioning myocardium after coronary revascularization but also the extent of improvement of regional wall motion in patients with old Q-wave infarction.
No Association of Menopause and Hormone Replacement Therapy With Carotid Artery Intima-Media Thickness
Authors: Nabulsi Azmi A. , Folsom Aaron R. , Szklo Moyses , White Alice , Higgins Millicent , Heiss Gerardo
Published: June 2012

Background
Cardiovascular disease is the major cause of death in older women. Information on the relation of menopause and hormone replacement therapy with carotid atherosclerosis is limited.

Methods and Results
We examined cross-sectionally the association of menopausal status, years since last menstruation, and hormone replacement therapy status with carotid artery intima-media thickness as determined by B-mode ultrasound. Female participants (n=5436) in the Atherosclerosis Risk in Communities Study without a history of symptomatic cardiovascular disease were included in the analyses. Menopause status in 45- to 54-year-old women who had never used hormone replacement therapy was not strongly associated with carotid intima-media thickness (mean=0.65 mm and 0.67 mm in premenopausal and postmenopausal women, respectively, adjusted for age, race, cigarette years of smoking, body mass index, sport index, systolic blood pressure, use of blood pressure medications, drinking status, diabetes, and education level). In postmenopausal women aged 55 to 64 years, women with ≤5 years since last menstruation had an adjusted average intima-media thickness (0.74 mm) comparable to those with >5 years since last menstruation (0.75 mm) (
P
>.05). Although hormone replacement therapy use was associated with a more favorable lipid and hemostasis profile than nonuse, its use was not associated with intima-media thickness in postmenopausal women aged 55 to 64 years (adjusted average=0.74 mm for current users of estrogen alone and ≈0.75 mm each for current users of estrogen plus progestin, former users, and never users).

Conclusions
The data suggest that the well-known associations of hormone replacement therapy with reductions in atherosclerotic cardiovascular disease may be attributable more to acute physiological effects, such as hemodynamic changes or reduced thrombosis, than to atherosclerosis itself.
The Asp
9
Asn Mutation in the Lipoprotein Lipase Gene Is Associated With Increased Progression of Coronary Atherosclerosis
Authors: Jukema J. Wouter , van Boven Ad J. , Groenemeijer Bjo¨rn , Zwinderman Aeilko H. , Reiber Johan H.C. , Bruschke Albert V.G. , Henneman J.A. , Molhoek G.P. , Bruin T. , Jansen H. , Gagne´ Eric , Hayden Michael R. , Kastelein John J.P.
Published: June 2012

Background
Many patients suffering from premature coronary artery disease report a family history for such events. A mutation in a particular gene, which confers susceptibility for atherosclerosis, will be found more frequently in individuals suffering from coronary atherosclerosis than in the general population. We have recently reported the identification of an Asp
9
Asn substitution in the lipoprotein lipase (LPL) enzyme. We analyzed the impact of this mutation on the progression of coronary atherosclerosis and the effect of pravastatin in both carriers and noncarriers.

Methods and Results
All patients were enrolled in the quantitative coronary angiographic clinical trial REGRESS, which studied the impact of pravastatin therapy on coronary atherosclerosis. The Asp
9
Asn mutation was identified in 38 of 819 (4.8%) patients. Carriers of the mutation more often had a positive family history of cardiovascular disease and lower HDL cholesterol levels than noncarriers. In the placebo group, carriers showed more progression of coronary atherosclerosis than noncarriers: mean reduction of the minimum obstruction diameter of −0.25 mm versus −0.12 mm (
P
=.029) and increase of percentage diameter stenosis of 6.4% versus 1.4% (
P
=.004). Moreover, the adjusted relative risk for a clinical event for carriers was calculated at 2.16 (95% CI, 1.09 to 4.29;
P
=.027). Although the lipid-lowering effect of pravastatin was attenuated in carriers, it appeared that these patients showed a response similar to noncarriers in terms of less progression of atherosclerosis and event-free survival.

Conclusions
This study shows that heterozygosity for a mutation in the LPL gene, which causes only subtle changes in fasting plasma lipids, may promote the progression of coronary atherosclerosis and diminish clinical event–free survival.
Fibrinolytic Factors and the Risk of Myocardial Infarction or Sudden Death in Patients With Angina Pectoris
Authors: Juhan-Vague Ire`ne , Pyke Stephen D.M. , Alessi Marie Christine , Jespersen Jorgen , Haverkate Frits , Thompson Simon G.
Published: June 2012

Background
Disturbances of the fibrinolytic system that lead to decreased removal of fibrin deposits may be important risk factors for coronary thrombosis. There is as yet no consensus on the prognostic value of fibrinolytic parameters, which may be attributed in part to the choice of confounding variables controlled for.

Methods and Results
The ECAT study is a prospective multicenter study of 3043 patients with angina pectoris followed for 2 years. Baseline measurements included 10 fibrinolytic variables. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. They are presented before and after adjustment for clusters of confounding variables that are markers of different mechanisms: insulin resistance (body mass index, triglyceride, and HDL cholesterol), inflammation (fibrinogen and C-reactive protein), and endothelial cell damage (von Willebrand factor). An increased incidence of events was associated with higher baseline concentrations of tissue plasminogen activator (TPA) antigen (
P
=.0002), plasminogen activator inhibitor-1 (PAI-1) activity (
P
=.02), and PAI-1 antigen (
P
=.001). The associations of PAI-1 activity and PAI-1 antigen with risk of events disappeared after adjustment for parameters reflecting insulin resistance but were not affected by other adjustments. TPA antigen was affected to a similar extent by adjustment for parameters reflecting insulin resistance, inflammation, or endothelial cell damage, but the risk association disappeared only after combined adjustments.

