bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Vagal Reflex Modulates Intestinal Vascular Capacitance and Ventricular Preload in Anesthetized Dogs With Acute Myocardial Infarction
Authors: Wang Steven Y. , Manyari Dante E. , Tyberg John V.
Published: June 2012

Background
The purpose of the present study was to examine the effects of the cardiac vagal reflex on intestinal vascular capacitance and cardiac filling pressure during experimental acute myocardial infarction (AMI).

Methods and Results
AMI was induced in anesthetized dogs through injection of microspheres into the left main coronary artery. Intestinal blood volume was measured with blood-pool scintigraphy. Portal venous pressure was varied through graded inflation of a portal venous constrictor to determine the intestinal vascular pressure-volume relation. Induction of AMI decreased intestinal blood volume to 88±3% of the control value (
P
<.01) and shifted the pressure-volume relation toward the pressure axis. This change was associated with increased left ventricular (LV) end-diastolic pressure (LVEDP) (from 6±1 to 17±2 mm Hg,
P
<.01) and LV segment length (to 112±4% of the control value,
P
<.01). During AMI, blockade of the cardiac vagal reflex by intrapericardial application of 2% lidocaine further decreased intestinal blood volume (to 83±3% of the control value,
P
<.05, versus AMI without lidocaine), increased LVEDP (to 22±2 mm Hg,
P
<.05, versus AMI without lidocaine), and tended to increase LV segment length (to 115±5%,
P
<.10). Lidocaine had no effect in dogs with AMI that had been vagotomized.

Conclusions
These results suggest that the cardiac vagal reflex modulates the decrease in the intestinal vascular capacitance induced by AMI and modulates ventricular preload through pooling of blood in the intestinal circulation.
An Oligosaccharide Sialyl-Lewis
x
Analogue Does Not Reduce Myocardial Infarct Size After Ischemia and Reperfusion in Dogs
Authors: Gill Edward A. , Kong Yinong , Horwitz Lawrence D.
Published: June 2012

Background
Polymorphonuclear leukocytes, particularly neutrophils, are important mediators of ischemia/reperfusion–induced myocardial and coronary vascular injury. The selectin family of glycoprotein receptors mediates neutrophil “rolling,” a loose, transient adhesion to the coronary endothelium that precedes the firmer adhesion associated with cardiovascular injury. The oligosaccharide sialyl-Lewis
x
(SLe
x
) is the probable neutrophil counterligand for endothelial E- and P-selectin. Administration of analogues of SLe
x
could potentially prevent neutrophil rolling by competing for the selectin-adhesion sites. We investigated the effects of treatment with an analogue of SLe
x
in a chronic canine model of ischemia/reperfusion.

Methods and Results
Anesthetized mongrel dogs were subjected to 90 minutes of ischemia through occlusion of the left anterior descending coronary artery and 48 hours of reperfusion. Five minutes before the onset of reperfusion, dogs received either the SLe
x
analogue CY-1503 at a dose of 20 mg/kg or normal saline. Myocardial infarct size was measured through triphenyltetrazolium chloride staining, and polymorphonuclear leukocyte accumulation was evaluated through measurement of cardiac myeloperoxidase activity. After adjustment for blood flow, the mean infarct size of control dogs (44.7±4.2%) was not different from that of treated dogs (33.4±4.0%,
P
=.06), although there was a trend toward a slightly lower value in the treated dogs. Myeloperoxidase activity was not different in the infarcted myocardium of the treated group compared with that of the control group (2.7±0.71 treated versus 1.08±0.41 units/mg protein control,
P
=.06).

Conclusions
We conclude that CY-1503 does not substantially or consistently reduce myocardial infarct size or neutrophil accumulation in dogs subjected to ischemia followed by a prolonged period (48 hours) of reperfusion.
Mechanism of Catecholamine-Induced Proliferation of Vascular Smooth Muscle Cells
Authors: Yu Sheu-Meei , Tsai Sheng-Yi , Guh Jih-Hwa , Ko Feng-Nien , Teng Che-Ming , Ou Jonathan T.
Published: June 2012

Background
Catecholamines have been shown to aggravate atherosclerosis in animals and humans, and abnormal proliferation of vascular smooth muscle cells (VSMC) is a key event in the early stage of atherosclerosis. Catecholamines may be involved in such cell growth. Therefore, a series of experiments using cultured VSMC was performed to elucidate their possible mitogenic effect.

Methods and Results
We examined the mitogenic effect of catecholamines using rat aortic smooth muscle cells (VSMC) by measuring [
3
H]thymidine incorporation, checking with flow cytometry, and counting the cell number directly. Furthermore, the catecholamine-activated signal transduction pathway was assessed by measurement of the formation of inositol 1,4,5-triphosphate, intracellular Ca
2+
concentration, mitogen-activated protein kinase (MAPK) activity, and mitogenic gene expression. Norepinephrine (NE) and phenylephrine stimulated [
3
H]thymidine incorporation and cell growth. Clonidine and isoproterenol showed little of such effects. Prazosin was more effective than either yohimbine or propranolol in suppressing the mitogenic effect of NE, indicating that catecholamine-induced VSMC proliferation is mediated by α
1
-adrenoceptors. The α
1
-adrenoceptor activation was coupled to pertussis toxin–insensitive G
q
-protein and triggered phosphoinositide hydrolysis with subsequent activation of protein kinase C and MAPK in VSMC. In response to NE, both 42- and 44-kD MAPK were activated and tyrosine was phosphorylated. α
1
-Adrenoceptor stimulation with NE also caused accumulation of c-
fos,
c-
jun,
and c-
myc
mRNA. Chloroethylclonidine completely blocked the α
1
-adrenoceptor–mediated mitogenesis.

