bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Sensitivity to Nitric Oxide Synthase Inhibition in Patients With Heart Failure
Authors: Hare Joshua M. , Givertz Michael M. , Creager Mark A. , Colucci Wilson S.
Published: June 2012

Background
—We previously showed that cardiac nitric oxide (NO) inhibits the positive inotropic response to β-adrenergic stimulation in humans with left ventricular (LV) dysfunction. Whether this effect is specific to heart failure per se or is a generalized feature of normal human myocardium is unknown. We therefore tested the hypothesis that inhibition of cardiac NO potentiates the positive inotropic response to β-adrenergic stimulation in patients with symptomatic LV failure but not in subjects with normal LV function.

Methods and Results
—We studied 11 patients with LV failure due to idiopathic dilated cardiomyopathy and 7 control subjects with normal LV function. The β-adrenergic agonist dobutamine was infused via a peripheral vein before and during concurrent intracoronary artery infusion of acetylcholine, which activates the agonist-coupled isoforms of NO synthase, and
N
G
-monomethyl-
l
-arginine, which inhibits all isoforms of NO synthase. Changes in contractility were assessed by measuring the peak rate of rise of LV pressure (+dP/dt). Dobutamine increased +dP/dt by 40±6% and 73±14% in patients with heart failure and control subjects, respectively. Acetylcholine inhibited the +dP/dt response to dobutamine to a similar degree in patients with heart failure and control subjects (−39±8% and −31±4%, respectively;
P
=NS). Infusion of
N
G
-monomethyl-
l
-arginine potentiated the +dP/dt response to dobutamine by 51±15% (
P
=.01 versus dobutamine) in patients with heart failure but had no effect in control subjects (−6±4%;
P
=NS versus dobutamine;
P
=.0002 versus heart failure patients).

Conclusions
—Inhibition of cardiac NO augments the positive inotropic response to β-adrenergic receptor stimulation in patients with heart failure due to idiopathic dilated cardiomyopathy but not in control subjects with normal LV function.
Body Weight Reduction, Sympathetic Nerve Traffic, and Arterial Baroreflex in Obese Normotensive Humans
Authors: Grassi Guido , Seravalle Gino , Colombo Manuela , Bolla Giambattista , Cattaneo Bianca M. , Cavagnini Francesco , Mancia Giuseppe
Published: June 2012

Background
—Previous studies have shown that sympathetic cardiovascular outflow is increased in obese normotensive subjects and that this increase is associated with a baroreflex impairment. The purpose of this study was to determine whether these abnormalities are irreversible or can be favorably affected by body weight reduction.

Methods and Results
—In 20 obese normotensive subjects (age, 31.3±1.7 years; body mass index, 37.6±0.9 kg/m
2
, mean±SEM), we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (ECG), postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography) at rest and during baroreceptor stimulation and deactivation induced by increases and reductions of blood pressure via stepwise intravenous infusions of phenylephrine and nitroprusside. Measurements were repeated in 10 subjects after a 16-week hypocaloric diet with normal sodium content (4600 to 5000 J and 210 mmol NaCl/d) and in the remaining 10 subjects after a 16-week observation period without any reduction in the caloric intake. The hypocaloric diet significantly reduced body mass index, slightly reduced blood pressure, and caused a significant and marked decrease in both muscle sympathetic nerve activity (from 50.0±5.1 to 32.9±4.6 bursts per 100 heart beats,
P
<.01) and plasma norepinephrine (from 356.2±43 to 258.4±29 pg/mL,
P
<.05). This was associated with a significant improvement in the sensitivity of the baroreceptor heart rate (+71.5±11%,
P
<.01) and muscle sympathetic nerve activity (+124.5±22%,
P
<.001) reflex. Total body glucose uptake also increased significantly (+60.8±12.0%,
P
<.05), indicating an increase in insulin sensitivity. All variables remained unchanged in subjects not undergoing caloric restriction.

Conclusions
—In obese normotensive subjects, a reduction in body weight induced by a hypocaloric diet with normal sodium content exerts a marked reduction in sympathetic activity owing to central sympathoinhibition. This can be due to the consequences of an increased insulin sensitivity but also to a restoration of the baroreflex control of the cardiovascular system with weight loss.
Reduced Penetrance, Variable Expressivity, and Genetic Heterogeneity of Familial Atrial Septal Defects
Authors: Benson D. Woodrow , Sharkey Angela , Fatkin Diane , Lang Peter , Basson Craig T. , McDonough Barbara , Strauss Arnold W. , Seidman J. G. , Seidman Christine E.
Published: June 2012

Background
—Secundum atrial septal defect (ASD) is a common congenital heart malformation that occurs as an isolated anomaly in 10% of individuals with congenital heart disease. Although some embryological pathways have been elucidated, the molecular etiologies of ASD are not fully understood. Most cases of ASD are isolated, but some individuals with ASD have a family history of this defect or other congenital heart malformations.