Conclusions
The prognostic role of PAI-1 in predicting coronary events is related principally to insulin resistance, whereas that of TPA antigen could be explained only by its relationship with different mechanisms, including insulin resistance, inflammation, and endothelial cell damage.
Serum Lipoprotein(a) Level Is Related to Thrombin Generation and Spontaneous Intermittent Coronary Occlusion in Patients With Acute Myocardial Infarction
Authors: Haider Agha W. , Andreotti Felicita , Thompson Gilbert R. , Kluft Cornelis , Maseri Attilio , Davies Graham J.
Published: June 2012

Background
Thrombotic occlusion of the infarct-related coronary artery is often intermittent in the early, evolving phase of acute myocardial infarction. To assess their relationship to this pattern of coronary occlusion, serum or plasma concentrations of cholesterol, triglyceride, lipoprotein(a), and coagulation and fibrinolytic factors were measured in venous blood before the initiation of thrombolytic therapy.

Methods and Results
Thirty-two patients (23 men, 9 women; age, 30 to 70 years) with acute myocardial infarction received intravenous recombinant tissue plasminogen activator (20 to 60 megaunits) within 6 hours of the onset of symptoms. Continuous ECG ST-segment recording demonstrated intermittent occlusion of the infarct-related coronary artery in 12 patients (group 1) before the start of thrombolytic treatment and persistent occlusion in 20 patients (group 2). Groups 1 and 2 were similar in age, sex, race, duration of symptoms, blood sample collection time, location of the infarct-related coronary artery, and extent of coronary artery disease. The serum level (median [interquartile range]) of lipoprotein(a) was 34 (13 to 47) mg/dL versus 11.5 (5 to 27) mg/dL (
P
=.02), and the plasma level (median [interquartile range]) of thrombin–antithrombin III complex was 10.85 (6.4 to 21.5) versus 6.8 (4.2 to 8.7) μg/L
−1
(
P
<.04) in groups 1 and 2, respectively. The levels of the other factors were similar in both groups.

Conclusions
The phenomenon of spontaneous intermittent closure and reopening of coronary arteries early during acute myocardial infarction in humans is associated with a higher level of lipoprotein(a) and of a marker of thrombin generation, suggesting that lipoprotein(a) and thrombin are closely related to coronary patency in these patients.
Comparable Potent Coronary Constrictor Effects of Endothelin-1 and Big Endothelin-1 in Humans
Authors: Pernow John , Kaijser Lennart , Lundberg Jan M. , Ahlborg Gunvor
Published: June 2012

Background
Endothelin-1 (ET-1) is a potent vasoconstrictor produced from the precursor big ET-1 in endothelial cells. The coronary effects of these peptides in humans in vivo are unknown. Therefore, the effects of ET-1 and big ET-1 on coronary blood flow in relation to plasma ET-1 and big ET-1 levels were compared in healthy subjects.

Methods and Results
The peptides were infused intravenously at the rates of 0.2, 1, and 8 pmol/kg per minute. Each dose was administered for 20 minutes except the highest dose of ET-1, which was administered for 10 minutes. ET-1 and big ET-1 evoked dose-related increases in mean arterial blood pressure from 93±4 to 107±4 mm Hg and from 89±2 to 122±5 mm Hg, respectively, at the highest dose. ET-1 and big ET-1 reduced coronary sinus blood flow, measured with thermodilution, by a maximum of 25±4% and 28±8% and increased coronary vascular resistance by 50±9% and 107±26%, respectively. Coronary sinus, but not arterial, oxygen saturation was reduced in parallel with the coronary sinus blood flow. The effects of ET-1 and big ET-1 were similar at corresponding time points. During infusion of ET-1, a 19±5% extraction of ET-1 was observed over the coronary vascular bed (
P
<.05). Administration of big ET-1 elevated arterial plasma ET-1 levels by 2.4-fold, and after correction for the local extraction of ET-1, a myocardial production of ET-1 was observed.

Conclusions
ET-1 and big ET-1 induce comparable increases in blood pressure and coronary constriction in humans in vivo. The results also suggest a net local removal of circulating ET-1 and big ET-1 and a local conversion of big ET-1 into ET-1 within the coronary vascular bed.
Endothelial Dysfunction Late After Kawasaki Disease
Authors: Dhillon Rami , Clarkson Peter , Donald Ann E. , Powe Amanda J. , Nash Margot , Novelli Vas , Dillon Michael J. , Deanfield John E.
Published: June 2012

Background
Kawasaki disease (KD) is a systemic vasculitis of childhood with widespread vascular endothelial damage in the acute stage. Long-term complications, such as myocardial infarction and death, are recognized, but the extent and nature of late vascular abnormalities that might predispose to these events have not been studied.