Conclusions
The effect of catecholamines appears to be mediated via the activation of the chloroethylclonidine-sensitive α
1
-adrenoceptors that triggers the phosphoinositide hydrolysis and activates the MAPK pathway, leading to DNA synthesis and cell proliferation.
Effects of Cigarette Smoking on the Angiographic Evolution of Coronary Atherosclerosis
Authors: Waters David , Lespe´rance Jacques , Gladstone Peter , Boccuzzi Stephen J. , Cook Thomas , Hudgin Roger , Krip Gordon , Higginson Lyall
Published: June 2012

Background
Although smoking increases both the risk of developing coronary disease and the risk of coronary events in patients with known coronary atherosclerosis, the effect of smoking on the evolution of coronary atherosclerosis as assessed by serial angiography is poorly defined.

Methods and Results
Ninety smokers with coronary atherosclerosis shown on a recent angiogram and with fasting cholesterol levels between 220 and 300 mg/dL were enrolled in a randomized, double-blind, placebo-controlled trial of cholesterol-lowering therapy, along with 241 nonsmokers and ex-smokers. Lovastatin at a mean dose of 36 mg/d lowered total and LDL cholesterol by 21±11% and 29±11%, respectively, but these levels changed by <2% in placebo-treated patients. Coronary arteriography was repeated after 2 years in 72 smokers and their 557 lesions were measured blindly with an automated quantitative system, along with 1752 lesions in 227 nonsmokers. Coronary change score, the per-patient mean of the minimal lumen diameter changes for all qualifying lesions, worsened by 0.16±0.16 mm in smokers and by 0.07±0.15 mm in nonsmokers in the placebo group (
P
<.001). Lovastatin-treated smokers had less worsening (0.07±0.15 mm) than placebo-treated smokers (
P
=.024). One or more coronary lesions progressed in 16 of 34 lovastatin-treated smokers and in 28 of 38 placebo-treated smokers (47% versus 74%,
P
<.001). In the placebo group, new coronary lesions developed in 21 of 38 smokers and in 28 of 115 nonsmokers (55% versus 24%,
P
<.001); fewer lovastatin-treated smokers developed new lesions (15% versus 55%,
P
<.001).

Conclusions
Smoking accelerates coronary progression and new lesion formation as assessed by serial quantitative coronary arteriography. Lovastatin slows the progression of coronary atherosclerosis and prevents the development of new coronary lesions in smokers.
Environmental Tobacco Smoke and Coronary Heart Disease in the American Cancer Society CPS-II Cohort
Authors: Steenland Kyle , Thun Michael , Lally Cathy , Heath Clark
Published: June 2012

Background
Thirteen of 14 epidemiological studies have shown an increased risk of ≈20% for coronary heart disease (CHD) for never-smokers exposed to environmental tobacco smoke (ETS), but this association remains controversial. If true, ETS might account for an estimated 35 000 to 40 000 heart disease deaths per year in the United States.

Methods and Results
We have conducted the largest study to date, a prospective study of 353 180 female and 126 500 male never-smokers enrolled in 1982 in the American Cancer Society's Cancer Prevention Study II and followed through 1989. Analyses focused on subcohorts of 309 599 married pairs and of 135 237 subjects concordant for self-reported exposure and exposure reported by each one's spouse. More than 2800 CHD deaths (ICD 410-414) occurred among married pairs; 10% of married men and 28% of married women were married to currently smoking spouses, while 10% and 32%, respectively, were married to former smokers. After controlling for many cardiovascular risk factors, we found 22% higher CHD mortality (rate ratio, 1.22; 95% CI, 1.07 to 1.40) among never-smoking men married to currently smoking wives compared with those married to wives who had never smoked. The corresponding rate ratio for women was 1.10 (0.96 to 1.27). Never-smokers living with former smokers showed no increased risk. When analyses were restricted to subjects whose ETS exposure was classified via both their own self-report and a spouse's report, the rate ratio was 1.23 (1.03 to 1.47) for currently exposed men and 1.19 (0.97 to 1.45) for women.

Conclusions
Results are consistent with prior reports that never-smokers currently exposed to ETS have about 20% higher CHD death rates. However, our data do not show consistent dose-response trends and are possibly subject to confounding by unmeasured risk factors.
Changes in Early and Late Diastolic Filling Patterns Induced by Long-term Adrenergic β-Blockade in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Andersson Bert , Caidahl Kenneth , di Lenarda Andrea , Warren Sanford E. , Goss Franz , Waldenstro¨m Anders , Persson Stig , Wallentin Ingemar , Hjalmarson Åke , Waagstein Finn
Published: June 2012

Background
β-Blockers have been used in patients with idiopathic dilated cardiomyopathy to improve cardiac performance and theoretically would be beneficial to diastolic function. However, there are few reports on changes in diastolic function during chronic pharmacological treatment of congestive heart failure.

Methods and Results
The present study was a substudy in the international Metoprolol in Dilated Cardiomyopathy Trial. Transmitral Doppler echocardiography was used to evaluate diastolic function in 77 patients randomly assigned to placebo (n=37) or metoprolol (n=40). The patients were treated for 12 months. Changes in Doppler flow variables in the metoprolol group implied a less restrictive filling pattern, expressed as an increase in E-wave deceleration time (placebo, 185±126 to 181±64 ms; metoprolol, 152±63 to 216±78 ms;
P
=.01, placebo versus metoprolol). Maximal increase in deceleration time had occurred by 3 months, whereas systolic recovery was achieved gradually and maximal effect was seen by 12 months of treatment. Although deceleration time was correlated to heart rate at baseline, changes in deceleration time were not significantly correlated to changes in heart rate during treatment.