Methods and Results
—Clinical evaluation of three families identified individuals with ASD in multiple generations. ASD was transmitted as an autosomal dominant trait in each family. ASD was the most common anomaly, but other heart defects occurred alone or in association with ASD in individuals from each kindred. Genome-wide linkage studies in one kindred localized a familial ASD disease gene to chromosome 5p (multipoint LOD score=3.6, θ=0.0). Assessment of 20 family members with the disease haplotype revealed that 9 had ASD, 8 were clinically unaffected, and 3 had other cardiac defects (aortic stenosis, atrial septal aneurysm, and persistent left superior vena cava). Familial ASD did not map to chromosome 5p in two other families.

Conclusions
—Familial ASD is a genetically heterogeneous disorder; one disease gene maps to chromosome 5p. Recognition of the heritable basis of familial ASD is complicated by low disease penetrance and variable expressivity. Identification of ASD or other congenital heart defects in more than one family member should prompt clinical evaluation of all relatives.
Exacerbated Transplant Arteriosclerosis in Inducible Nitric Oxide–Deficient Mice
Authors: Koglin J örg , Glysing-Jensen Troels , Mudgett John S. , Russell Mary E.
Published: June 2012

Background
—Inducible NO synthase (NOS2, or iNOS) is upregulated in grafts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclear. NOS2 may regulate lesion development by modulating the early alloimmune response and/or late myointimal thickening.

Methods and Results
—To determine whether NOS2-mediated pathways protect against or promote transplant arteriosclerosis, we used NOS2-deficient mice as recipients in our vascularized chronic cardiac rejection model. The severity of vascular thickening in 55-day grafts placed into NOS2 −/− recipients (n=13) was compared with that in wild-type recipients (n=15). Computer-assisted analysis of all elastin-stained vessels (n=283) showed significantly increased luminal occlusion (77.1±9.4% versus 40.8±13.6%,
P
<.0001) and intima/media ratios in allografts from NOS2 −/− recipients (1.9±1.3 versus 0.4±0.3,
P
=.0002). To elucidate potential mechanisms, we studied NOS2 effects on T-cell differentiation (Th
1
/Th
2
) and neointimal smooth muscle cell accumulation. Normalized mRNA levels for Th
1
- (signal transducer and activator of transcription [STAT] 4, interleukin [IL]-2, interferon-γ) and Th
2
- (STAT 6, IL-4, and IL-5) associated factors were comparable in both groups. In contrast, quantitative analysis of the α-actin–positive area showed a significant increase in the contribution of smooth muscle cells within the neointima in allografts from NOS2 −/− recipients (28.2±2.0%) compared with wild-type controls (13.2±2.3%;
P
<.0001).

Conclusions
—NOS2 plays a protective role in the development of transplant arteriosclerosis, suppressing neointimal smooth muscle cell accumulation.
Public Locations of Cardiac Arrest
Authors: Becker Linda , Eisenberg Mickey , Fahrenbruch Carol , Cobb Leonard
Published: June 2012

Background
—The purpose of this study was to describe the public locations of cardiac arrest and to estimate the annual incidence of cardiac arrest per site to determine optimal placement of automatic external defibrillators (AEDs). This was a retrospective cohort study.

Methods and Results
—Locations of cardiac arrest were abstracted from data collected by emergency medical service programs in Seattle and King County, Washington, from January 1, 1990, through December 31, 1994. Types of commercial and civic establishments were tallied and grouped into 23 location categories consistent with Standard Industrial Codes, and the number of sites within each location category was determined. With the addition of “public outdoors” and “automobiles” as categories, there were 25 location categories. During the study period, 7185 arrests occurred, 1130 (16%) of which were in public locations. An annual incidence of cardiac arrest per site was calculated. Ten location categories with 172 sites were identified as having a higher incidence of cardiac arrest (≥.03 per year per site). Thirteen location categories had a lower incidence of arrest (≤.01 per year per site). There were ≈71 000 sites within these categories.

Conclusions
—Placement of 276 AEDs in the 172 higher-incidence sites would have provided treatment for 134 cardiac arrest patients in a 5-year period, 60% of whom were in ventricular fibrillation. We estimate between 8 and 32 lives could be saved in 5 years. To cover the remaining 347 arrests occurring in public in a 5-year period, defibrillators would have to be placed in 71 000 sites, not including outdoors and automobiles. Placement of AEDs in public locations can be guided by the site-specific incidence of arrest.
Mechanism of β-Adrenergic Receptor Upregulation Induced by ACE Inhibition in Cultured Neonatal Rat Cardiac Myocytes
Authors: Yonemochi Hidetoshi , Yasunaga Seikoh , Teshima Yasusi , Iwao Tetsu , Akiyoshi Kumiko , Nakagawa Mikiko , Saikawa Tetsunori , Ito Morio
Published: June 2012

Background
—Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of β-adrenergic receptors (β-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes.