Methods and Results
We used high-resolution ultrasound to study endothelial function in the brachial artery of 20 patients 5 to 17 years after acute KD (median, 11 years) and compared findings with those in 20 age- and sex-matched control subjects. Vascular responses to reactive hyperemia (with flow increase leading to endothelium-dependent dilation) and to sublingual glyceryl trinitrate (GTN; endothelium-independent dilation) were recorded. The relationship between endothelium-dependent vascular responses and features of the acute illness was examined. There was no difference in baseline vessel diameter, degree of reactive hyperemia, or response to GTN between patients and control subjects. In contrast, flow-mediated dilation was markedly reduced in KD patients compared with control subjects (3.1% versus 9.4%;
P
<.001). Late endothelium-dependent responses were not related to features of the acute illness.

Conclusions
Abnormalities of systemic endothelial function are present many years after resolution of acute KD, even in patients without detectable early coronary artery involvement. Because this may be an important factor in the genesis of late vascular complications, long-term follow-up of all patients with KD is indicated.
AREVA: Multicenter Randomized Comparison of Low-Dose Versus Standard-Dose Anticoagulation in Patients With Mechanical Prosthetic Heart Valves
Authors: Acar Jean , Iung Bernard , Boissel Jean Pierre , Samama Michel Meyer , Michel Pierre Louis , Teppe Jean Paul , Pony Jean Claude , Le Breton Herve´ , Thomas Daniel , Isnard Richard , de Gevigney Guy , Viguier Emmanuelle , Sfihi Ali , Hanania Guy , Ghannem Mohamed , Mirode Ali , Nemoz Chantal
Published: June 2012

Background
Moderate anticoagulation may be proposed to reduce the risk of hemorrhage for certain patients with a mechanical prosthesis, but the consequences for risk of thromboembolism are debated.

Methods and Results
The purpose of the AREVA trial was to compare moderate oral anticoagulation (international normalized ratio [INR] of 2.0 to 3.0) with the usual regimen (INR of 3.0 to 4.5) after a single-valve replacement with a mechanical prosthesis, either Omnicarbon or St Jude. Patients included were between 18 and 75 years old, in sinus rhythm, and with a left atrial diameter ≤50 mm on the time-motion echocardiogram. Patients were randomized for INR after surgery. From 1991 to 1994, 433 patients underwent valve replacement (aortic, 414; mitral, 19) with 353 St Jude and 80 Omnicarbon prostheses; 380 patients were randomized for INR: 188 for INR 2.0 to 3.0 and 192 for INR 3.0 to 4.5. Mean follow-up was 2.2 years (1 to 4 years). Analysis of 18 001 INR samples showed that the mean of the median of INR was 2.74±0.35 in the 2.0 to 3.0 group and 3.21±0.33 in the 3.0 to 4.5 group (
P
<.0001). Thromboembolic events, as assessed from clinical data and CT brain scans, occurred in 10 patients in the 2.0 to 3.0 INR group and 9 patients in the 3.0 to 4.5 INR group (
P
=.78). Hemorrhagic events occurred in 34 patients in the 2.0 to 3.0 INR group and 56 patients in the 3.0 to 4.5 INR group (
P
<.01), with 13 and 19 major hemorrhagic events, respectively (
P
=.29).

Conclusions
In selected patients with mechanical prostheses, moderate anticoagulation prevents thromboembolic events as effectively as conventional anticoagulation and reduces the incidence of hemorrhagic events.
Vasodilator Effects of Endothelin-Converting Enzyme Inhibition and Endothelin ET
A
Receptor Blockade in Chronic Heart Failure Patients Treated With ACE Inhibitors
Authors: Love Michael P. , Haynes William G. , Gray Gillian A. , Webb David J. , McMurray John J.V.
Published: June 2012

Background
The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ET
A
receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ET
A
and ET
B
receptors in healthy subjects and patients with CHF.

Methods and Results
Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF) was measured by venous occlusion plethysmography. In CHF patients (n=10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ET
A
receptor antagonist) increased FBF by 52±10% (
P
=.0006) and 31±6% (
P
=.002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15±5% (
P
=.0007). Forearm vasoconstriction to endothelin-1 (an ET
A
and ET
B
receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n=10; CHF versus control subjects,
P
<.001), whereas vasoconstriction to sarafotoxin S6c (an ET
B
receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n=10; CHF versus control subjects,
P
<.05).

Conclusions
ECE inhibitors and ET
A
receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ET
A
and ET
B
receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.
Cardiovascular Effects of an Ultra–Short-Acting Nitric Oxide–Releasing Compound, Zwitterionic Diamine/NO Adduct, in Dogs
Authors: Zhang Ping , Ohara Akitoshi , Mashimo Takashi , Sun Jianhua , Shibuta Satoshi , Takada Koji , Kosaka Hiroaki , Terada Masaru , Yoshiya Ikuto
Published: June 2012

Background
This study was conducted to clarify the cardiovascular effects of a new NO-releasing compound, NOC-7, and to compare it with other nitrovasodilators, sodium nitroprusside (SNP) and nitroglycerin, in dogs anesthetized with pentobarbital.