Conclusions
During the first 3 months of treatment, maximal effects on diastolic variables were reached, whereas the most prominent effect on systolic function was seen late in the study. It is suggested that effects on diastolic filling account for subsequent later myocardial systolic recovery. The E-wave deceleration time, which in recent studies has been shown to be a powerful predictor of survival, was significantly improved in the metoprolol-treated patients.
Existence of the Frank-Starling Mechanism in the Failing Human Heart
Authors: Holubarsch Christian , Ruf Thorsten , Goldstein Daniel J. , Ashton Robert C. , Nickl Werner , Pieske Burkert , Pioch Katja , Lu¨demann Jens , Wiesner Sandra , Hasenfuss Gerd , Posival Herbert , Just Hanjo¨rg , Burkhoff Daniel
Published: June 2012

Background
The Frank-Starling mechanism is one of the most important physiological principles for regulation of contractile performance. We therefore studied the question of whether this mechanism may be absent or attenuated in end-stage failing human left ventricular myocardium.

Methods and Results
Different methodological approaches were used to analyze the effects of this mechanism on the organ, tissue, and sarcomere levels: (1) In excised human whole left ventricles (2 donor hearts, 5 failing hearts), diastolic and systolic pressure-volume relationships were obtained. (2) In isolated muscle strip preparations from the left ventricular wall of donor hearts (n=14) and failing hearts from patients with idiopathic dilated cardiomyopathy (n=21) and ischemic cardiomyopathy (n=11), peak developed force was measured at different muscle lengths of the preparation. (3) Skinned fiber preparations were obtained from failing right and left ventricles (n=12). In all three studies, we clearly observed the existence of the Frank-Starling mechanism: (1) In isolated failing human left ventricles, peak developed isometric pressure is increased when the preload is elevated. (2) Peak developed tension is increased by ≈50% to 70% (
P
<.01) in left ventricular preparations of failing and nonfailing ventricles when the muscles are stretched from 90% to 100% optimum length. (3) An increase in sarcomere length leads to a sensitization of contractile proteins of ventricular skinned fiber preparations from failing human hearts. At 1.9-μm sarcomere length, the EC
50
value was 5.56±0.06, and at 2.3 μm it was 5.70±0.05 (
P
<.01; n=7).

Conclusions
The Frank-Starling mechanism is maintained in end-stage failing human hearts, whereas significant alterations of diastolic myocardial distensibility are evident in chronic heart failure.
Angiotensin-Converting Enzyme Gene Polymorphism Is Associated With Carotid Arterial Wall Thickness in Non–Insulin-Dependent Diabetic Patients
Authors: Hosoi Masayuki , Nishizawa Yoshiki , Kogawa Kyoko , Kawagishi Takahiko , Konishi Toshiaki , Maekawa Kiyoshi , Emoto Masanori , Fukumoto Shinya , Shioi Atsushi , Shoji Tetsuo , Inaba Masaaki , Okuno Yasuhisa , Morii Hirotoshi
Published: June 2012

Background
The insertion/deletion (
I/D
) polymorphism of the
ACE
gene has been shown to be associated with cardiovascular disease in healthy subjects as well as in patients with non–insulin-dependent diabetes mellitus (NIDDM). We investigated the relationship between the
ACE
gene polymorphism and the wall thickness of both carotid and femoral arteries in NIDDM patients.

Methods and Results
We measured the intimal plus medial thickness (IMT) of both carotid and femoral arteries using high-resolution B-mode ultrasonography in 288 Japanese NIDDM patients (160 men, 128 women). No significant differences among the three genotypes were found with respect to age, sex, duration of diabetes, body mass index, blood pressure, plasma glucose, hemoglobin A
1C
, total cholesterol, triglycerides, HDL cholesterol, or cigarette-years. Plasma ACE levels were strongly associated with
I/D
polymorphism, with an additive effect of the
D
alleles. The carotid IMT of the patients carrying the
D
allele (
DD+ID
genotype) was significantly higher than that of the patients not carrying the
D
allele (
II
genotype) (
P
=.037), whereas the femoral IMT was not affected by the
I/D
polymorphism. Multiple regression analysis demonstrated that the risk factors for carotid IMT of patients with NIDDM were age, non-HDL cholesterol, and
D
allele of the
ACE
gene (
R
2
=.155,
P
<.0001).

Conclusions
The
D
allele of the
ACE
gene may be a risk factor for the development of wall thickening of the carotid but not the femoral artery in NIDDM patients.
Endothelin-1–Induced Release of Thromboxane A
2
Increases the Vasoconstrictor Effect of Endothelin-1 in Postischemic Reperfused Rat Hearts
Authors: Zaugg Christian E. , Hornstein Pius S. , Zhu Peili , Simper David , Lu¨scher Thomas F. , Allegrini Peter R. , Buser Peter T.
Published: June 2012

Background
The release and vasoconstrictor effect of endothelin-1 (ET-1) are increased after myocardial ischemia, suggesting a role for ET-1 in ischemia/reperfusion injury. However, the mechanisms of the increased vasoconstriction by ET-1 are unknown. The aim of this study was to test whether ET-1–induced release of thromboxane A
2
(TXA
2
) contributes to the vasoconstrictor effect of ET-1 in nonischemic hearts and whether such release can increase the vasoconstrictor effect of ET-1 in postischemic reperfused hearts.