Methods and Results
A bolus injection of NOC-7 decreased mean aortic blood pressure in a dose-dependent manner. The onset was rapid and the recovery quick. Continuous infusion of NOC-7 decreased mean aortic pressure from 115±3.9 to 84±2.9 mm Hg and infusion of SNP, from 118±3.8 to 87±3.1 mm Hg. The optimum doses of NOC-7 and SNP were determined to be 2.73±0.77 and 11.5±6.1 μg·kg
−1
·min
−1
, respectively. During infusion of NOC-7, heart rate and cardiac output were increased (
P
<.05), pulmonary artery pressure was not changed, and systemic and pulmonary vascular resistances were decreased (
P
<.05). Electromagnetic flowmetry showed that portal venous and internal carotid arterial blood flow were increased (
P
<.05) and that hepatic and renal arterial blood flows were not changed. These hemodynamic changes during NOC-7 infusion were similar to those with SNP. The plasma level of NO
2
−
/NO
3
−
did not change, but methemoglobin increased slightly (
P
<.05). Comparison between hypotensive responses before and after a 3.5-hour infusion of NOC-7 or nitroglycerin showed that acute tolerance developed to nitroglycerin but not to NOC-7.

Conclusions
The results indicate that NOC-7 may be useful as an ultra–short-acting nitrovasodilator that has no major adverse effect or tolerance.
Effect of Nonspecific Binding to Plasma Proteins on the Antithrombin Activities of Unfractionated Heparin, Low-Molecular-Weight Heparin, and Dermatan Sulfate
Authors: Cosmi Benilde , Fredenburgh James C. , Rischke Janice , Hirsh Jack , Young Edward , Weitz Jeffrey I.
Published: June 2012

Background
Nonspecific binding to plasma proteins decreases the anti–factor Xa (anti-Xa) activity of unfractionated heparin (UFH) but not that of low-molecular-weight heparin (LMWH). However, plasma proteins could influence the anti-thrombin (anti-IIa) activity of LMWH. To explore this possibility, we compared the effects of plasma proteins on the anti-IIa activities of UFH and LMWH. We also examined their effects on the anti-IIa activity of dermatan sulfate (DS) because, like UFH, DS binds to plasma proteins.

Methods and Results
There was almost complete recovery of anti-IIa activity when UFH, LMWH, or DS was added to plasma from each of 20 healthy volunteers. The addition of a chemically modified heparin with low affinity for antithrombin III to plasma containing UFH increased the anti-IIa activity in a concentration-dependent fashion by displacing UFH from plasma proteins. In contrast, addition of low-affinity heparin had no effect on the anti-IIa activity of LMWH. LMWH does not bind to plasma proteins because the bulk of the LMWH chains are <6000 D, and only heparin fractions >6000 D bind nonspecifically to plasma proteins. As further evidence that plasma proteins do not influence the anti-IIa activity of LMWH, the rate of thrombin inhibition in plasma in the presence of LMWH is virtually identical to that in buffer containing physiological amounts of the major antithrombins. In contrast, with UFH or DS, the rate of thrombin inhibition is twofold slower in plasma than in buffer.

Conclusions
Nonspecific binding of UFH to plasma proteins most likely contributes to the variable anti-IIa response to UFH in patients with thromboembolic disease. Although DS also binds to plasma proteins, the clinical significance of this finding is unclear. In contrast, because LMWH does not bind to plasma proteins, the anti-IIa activity of LMWH should be just as predictable as its anti-Xa activity.
Viral Infection of the Myocardium in Endocardial Fibroelastosis
Authors: Ni Jiyuan , Bowles Neil E. , Kim Young-Hwue , Demmler Gail , Kearney Debra , Bricker J. Timothy , Towbin Jeffrey A.
Published: June 2012

Background
Endocardial fibroelastosis, previously a common disease of children, often resulted in congestive heart failure and death. Virus-induced myocarditis was the suspected first step in the pathogenesis of the disease, with enteroviruses and mumps virus considered potential causes. Direct evidence for their involvement was limited, however, and during the past two decades, a significant decline in the incidence of endocardial fibroelastosis occurred. Recently, we demonstrated polymerase chain reaction to be a rapid and sensitive method for identification of the viral genome in the myocardium of patients with myocarditis and dilated cardiomyopathy. The purpose of this study was to analyze myocardial samples of patients with endocardial fibroelastosis for the viral genome.

Methods and Results
Myocardial samples from 29 patients with autopsy-proven endocardial fibroelastosis were analyzed for viral genome (enterovirus, adenovirus, mumps, cytomegalovirus, parvovirus, influenza, herpes simplex virus) by use of polymerase chain reaction or reverse transcriptase–polymerase chain reaction. In 90% of samples, the viral genome was amplified; >70% of the samples were positive for mumps viral RNA, while 28% amplified adenovirus. In contrast, only 1 of 65 control samples amplified a virus (enterovirus). Two regions of mumps virus were amplified: the nucleocapsid gene and the polymerase-associated protein gene. Interestingly, only 3 of the 21 samples that were positive for mumps RNA were positive with both sets of primers, indicating that the persistence of mumps virus in the myocardium may be related to the selection of defective virus mutants.

Conclusions
These data suggest an etiologic role for viral infection in endocardial fibroelastosis, supporting the hypothesis that endocardial fibroelastosis is a sequela of a viral myocarditis, in particular of that due to mumps virus.
Mechanisms of Altered Contractile Responses to Vasopressin and Endothelin in Canine Coronary Collateral Arteries
Authors: Rapps Julie A. , Jones Allan W. , Sturek Michael , Magliola Lawrence , Parker Janet L.
Published: June 2012

Background
Mature coronary collateral arteries are hyperresponsive to vasopressin; in contrast, contractile responses of collaterals to endothelin are attenuated. Our goal was to determine the cellular mechanisms underlying these differences in reactivity using two sizes of canine collateral arteries isolated from hearts subjected to chronic coronary occlusion.

Methods and Results
Contractile responses to vasopressin (100 nmol/L) were enhanced threefold to fourfold in near-resistance (≈200 μm lumen diameter) and conduit (≈500 μm lumen diameter) collateral arteries compared with similarly sized noncollateral coronary arteries (
P
<.01). In contrast, contractions of both sizes of collaterals in response to endothelin (0.01 to 30 nmol/L) were smaller than responses of size-matched noncollateral arteries (
P
<.05). Pretreatment with either indomethacin (5 μmol/L), a cyclooxygenase inhibitor, or
N
G
-nitro-
l
-arginine methyl ester (100 μmol/L), a nitric oxide synthase inhibitor, did not alter the relative responsiveness of collateral arteries to vasopressin or endothelin compared with noncollateral arteries. Vasopressin produced greater increases of intracellular free Ca
2+
(measured by use of fura-2 microfluorometry and Ca
2+
-dependent
42
K
+
efflux) in smooth muscle of collateral arteries than in smooth muscle of noncollateral arteries (
P
<.05). Surprisingly, endothelin-induced increases of Ca
2+
were not different in smooth muscle of collateral and noncollateral arteries (
P
>.05).

Conclusions
We conclude that altered contractile responsiveness of collateral arteries to vasopressin and endothelin does not result from altered synthesis/release of nitric oxide or prostaglandins. Parallel enhancement of vasopressin-mediated Ca
2+
and contractile responses suggests increases in vasopressin receptor number, affinity, and/or efficiency of coupling mechanisms in collateral smooth muscle. The dissociation between endothelin-induced contractile and Ca
2+
responses of collaterals indicates that the mechanisms involved in increasing Ca
2+
sensitivity of contractile proteins during endothelin stimulation may be altered in collateral arteries.
Beneficial Effects of Amlodipine in a Murine Model of Congestive Heart Failure Induced by Viral Myocarditis
Authors: Wang Wei Zhong , Matsumori Akira , Yamada Takehiko , Shioi Tetsuo , Okada Ikutaro , Matsui Shigeo , Sato Yukihito , Suzuki Hiroshi , Shiota Kohei , Sasayama Shigetake
Published: June 2012

Background
Although calcium channel blockers have not been shown to be beneficial for the treatment of patients with heart failure, a recent clinical trial demonstrated a favorable effect of amlodipine on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy. We investigated the effects of amlodipine on a murine model of congestive heart failure induced by the M variant of encephalomyocarditis virus (EMCV).

Methods and Results
Four-week-old male DBA/2 mice were inoculated with EMCV and administered amlodipine, diltiazem, or vehicle PO for 2 weeks. The heart weight–to–body weight ratio and the histopathological grades of myocardial lesions were significantly lower and survival was significantly increased in the amlodipine-treated group (
P
<.01,
P
<.05, and
P
<.05, respectively) than in the control group. In vitro, amlodipine added to murine J774A.1 macrophages concomitant with EMCV inhibited nitrite formation in a concentration-dependent manner, but diltiazem did not. Furthermore,
N
G
-monomethyl-
l
-arginine, an inhibitor of NO synthesis, decreased myocardial lesions significantly in this murine model. Immunohistochemistry revealed that the number of cells stained with antibody against an inducible NO synthase decreased significantly in the amlodipine-treated group compared with that in the control group (
P
<.01).

Conclusions
Amlodipine appears to have a protective effect against myocardial injury in this animal model of congestive heart failure. The therapeutic effect of amlodipine may be in part resulting from inhibition of overproduction of NO.
Prothrombotic Effects of Erythrocytes on Platelet Reactivity
Authors: Santos M. Teresa , Valles Juana , Aznar Justo , Marcus Aaron J. , Broekman M. Johan , Safier Lenore B.
Published: June 2012

Background
Aspirin effectively reduces the incidence of secondary vascular occlusive events in only 25% of patients. Low-dose aspirin as currently used blocks platelet production of prothrombotic thromboxane A
2
and allows endothelial synthesis of antithrombotic prostacyclin. This regimen minimizes gastrointestinal toxicity. We previously showed that intact erythrocytes markedly enhance platelet reactivity. Therefore we investigated whether supplementation of low-dose aspirin with a single high dose at 2-week intervals could more effectively block erythrocyte promotion of platelet reactivity.

Methods and Results
Effects of different aspirin regimens on erythrocyte enhancement of platelet reactivity in normal volunteers were measured with the use of an assay that evaluates both platelet activation and recruitment. After 15 days of daily ingestion of 50 mg aspirin, reactivity of platelets alone was inhibited. However, erythrocyte promotion of platelet activation and recruitment was only inhibited by ≈50% and persisted in the total absence of thromboxane synthesis. In contrast, if 50 mg/d aspirin was preceded by a single loading dose of 500 mg aspirin, the erythrocyte prothrombotic effect was strongly inhibited (≈90%) for 2 to 3 weeks. However, over time, erythrocytes “escaped” from this inhibition, and once again became prothrombotic, even on a daily regimen of 50 mg aspirin.