Methods and Results
ET-1–induced release of TXA
2
was assessed by measurement of the concentrations of its stable metabolite thromboxane B
2
(TXB
2
) in the coronary effluent of nonischemic and reperfused isolated rat hearts before and after administration of 0.01 nmol ET-1 using an enzyme immunoassay. The contribution of ET-1–induced release of TXA
2
to the vasoconstrictor effect of ET-1 was assessed by measurement of the effects of ET-1 with and without the cyclooxygenase inhibitor indomethacin or the TXA
2
/endoperoxide receptor antagonist SQ 30,741 using
31
P magnetic resonance spectroscopy. In nonischemic hearts, ET-1 led to a small increase in TXB
2
in the coronary effluent (3.9±1.5 pg/mL; n=3), but neither indomethacin nor SQ 30,741 significantly diminished the vasoconstrictor effects of ET-1 (reduction of coronary flow, 4.0±0.4 and 4.5±0.3 mL/min, respectively, versus 4.9±0.5 mL/min for ET-1 alone; n=8, 6, and 9, respectively). In postischemic reperfused hearts, however, ET-1 led to a greater increase in TXB
2
(13.7±1.5 pg/mL;
P
<.05 versus nonischemic hearts; n=3), and both indomethacin and SQ 30,741 diminished the vasoconstrictor effects of ET-1 (reduction of coronary flow, 2.6±0.3 and 2.2±0.3 mL/min, respectively, versus 4.0±0.1 mL/min for ET-1 alone; n=8, 8, and 6, respectively;
P
<.05). Furthermore, indomethacin and SQ 30,741 prevented the detrimental effects of ET-1 on left ventricular developed pressure, intracellular pH, and phosphocreatine during reperfusion.

Conclusions
ET-1–induced release of TXA
2
does not significantly contribute to the vasoconstrictor effect of ET-1 in nonischemic hearts but can increase the vasoconstrictor effect of ET-1 in postischemic reperfused hearts.
Noninvasive Quantification of Regional Myocardial Metabolic Rate for Oxygen by Use of
15
O
2
Inhalation and Positron Emission Tomography
Authors: Iida Hidehiro , Rhodes Christopher G. , Araujo Luis I. , Yamamoto Yusuke , de Silva Ranil , Maseri Attilio , Jones Terry
Published: June 2012

Background
A method has been developed to measure the regional myocardial metabolic rate of oxygen consumption (rMMR
o
2
) and oxygen extraction fraction (rOEF) quantitatively and noninvasively in humans by use of
15
O
2
inhalation and positron emission tomography. This article describes the theory, an error analysis of the technique, and procedures of the method used in a human feasibility study.

Methods and Results
Inhaled
15
O
2
is transported to peripheral tissues, where it is converted to
15
O-labeled water of metabolism, which exchanges with the relatively large extravascular tissue space. Quantification of this buildup of radioactivity allows the calculation of rMMR
o
2
and rOEF. However, a correction for the spillover of the pulmonary gas radioactivity signal into myocardial regions is required and has been made by use of a gas volume distribution estimated from the transmission scan. This was validated by comparative measurements using the inert gas [
11
C]CH
4
in four greyhounds. Spillover of the cardiac chamber radioactivity has been corrected for with an inhaled [
15
O]CO (blood volume) scan. The underestimation of myocardial radioactivity due to wall motion and thickness has been corrected for by use of values of tissue fraction obtained from the flow measurement [
15
O](CO
2
scan). Values of rOEF were similar (within 4%) whether obtained from gas volume measurements determined from the transmission or [
11
C]CH
4
scan data.
15
O
2
scan information from six healthy volunteers showed a clear distribution of myocardial radioactivity after the vascular and pulmonary gas
15
O background was subtracted. Subsequent compartmental analysis resulted in values for rOEF and rMMR
o
2
of 0.60±0.11 and 0.10±0.03 mL·min
−1
·g
−1
in the human myocardium at rest.

Conclusions
The results of this study are in good agreement with established values. This is the first known approach to allow the direct quantitative determination of rOEF and oxygen metabolism to be made noninvasively on a regional basis.
Transesophageal Echocardiographic Assessment of Papillary Muscle Rupture
Authors: Moursi Mohammed H. , Bhatnagar Sudhir K. , Vilacosta Isidre , Roman Jose A. San , Espinal Miguel A. , Nanda Navin C.
Published: June 2012

Background
In some patients with papillary muscle rupture, the ruptured head may not prolapse into the left atrium, which makes diagnosis by transthoracic or transesophageal echocardiography difficult.

Methods and Results
In an attempt to find additional or more definite diagnostic echocardiographic features, we analyzed intraoperative transesophageal echocardiograms of 21 consecutive patients with papillary muscle rupture (20 involved the left ventricle and 1 involved the right ventricle) confirmed at surgery. In 7 (35%) of 20 patients with left ventricular papillary muscle rupture, the ruptured head was not seen to prolapse into the left atrium. In these patients, examination of the left ventricle proved most useful. Abnormal, large-amplitude erratic motion (1 to 5 cm in 17 patients; 0.5 cm in 1 patient) of a large echo density in the left ventricle consistent with the ruptured head was noted in 18 (90%) of these 20 patients. This included all 7 patients with nonprolapse of the ruptured papillary muscle head into the left atrium. Less prominent erratic motion or flutter of the papillary muscle still attached to the left ventricular wall was also noted but was less sensitive in the diagnosis of papillary muscle rupture. The single patient with right ventricular papillary muscle rupture showed erratic motion as well as prolapse of the ruptured head into the right atrium.