Conclusions
For clinical purposes, we recommend a loading dose of aspirin (500 mg), followed by daily administration of 50 mg. The loading dose should be repeated at 2-week intervals. This regimen blocks recovery of the erythrocyte capacity to promote platelet reactivity and may amplify the therapeutic potential of aspirin in cardiovascular disease.
Single LDL Apheresis Improves Endothelium-Dependent Vasodilatation in Hypercholesterolemic Humans
Authors: Tamai Osamu , Matsuoka Hidehiro , Itabe Hiroyuki , Wada Yoshifumi , Kohno Keisuke , Imaizumi Tsutomu
Published: June 2012

Background
Although long-term lipid-lowering therapy improves endothelium-dependent vasodilatation in humans, it remains unknown whether the short-term removal of LDL per se ameliorates endothelial dysfunction.

Methods and Results
To examine the effects of a single session of LDL apheresis on endothelial function in patients with hypercholesterolemia, we measured forearm blood flow (FBF) by strain-gauge plethysmography before and after single LDL apheresis while infusing acetylcholine (ACh; 4 to 24 μg/min) and sodium nitroprusside (SNP; 0.2 to 1.2 μg/min). The single session of LDL apheresis reduced total LDL (from 142.2±15.0 to 32.6±5.0 mg/mL,
P
<.0005) and oxidized LDL (from 111.6±22.8 to 30.0±5.4 ng/mL,
P
<.005). Although ACh and SNP increased FBF dose-dependently before and after LDL apheresis, the endothelium-dependent vasodilatation responses to ACh were significantly augmented (
P
<.01) after the single session of LDL apheresis without changes in the endothelium-independent vasodilatation responses to SNP. The plasma levels of total and oxidized LDL correlated with the degree of ACh-induced vasodilatation. Furthermore, the local production of nitrate/nitrite, metabolites of NO, during ACh infusion was significantly (
P
<.05) augmented by LDL apheresis, and there was a significant correlation between the degree of ACh-induced vasodilatation and the production in nitrate/nitrite (
r
=.99,
P
<.0005).

Conclusions
We demonstrated that even a single session of LDL apheresis with the reduction of total LDL and oxidized LDL improved endothelial function. Our results suggest that total LDL and/or oxidized LDL may directly impair endothelial function in the human forearm vessel.
Induction of Cytokine Expression in Leukocytes by Binding of Thrombin-Stimulated Platelets
Authors: Neumann Franz-Josef , Marx Nikolaus , Gawaz Meinrad , Brand Korbinian , Ott Ilka , Rokitta Claudia , Sticherling Christian , Meinl Christian , May Andreas , Schömig Albert
Published: June 2012

Background
Activated platelets tether and activate myeloid leukocytes. To investigate the potential relevance of this mechanism in acute myocardial infarction (AMI), we examined cytokine induction by leukocyte-platelet adhesion and the occurrence of leukocyte-platelet conjugates in patients with AMI.

Methods and Results
We obtained peripheral venous blood samples in 20 patients with AMI before and daily for 5 days after direct percutaneous transluminal coronary angioplasty (PTCA) and in 20 patients undergoing elective PTCA. Throughout the study period, CD41 immunofluorescence of leukocytes (flow cytometry) revealed increased leukocyte-platelet adhesion in patients with AMI compared with control patients (mean±SE of fluorescence [channels] before PTCA: 77±16 versus 35±9;
P
equals;.003). In vitro, thrombin-stimulated fixed platelets bound to neutrophils and monocytes. Within 2 hours, this resulted in increased mRNA for interleukin (IL)-1β, IL-8, and monocyte chemoattractant protein (MCP)-1 in unfractionated leukocytes. After 4 hours, IL-1β and IL-8 concentration of the cell-free supernatant had increased by 268±36% and 210±7%, respectively, and cellular MCP-1 content had increased by 170±8%. Addition of activated platelets to adherent monocytes had a similar effect and was associated with nuclear factor-κB activation. Inhibition of binding by anti–P-selectin antibodies reduced the effect of activated platelets on cytokine production.

Conclusions
In patients with AMI, leukocyte-platelet adhesion is increased. Binding of activated platelets induces IL-1β, IL-8, and MCP-1 in leukocytes. Our findings suggest that leukocyte-platelet adhesion contributes to the regulation of inflammatory responses in AMI.
Aortic Valve Replacement for Aortic Stenosis With Severe Left Ventricular Dysfunction
Authors: Connolly Heidi M. , Oh Jae K. , Orszulak Thomas A. , Osborn Sara L. , Roger Veronique L. , Hodge David O. , Bailey Kent R. , Seward James B. , Tajik A. Jamil
Published: June 2012

Background
Aortic valve replacement for aortic stenosis (AS) carries an increased risk in the presence of left ventricular (LV) systolic dysfunction. Few data are available on the outcome of such patients.