Conclusions
Transesophageal echocardiographic examination of the left ventricle is useful in the diagnosis of papillary muscle rupture, especially in those patients in whom the ruptured head does not prolapse into the left atrium. The left ventricle should be scrutinized thoroughly during transesophageal echocardiographic examination for erratic papillary muscle motion in all patients with suspected rupture.
Comparative Effects of Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor on Coronary Collateral Development and the Arterial Response to Injury
Authors: Lazarous Daisy F. , Shou Matie , Scheinowitz Mickey , Hodge Everett , Thirumurti Venugopal , Kitsiou Anastasia N. , Stiber Jonathan A. , Lobo Arlene D. , Hunsberger Sally , Guetta Esther , Epstein Stephen E. , Unger Ellis F.
Published: June 2012

Background
We have shown that the angiogenic peptides basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) enhance canine coronary collateral development when administered for ≥4 weeks. bFGF, a pluripotent mitogen of mesodermally derived cells, could theoretically exacerbate neointimal smooth muscle cell hyperplasia, a fundamental component of atherosclerosis. VEGF, an endothelial cell–specific mitogen and vascular permeability factor, could have deleterious effects related to vascular hyperpermeability. The present investigation had two aims: (1) to ascertain whether brief (7-day) systemic arterial treatment with bFGF or VEGF would improve myocardial collateral perfusion and (2) to determine whether these peptides induce neointimal accumulation in vivo.

Methods and Results
Dogs were subjected to ameroid-induced occlusion of the left circumflex coronary artery and randomized to bFGF 1.74 mg (n=9), VEGF 0.72 mg (n=9), or saline (n=10) as a daily left atrial bolus (days 10 to 16). Additional dogs were randomized to VEGF 0.72 mg (n=6) or saline (n=5); however, treatment was delayed by 1 week. Coincident with the institution of treatment, all dogs underwent balloon denudation injury of the iliofemoral artery. bFGF markedly increased maximal collateral flow but did not exacerbate neointimal accumulation. VEGF had no discernible effect on maximal collateral flow, but it exacerbated neointimal thickening after vascular injury.

Conclusions
Short-term treatment with bFGF enhanced collateral development without increasing neointimal accumulation at sites of vascular injury. Although VEGF did not increase collateral development as administered in this study, it significantly exacerbated neointimal accumulation. These data provide support for the clinical investigation of bFGF in selected patients with ischemic heart disease.
Functional and Bioenergetic Consequences of Postinfarction Left Ventricular Remodeling in a New Porcine Model
Authors: Zhang Jianyi , Wilke Norbert , Wang Ying , Zhang Yi , Wang Chunshen , Eijgelshoven Marcel H.J. , Cho Yong K. , Murakami Yo , Ugurbil Kamil , Bache Robert J. , From Arthur H.L.
Published: June 2012

Background
The underlying mechanisms by which left ventricular remodeling (LVR) leads to congestive heart failure (CHF) are unclear. This study examined the functional and bioenergetic abnormalities associated with postinfarction ventricular remodeling in a new, large animal model.

Methods and Results
Remodeling was induced by circumflex coronary artery ligation in young pigs. LV mass, volume, ejection fraction (EF), the ratio of scar surface area to LV surface area, and LV wall stresses were calculated from magnetic resonance imaging anatomic data and simultaneously measured LV pressure. Hemodynamics, transmural blood flow, and high-energy phosphates (spatially localized
31
P–nuclear magnetic resonance) were measured under basal conditions, during hyperperfusion induced by pharmacological vasodilation with adenosine, and during pyruvate infusion (11 mg/kg per minute IV). Six of 18 animals with coronary ligation developed clinical CHF while the remaining 12 animals had LV dilation (LVR) without CHF. The results were compared with 16 normal animals. EF decreased from 55.9±5.6% in normals to 34.6±2.3% in the LVR group (
P
<.05) and 24.2±2.8% in the CHF group (
P
<.05 versus LVR). The infarct scar was larger in CHF hearts than in LVR hearts (
P
<.05). In normals, LV myocardial creatine phosphate (CP)/ATP ratios were 2.10±0.10, 2.06±0.16, and 1.92±0.12 in subepicardium (EPI), mid myocardium (MID), and subendocardium (ENDO), respectively. In LVR hearts, the corresponding ratios were decreased to 1.99±0.13, 1.80±0.14, and 1.57±0.15 (ENDO
P
<.05 versus normal). In CHF hearts, CP/ATP ratios were 1.41±0.14, 1.33±0.15, and 1.25±0.15; (
P
<.05 versus LVR in EPI and MID). The calculated myocardial free ADP levels were significantly increased only in CHF hearts.

Conclusions
Bioenergetic abnormalities in remodeled myocardium are related to the severity of LV dysfunction, which, in turn, is dependent on the severity of the initiating myocardial infarction.
Neurally Mediated Negative Inotropic Effect Impairs Myocardial Function During Cholinergic Coronary Vasoconstriction in Pigs
Authors: Cinca Juan , Carren˜o Ana , Mont Llui´s , Blanch Pedro , Soler-Soler J.
Published: June 2012

Background
Myocardial dysfunction elicited during cholinergic coronary vasospasm is generally ascribed to myocardial ischemia. However, when pericoronary nerves extend to the ventricles, efferent vagal discharges that elicit coronary vasoconstriction may, at the same time, depress myocardial contractility by releasing acetylcholine into the myocardium. We analyzed whether a neurally mediated effect contributes to impairment of ventricular function during cholinergic coronary vasoconstriction.