Methods and Results
Between 1985 and 1992, 154 consecutive patients (107 men and 47 women) with LV systolic dysfunction (ejection fraction [EF] ≤35%) underwent aortic valve replacement for AS. The mean preoperative characteristics included EF, 27±6%; aortic valve mean gradient, 44±18 mm Hg; aortic valve area, 0.6±0.2 cm
2
; and cardiac output, 4.1±1.5 L/min. Simultaneous coronary artery bypass graft surgery was performed in 78 patients (51%). Perioperative (30-day) mortality was 9% (14 of 154 patients). Fifty patients died during follow-up. Coronary artery disease (
P
=.002) and a reduced preoperative cardiac output (
P
=.03) were significantly related to reduced overall survival rate by multivariate analysis. Postoperative improvement occurred in most patients; 88% were New York Heart Association class III or IV before surgery versus 7% after surgery. Postoperative EF was assessed in 76% of survivors; 76% of these demonstrated improvement. By multivariate analysis, change in EF was inversely related to coronary disease (
P
=.002) and preoperative aortic valve area (
P
=.03).

Conclusions
Despite LV dysfunction, the risk of aortic valve replacement for AS was acceptable and related to coronary artery disease and mean aortic gradient, and long-term survival was related to coronary disease and cardiac output. Improvement in symptoms and EF occurred in most patients.
8-Epi PGF
2α
Generation During Coronary Reperfusion
Authors: Delanty N. , Reilly M.P. , Pratico D. , Lawson J.A. , McCarthy J.F. , Wood A.E. , Ohnishi S.T. , Fitzgerald D.J. , FitzGerald G.A.
Published: June 2012

Background
Myocardial reperfusion is believed to be associated with free radical injury. However, indexes of oxidative stress in vivo have been limited by their poor specificity and sensitivity. Isoprostanes are stable products of arachidonic acid formed in a nonenzymatic, free radical–catalyzed manner. We have developed a sensitive and specific assay for one of these compounds, 8-epi prostaglandin (PG) F
2α
.

Methods and Results
To address its utility as an index of oxidative stress during coronary reperfusion, we measured urinary levels by gas chromatography/mass spectrometry in a canine model of coronary thrombolysis, in patients with acute myocardial infarction treated with thrombolytic therapy, and in patients after elective coronary artery bypass surgery. Urinary 8-epi PGF
2α
was unchanged after circumflex artery occlusion in a canine model of coronary thrombolysis (n=13; 437.2±56.4 versus 432.7±55.2 pmol/mmol creatinine) but increased significantly (
P
<.05) immediately after reperfusion (553.8±64.7 pmol/mmol). Urinary levels were increased (
P
<.001) in patients (n=12) with acute myocardial infarction given lytic therapy (265.8±40.8 pmol/mmol) compared with age-matched control subjects (n=20; 91.5±11.8 pmol/mmol) and patients with stable coronary disease (n=20; 95.7±6.3 pmol/mmol). Preoperative levels rose from 113.2±11.8 to 248.2±86.3 pmol/mmol at 30 minutes into revascularization to 332.2±82.6 pmol/mmol by 15 minutes after global myocardial reperfusion (
P
<.05) and dropped to 181.2±50.4 pmol/mmol at 30 minutes and 120.2±9.9 pmol/mmol at 24 hours after bypass surgery (n=5). Corresponding changes in spin adduct formation, found with electron paramagnetic resonance, were noted in 2 patients.

Conclusions
These data support the hypothesis that free radical generation occurs during myocardial reperfusion. Measurement of isoprostane production may serve as a noninvasive index of oxidative stress.
Efferent Vagal Innervation of the Canine Atria and Sinus and Atrioventricular Nodes
Authors: Chiou Chuen-Wang , Eble John N. , Zipes Douglas P.
Published: June 2012

Background
The purpose of this study was to investigate the functional pathways of efferent vagal innervation to the atrial myocardium and sinus and atrioventricular (AV) nodes.

Methods and Results
Using vagally induced atrial effective refractory period shortening, slowing of spontaneous sinus rate, and prolongation of AV nodal conduction time as end points of vagal effects, we determined the actions of phenol and epicardial radiofrequency catheter ablation (RFCA) applied to different sites at or near the atrial myocardium to inhibit these responses. We found that efferent vagal fibers to the atria are located both subepicardially and intramurally or subendocardially. Most efferent vagal fibers to the atria appear to travel through a newly described fat pad located between the medial superior vena cava and aortic root (SVC-Ao fat pad), superior to the right pulmonary artery, and then project onto two previously noted fat pads at the inferior vena cava–left atrial junction (IVC-LA fat pad) and the right pulmonary vein–atrial junction (RPV fat pad) and to both atria. A few vagal fibers may bypass the SVC-Ao fat pad and go directly to the IVC-LA or RPV fat pad and then innervate the atrial myocardium. Vagal fibers to the sinus and AV nodes also converge at the SVC-Ao fat pad (a few fibers to the sinus node go directly to the RPV fat pad) before projecting to the RPV and IVC-LA fat pads. Long-term vagal denervation of the atria and sinus and AV nodes can be produced by RFCA of these fat pads and results in vagal denervation supersensitivity. Vagal denervation prevents induction of atrial fibrillation in this model.

Conclusions
The newly described SVC-Ao fat pad receives most of the vagal fibers to the atria and sinus and AV nodes. Elimination of the fat pads with RFCA selectively vagally denervated the atria and sinus and AV nodes.
Early Versus Delayed Angiotensin-Converting Enzyme Inhibition Therapy in Acute Myocardial Infarction
Authors: Pfeffer Marc A. , Greaves Sally C. , Arnold J. Malcolm O. , Glynn Robert J. , LaMotte Frances S. , Lee Richard T. , Menapace Francis J. , Rapaport Elliot , Ridker Paul M. , Rouleau Jean-Lucien , Solomon Scott D. , Hennekens Charles H.
Published: June 2012

Background
Although ACE inhibitor therapy has been shown to reduce mortality in patients with acute myocardial infarction (MI), the optimal dose and the timing of its initiation have not been determined.