Methods and Results
Left ventricular (LV) function, ECG mapping, and coronary angiography were analyzed during pericoronary application of methacholine (MCh) to the left anterior descending coronary artery in 53 chloralose-anesthetized open-chest pigs. MCh induced local coronary vasoconstriction and depressed coronary blood flow (13.3±3.7 to 6.0±4.6 mL/min [54%]; ANOVA,
P
<.001), systolic LV pressure (105±10 to 91±10 mm Hg [13%],
P
<.001), peak LV (+)dP/dt (2890±524 to 2270±447 mm Hg/s [21%],
P
<.001), peak LV (−)dP/dt (1446±484 to 1048±276 mm Hg/s [27%],
P
<.001), and regional systolic segment shortening (0.32±0.09% to 0.18±0.14% [43%],
P
=.02) and caused local ST-segment elevation (0.9±0.8 to 8.4±3.9 mV,
P
<.001). These changes were not preceded by heart rate variations, were reproducible, and were inhibited by atropine. MCh during perfusion of nitroglycerin (2 μg·kg
−
1
·min
−
1
IV) continued to depress LV pressure (9%,
P
=.002), LV (+)dP/dt (16%,
P
<.01), LV (−)dP/dt (20%,
P
<.01), and segment shortening (18%,
P
=.03) even though coronary blood flow drop was markedly attenuated (7% versus 54%; ANOVA,
P
<.01). Disruption of pericoronary nerves with phenol attenuated MCh-induced LV pressure fall (
P
<.05). Histological data show that cholinergic and adrenergic pericoronary nerves extend into the ventricular myocardium.

Conclusions
A neurally mediated effect, in addition to ischemia, impairs LV function during cholinergic coronary constriction in a model with pericoronary nerves extending into the ventricles.
Transthoracic Echocardiography in Models of Cardiac Disease in the Mouse
Authors: Tanaka Nobuaki , Dalton Nancy , Mao Lan , Rockman Howard A. , Peterson Kirk L. , Gottshall Kim R. , Hunter John J. , Chien Kenneth R. , Ross John
Published: June 2012

Background
Transthoracic echocardiography (M-mode and Doppler) offers a noninvasive approach for in vivo evaluation of the mouse heart. The present study examines its usefulness for assessing the morphological/functional phenotype of the left ventricle (LV) in several transgenic and surgical murine models of cardiac disease.

Methods and Results
Observations were made in 83 intact, anesthetized mice. In mice with a surgical arteriovenous fistula, volume overload and LV dilation were detected. In normal mice, echocardiographic indexes of increased contractility (dobutamine) were confirmed by LV dP/dt
max
. In transgenic mice with overexpression of the β
2
-adrenergic receptor, heart rate and mean velocity of circumferential fiber shortening were increased, indicating enhanced contractility. In colony screening of transgenic mice overexpressing the H-
ras
gene, 45% had increased LV wall thickness (>0.9 mm), and those showing a striking increase were selected for breeding. In mice with LV hypertrophy (aortic constriction) and normal mice, the actual LV mass determined by echocardiography correlated well (
r
=.93), and 95% confidence limits were determined. The maximum intraobserver and interobserver coefficients of variation for M-mode data were 0.03±0.29 mm (±2 SD), <10% for LV internal dimensions but 27% to 30% for wall thickness.

Conclusions
These studies provide the first application of transthoracic echocardiography for morphological/functional characterization of the cardiac phenotype in transgenic and surgical murine models, including (1) high reliability for detecting LV chamber dilation and function; (2) reliability (and its limits) for determining abnormal LV wall thickness and LV mass; (3) identification of marked, sometimes asymmetrical, hypertrophy in a transgenic model of hypertrophic cardiomyopathy; and (4) usefulness for transgenic colony screening to identify markedly abnormal phenotypes.
Elevated Levels of Interleukin-6 in Unstable Angina
Authors: Biasucci Luigi M. , Vitelli Alessandra , Liuzzo Giovanna , Altamura Sergio , Caligiuri Giuseppina , Monaco Claudia , Rebuzzi Antonio G. , Ciliberto Gennaro , Maseri Attilio
Published: June 2012

Background
Elevated plasma levels of C-reactive protein have been found in the majority of patients with unstable angina. The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence that suggests that inflammation plays a role in this syndrome and is an indirect sign of increased production of interleukin-6, which is the major determinant of acute-phase–protein production by the liver. However, in unstable angina, there is no direct proof of the role played by interleukin-6.

Methods and Results
We measured levels of interleukin-6 in 38 patients with unstable angina at the time of their admission to the coronary care unit and in 29 patients with stable angina. In the same groups of patients, we also measured C-reactive protein. Interleukin-6 (undetectable, ie, <3 pg/mL, in healthy volunteers) was detectable in 23 (61%) of 38 patients with unstable angina but in only 6 (21%) of 29 with stable angina (
P
<.01). Median interleukin-6 levels were 5.25 pg/mL (range, 0 to 90 pg/mL) in patients with unstable angina but were below the detection limit of the assay in patients with stable angina (range, 0 to 7 pg/mL). A significant correlation was observed between interleukin-6 and C-reactive protein levels (
r
=.4,
P
=.013).

Conclusions
Our study demonstrates that raised levels of interleukin-6 are common in unstable angina, correlate with C-reactive protein, and are associated with prognosis, thus confirming the importance of the cytokine pathway for the production by the liver of acute-phase proteins and strengthening the importance of inflammation in this syndrome. Further studies are required to elucidate better the role of interleukins in unstable angina.
Randomized Comparison of Coronary Thrombolysis Achieved With Double-Bolus Reteplase (Recombinant Plasminogen Activator) and Front-Loaded, Accelerated Alteplase (Recombinant Tissue Plasminogen Activator) in Patients With Acute Myocardial Infarction
Authors: Bode Christoph , Smalling Richard W. , Berg Gunther , Burnett Curtis , Lorch Gerald , Kalbfleisch John M. , Chernoff Robert , Christie Leonard G. , Feldman Robert L. , Seals A. Allen , Weaver W. Douglas
Published: June 2012

Background
The therapeutic benefit of thrombolytic therapy has been shown to correlate directly with completeness (TIMI grade 3 flow) and speed of reperfusion of the infarct-related coronary artery. The purpose of the RAPID II study was to determine whether a double-bolus regimen of reteplase, a recently developed deletion mutant of wild-type tissue plasminogen activator, could improve 90-minute coronary artery patency rates achieved with the most successful standard regimen, an “accelerated” front-loaded infusion of alteplase.

Methods and Results
Three hundred twenty-four patients with acute myocardial infarction were randomized to receive (along with intravenous heparin and aspirin) either a 10 plus 10 megaunits double bolus of reteplase or front-loaded alteplase. The primary end point of “patency at 90 minutes, graded according to the TIMI classification” was centrally assessed in a blinded fashion. Infarct-related coronary artery patency (TIMI grade 2 or 3) and complete patency (TIMI grade 3) at 90 minutes after the start of thrombolytic therapy were significantly higher in the reteplase-treated patients (TIMI grade 2 or 3: 83.4% versus 73.3% for front-loaded alteplase-treated patients,
P
=.03; TIMI grade 3: 59.9% versus 45.2%,
P
=.01). At 60 minutes, the incidence of both, patency and complete patency, was also significantly higher in reteplase-treated patients (reteplase versus alteplase, TIMI grade 2 or 3: 81.8% versus 66.1%,
P
=.01; TIMI grade 3: 51.2% versus 37.4%,
P
<.03). Reteplase-treated patients required fewer acute additional coronary interventions (13.6% versus 26.5%,
P
<.01), and 35-day mortality was 4.1% for reteplase and 8.4% for alteplase (
P
=NS). There were no significant differences between reteplase and alteplase in bleedings requiring a transfusion (12.4% versus 9.7%) or hemorrhagic stroke (1.2% versus 1.9%).

Conclusions
Reteplase, when given as a double bolus of 10 plus 10 megaunits to patients with acute myocardial infarction, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and requires significantly fewer acute coronary interventions than front-loaded alteplase without an apparent increased risk of complications.
Blunted Coronary Reserve in Myotonic Dystrophy An Early and Gene-Related Phenomenon
Authors: Annane Djillali , Merlet Pascal , Radvanyi He´le`ne , Mazoyer Bernard , Eymard Bruno , Fiorelli Marco , Junien Claudine , Fardeau Michel , Ounnoughene Zine , Gajdos Philippe , Syrota Andre´ , Duboc Denis
Published: June 2012

Background
In myotonic dystrophy (DM), striated muscle is involved in relation to the size of the DNA mutation. Smooth muscle may be similarly impaired at the level of the urinary and digestive apparatus and possibly at the level of small vessels, since microangiopathy has been described in the iris and digital capillaries. Our purpose was to study the function of the myocardial microvasculature in relation to the size of the mutation in DM patients without clinical cardiac involvement and with normal left ventricular dimensions and function and normal large coronary arteries.

Methods and Results
In 6 control subjects and 10 DM patients, we investigated the coronary blood flow reserve using positron emission tomography with
15
O-labeled water. Global and regional flow reserves were obtained from myocardial regions of interest manually drawn on a static FDG image encompassing, respectively, the whole left ventricle and the anterior, septal, and lateral walls. The DNA mutation size was determined on circulating lymphocytes in each DM patient. Compared with control subjects, DM patients had decreased global (2.39±0.39 versus 4.00±0.67,
P
=.00003) and regional (anterior, 2.39±0.64 versus 3.87±0.92,
P
=.002; septal, 2.60±0.48 versus 4.00±0.70,
P
=.0003; lateral, 2.26±0.58 versus 4.16±1.11,
P
=.0005) coronary reserves. In DM patients, the coronary reserve correlated strongly and inversely with the DNA mutation size (
r
=−.77,
P
=.009).

Conclusions
The study demonstrated that global and regional coronary reserves are impaired, in relation to the DNA mutation size, in symptom-free DM patients with normal ventricular dimensions and function and normal large coronary vessels. We suggest that a gene-related blunted coronary reserve resulting from an impairment of vascular smooth muscle is an early component of DM cardiomyopathy.
Increased Neutrophil-Platelet Adhesion in Patients With Unstable Angina
Authors: Ott I. , Neumann F.-J. , Gawaz M. , Schmitt M. , Scho¨mig A.
Published: June 2012

Background
Neutrophil-platelet adhesion may occur as a consequence of platelet activation. The role of this heterotypic adhesion in ischemic disorders is poorly understood thus far.

Methods and Results
Systemic venous blood samples were taken from 25 patients with stable angina pectoris and 25 patients with unstable angina pectoris. Neutrophil activation and neutrophil-platelet adhesion were evaluated by two-color flow cytometry. Patients with unstable angina showed a significant increase in neutrophil-platelet adhesion compared with patients with stable angina (mean±SEM, 132.1±20.5 versus 29.8±4.7 anti-glycoprotein IIb/IIIa mean fluorescence intensity,
P
=.0001). Systemic neutrophil activation was found in patients with unstable angina compared with those with stable angina assessed by cell surface CD11b expression and shedding of L-selectin (115.6±10.3 versus 74.0±6.3 anti-CD11b mean fluorescence intensity,
P
=.002; 49.8±6.0 versus 72.1±4.0 anti–L-selectin mean fluorescence intensity,
P
=.006). Markers of neutrophil activation were related to the extent of neutrophil-platelet adhesion (CD11b:
r
=.5,
P
=.0005; L-selectin:
r
=.42,
P
=.012). In vitro studies revealed that binding of purified platelet membranes to control neutrophils caused a dose-dependent increase in CD11b surface expression, a decrease in surface L-selectin, and the release of superoxide anions.