Methods and Results
In a double-blind trial of 352 patients with anterior MI, we compared the safety and effectiveness of early (day 1) versus delayed (day 14) initiation of the ACE inhibitor ramipril (10 mg) on echocardiographic measures of left ventricular (LV) area and ejection fraction (EF). An early, low-dose ramipril (0.625 mg) arm was also evaluated. Clinical events did not differ. During the first 14 days, the risk of manifesting a systolic arterial pressure of ≤90 mm Hg was increased in both ramipril groups. LVEF increased in all groups during this period, but the early, full-dose ramipril group had the greatest improvement in EF (increase: full, 4.9±10.0; low, 3.9±8.2%; delayed, 2.4±8.8%;
P
for trend <.05) and was the only group that did not demonstrate a significant increase in LV diastolic area.

Conclusions
The results of the present study demonstrated that in patients with anterior MI, the early use of ramipril (titrated to 10 mg) attenuated LV remodeling and was associated with a prompter recovery of LVEF. The use of low-dose regimen did not prevent hypotension and had only intermediate benefits on LV size and function. The more favorable effects on LV topography of the early use of full-dose ramipril support the results of the major clinical trials, which have demonstrated an early survival benefit of ACE inhibition.
Remodeling of Autologous Saphenous Vein Grafts
Authors: Shi Yi , O’Brien James E. , Mannion John D. , Morrison Richard C. , Chung Wooksung , Fard Ali , Zalewski Andrew
Published: June 2012

Background
Aortocoronary saphenous vein grafts (SVGs) undergo structural changes that render them susceptible to atherosclerosis. Accordingly, the origin of neointimal hyperplasia was examined in porcine arterialized SVGs to determine the mechanism of vein graft remodeling.

Methods and Results
At 2 to 4 days after surgery, the percentage of cells lacking differentiation markers characteristic for smooth muscle (SM) cells (ie, α-SM actin, desmin, and SM myosin) increased within the media of SVGs interposed in the carotid arteries (
P
<.001). At 7 to 14 days, these cells acquired a differentiated phenotype (ie, α-SM-actin positive/variable desmin/SM-myosin negative) and accumulated in the neointima. At 3 months, the neointima was positive for α-SM actin but mostly negative for desmin, which contrasted with medial SMCs that were invariably positive for α-SM actin, desmin, and SM myosin. To determine the role of nonmuscle cells in the above process, perivascular wound fibroblasts were selectively labeled and found to translocate through the media of newly placed SVGs, contributing to neointimal formation. These migrating cells differentiated to myofibroblasts exhibiting sustained α-SM-actin expression. The intima of human SVGs, retrieved during repeat aortocoronary bypass surgery, exhibited the profile of cytoskeletal proteins that resembled myofibroblasts seen in porcine SVGs.

Conclusions
Perivascular fibroblasts may infiltrate injured media of arterialized SVGs, differentiate to myofibroblasts (acquiring α-SM actin), and contribute to vein graft remodeling. The similarities between porcine and human SVGs regarding the repertoire of cytoskeletal proteins suggest the involvement of myofibroblasts in graft remodeling in the clinical setting.
Apoptosis in Human Acute Myocardial Infarction
Authors: Saraste Antti , Pulkki Kari , Kallajoki Markku , Henriksen Kenth , Parvinen Martti , Voipio-Pulkki Liisa-Maria
Published: June 2012

Background
After reopening of the infarct-related coronary artery, cardiomyocytes continue to die during reperfusion. The mechanisms of cell death have been subject to debate. We studied whether an apoptotic type of cell death occurs in human acute myocardial infarction (AMI).

Methods and Results
We studied myocardial samples of eight patients who died of AMI and had patent infarct-related arteries at autopsy. Six of the patients had received initially successful thrombolysis. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the in situ DNA end-labeling method. Apoptotic cardiomyocytes were observed particularly in the border zones of histologically infarcted myocardium, whereas very few apoptotic cells were present in the remote noninfarcted myocardium. Internucleosomal fragmentation was confirmed by agarose gel electrophoresis of DNA isolated from the representative myocardial areas.

Conclusions
This study provides evidence that in addition to overt necrosis, a subset of myocytes undergo apoptosis during ischemia-reperfusion injury. Apoptosis may provide a new target for cardioprotection during evolving AMI in humans.
TNK-Tissue Plasminogen Activator in Acute Myocardial Infarction
Authors: Cannon Christopher P. , McCabe Carolyn H. , Gibson C. Michael , Ghali Magdi , Sequeira Rafael F. , McKendall George R. , Breed Judy , Modi Nishit B. , Fox Norma Lynn , Tracy Russell P. , Love Ted W. , Braunwald Eugene
Published: June 2012

Background
TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA.

Methods and Results
The Thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151±55 mL/min and a half-life of 17±7 minutes. Comparable values for wild-type TPA are 572±132 mL/min and 3.5±1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients.

Conclusions
TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.