Conclusions
Thus, this study demonstrates that increased neutrophil-platelet adhesion may contribute to neutrophil activation in unstable angina.
Luminal Foam Cell Accumulation Is Associated With Smooth Muscle Cell Death in the Intimal Thickening of Human Saphenous Vein Grafts
Authors: Kockx Mark M. , De Meyer Guido R.Y. , Bortier Hilde , de Meyere Nathan , Muhring Johannes , Bakker Annette , Jacob Willem , Van Vaeck Luc , Herman Arnold
Published: June 2012

Background
Occlusion of saphenous vein grafts is a major problem after coronary artery bypass graft surgery. Diffuse intimal thickening develops in all implanted aortocoronary saphenous vein grafts within 6 months to 1 year. In some regions of the thickened intima, foam cells accumulate along the luminal margin. This particular morphology resembles the morphology of unstable atherosclerotic plaques as they occur in coronary arteries. In the present study, we focused on the possible topographic relation between luminal foam cell accumulation and cell death of smooth muscle cells (SMCs) within the adjacent thickened intima.

Methods and Results
Segments of occluded and suboccluded implanted human aortocoronary saphenous vein grafts were obtained during reintervention coronary artery bypass graft surgery in 30 patients. In the regions of the vein grafts with luminal foam cell accumulation, the percentage of SMC α-actin immunoreactive area of the superficial intimal thickening was 6±1.4%, which was different from the 17.6±2.3% of the deep intimal thickening. A strong negative correlation between the number of foam cell nuclei and the percentage of SMC α-actin immunoreactive area in the adjacent superficial intimal thickening was present (
r
=−.77,
P
<.001). Within the superficial intimal thickening, cytoplasmic and DNA fragmentation could be detected, which points to apoptotic cell death. A fraction of the cytoplasmic fragments fitted the ultrastructural characteristics of matrix vesicles and showed pronounced calcium and phosphorus accumulation as demonstrated with the use of x-ray microanalysis.

Conclusions
The close spatial relation among foam cell accumulation, pronounced intimal SMC loss, and cell death suggests the presence of a foam cell–derived factor that can induce cell death in the SMC population of the intimal thickening. The depletion of the intimal SMC population could promote plaque rupture and thrombotic complications in the grafts.
Chronic Hyperglycemia Impairs Endothelial Function and Insulin Sensitivity Via Different Mechanisms in Insulin-Dependent Diabetes Mellitus
Authors: Ma¨kimattila Sari , Virkama¨ki Antti , Groop Per-Henrik , Cockcroft John , Utriainen Tapio , Fagerudd Johan , Yki-Ja¨rvinen Hannele
Published: June 2012

Background
We explored whether chronic hyperglycemia is associated with defects in endothelium-dependent vasodilatation in vivo and whether defects in the hemodynamic effects of insulin explain insulin resistance.

Methods and Results
Vasodilator responses to brachial artery infusions of acetylcholine, sodium nitroprusside, and
N
G
-monomethyl-
l
-arginine and, on another occasion, in vivo insulin sensitivity (euglycemic insulin clamp combined with the forearm catheterization technique) were determined in 18 patients with insulin-dependent diabetes mellitus (IDDM) and 9 normal subjects. At identical glucose and insulin levels, insulin stimulation of whole-body and forearm glucose uptake was 57% reduced in the IDDM patients compared with normal subjects (
P
<.001). The defect in forearm glucose uptake was attributable to a defect in glucose extraction (glucose AV difference, 1.1±0.2 versus 1.9±0.2 mmol/L,
P
<.001, IDDM versus normal subjects), not blood flow. Within the group of IDDM patients, hemoglobin A
1c
was inversely correlated with forearm blood flow during administration of acetylcholine (
r
=−.50,
P
<.02) but not sodium nitroprusside (
r
=.07). The ratio of endothelium-dependent to endothelium-independent blood flow was ≈40% lower in patients with poor glycemic control than in normal subjects or patients with good or moderate glycemic control.

Conclusions
We conclude that chronic hyperglycemia is associated with impaired endothelium-dependent vasodilatation in vivo and with a glucose extraction defect during insulin stimulation. These data imply that chronic hyperglycemia impairs vascular function and insulin action via distinct mechanisms. The defect in endothelium-dependent vasodilatation could contribute to the increased cardiovascular risk in diabetes.
Tonic Chemoreflex Activation Does Not Contribute to Elevated Muscle Sympathetic Nerve Activity in Heart Failure
Authors: van de Borne Philippe , Oren Ron , Anderson Erling A. , Mark Allyn L. , Somers Virend K.
Published: June 2012

Background
Sympathetic activation in heart failure may be due to an increase in sympathetic excitatory influences or to a decrease in inhibitory signals to the brain stem. Chemoreflex sensitivity may be increased in patients with heart failure. The present study tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in heart failure.

Methods and Results
We recorded sympathetic nerve activity to muscle circulation from the peroneal nerve of 12 chronic heart failure patients while the patients were breathing room air and during deactivation of the chemoreceptors while the patients were breathing a 100% O
2
gas mixture. All patients except 2 were in class III of the New York Heart Association functional classification. Left ventricular ejection fraction defined by radionuclide ventriculography was 24±2% (mean±SE). We also obtained measurements of resting sympathetic nerve activity in 9 healthy control subjects to document that sympathetic nerve activity was elevated in heart failure subjects. Resting sympathetic nerve activity was 59±5 bursts/min in heart failure patients versus 36±4 bursts/min in control subjects (
P
<.01). In heart failure patients, oxygen administration increased oxygen saturation from 94±0.9% to 99±0.3% (
P
<.0001). This increase in oxygen saturation did not affect resting muscle sympathetic nerve activity (798±122 U/min while patients breathed room air and 824±35 U/min during 100% O
2
breathing) or blood pressure.

Conclusions
Increased efferent sympathetic activity to muscle circulation in patients with heart failure is not explained by tonic activation of excitatory chemoreflex afferents.