Methods and Results
—The density of β-ARs on the myocyte surface was determined with a binding assay with [
3
H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 μmol/L) increased β-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT
1
) receptor antagonist, CV-11974, nor angiotensin-I affected β-AR density. However, the bradykinin B
2
receptor antagonist Hoe 140 abolished the effect of captopril on β-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 nmol/L) but neither indomethacin nor L-NAME also inhibited captopril-induced upregulation of β-ARs. Exogenous bradykinin increased the spontaneous beating frequency of cultured myocytes and Hoe 140 abolished this effect. Bradykinin level in the medium increased 1.4-fold by the treatment of cultured myocytes with captopril for 24 hours.

Conclusions
—The results suggest that captopril enhances β-AR responsiveness by inducing β-AR upregulation and that the latter effect is mediated by activation of bradykinin B
2
receptors and protein kinase C. These observations also offer insight into the different roles of ACE inhibitors and AT
1
receptor antagonists in the treatment of heart failure.
99m
Tc-HL91
Authors: Okada Robert D. , Johnson Gerald , Nguyen Kiem N. , Liu Zhonglin , Edwards Barbara , Archer Colin M. , North Timothy L. , King Adam C. , Kelly James D.
Published: June 2012

Background
—
99m
Tc-HL91 is a new hypoxia imaging agent that demonstrates increased uptake and retention in globally hypoxic myocardium in vitro. The purpose of this study was to determine whether
99m
Tc-HL91 could detect regional ischemia in vivo by gamma camera imaging.

Methods and Results
—Eight open-chest dogs with left circumflex (LCx) stenoses were studied. Injection of 5 mCi of
99m
Tc-HL91 and microspheres was followed by imaging over 4 hours. Heart slices were imaged, then stained with triphenyltetrazolium chloride (TTC), and tissues were well-counted. TTC staining demonstrated no injury. Mean LCx blood flow was 0.32±0.04 mL · min
−1
· g
−1
, and mean left anterior descending coronary artery (LAD) flow was 0.96±0.02 mL · min
−1
· g
−1
(ratio, 0.33). “Hot spots” were detected in 8 of 8 experiments in vivo within 60 minutes and improved over 4 hours. Region of interest analysis of LCx/LAD activity ratios demonstrated significant increases within 30 minutes (final ratio, 3.0;
P
<0.05). LCx and LAD washout curves demonstrated significant differences within 15 minutes. Washout curves were biexponential over 1 hour, followed by linear retention from 1 to 4 hours. Four-hour fractional retention was 0.12 for LAD and 0.44 for LCx (
P
<0.01). Myocardial flow versus tracer uptake demonstrated 2 phases: phase 1 (flow, 0.05 to 0.7 mL · min
−1
· g
−1
) had an inverse linear correlation (
r
=−0.80); phase 2, (flow, >0.7 mL · min
−1
· g
−1
) had no correlation. Ischemic heart/liver ratios remained near 1.0 for 4 hours.

Conclusions
—
99m
Tc-HL91 positively identifies regional myocardial ischemia in a canine model using
99m
Tc imaging. Quantitative techniques allowed identification of ischemic myocardium within 15 minutes of tracer administration.
Role of Endothelin-A Receptors in Ischemic Contracture and Reperfusion Injury
Authors: Brunner Friedrich , Opie Lionel H.
Published: June 2012

Background
—Circulating endothelin (ET)-1 is elevated in ischemia/reperfusion and may exert proischemic effects. The aim of the present study was to characterize the effects of ET-1 in rat isolated hearts using subtype-selective ET receptor antagonists, agents modulating the cytosolic Ca
2+
concentration, or the activity of cGMP-dependent protein kinase.

Methods and Results
—Rat hearts perfused at constant pressure were made ischemic by reducing flow to 0.2 mL · min
-1
· g
−1
, followed by reperfusion at normal pressure (each phase, 25 minutes). Drugs were infused during the ischemic phase only. Parameters monitored were extent and time-to-onset of contracture in ischemia, left ventricular developed pressure (LVDevP), coronary flow (CF), and diastolic relaxation during reperfusion. The ET
A
receptor-selective antagonist PD 155080 (50 nmol/L) reduced peak ischemic contracture (−49%) and delayed its time to onset (+56%) and improved recovery of reperfusion LVDevP (+12%), CF (+16%), and diastolic relaxation (+50%). Infusion of an ET
A
/ET
B
-nonselective antagonist, PD 142893 (200 nmol/L), had similar effects on all parameters, whereas infusion of BQ-788 (20 nmol/L), an ET
B
receptor-selective antagonist, was without effect. Exogenous ET-1 (100 pmol/L) hastened contracture and increased its extent (+23%) and reduced recovery of both LVDevP (−31%) and CF (−18%), effects that were counteracted by HOE 642 (10 μmol/L), a Na
+
/H
+
exchange inhibitor, but not by nicardipine (30 μmol/L), a Ca
2+
entry blocker; activation of cGMP-dependent protein kinase by the cell-permeable cGMP analog Sp-8-p-chlorophenylthioguanosine-3’,5’-cyclic monophosphorothioate (10 μmol/L) improved function without preventing the effects of ET-1.

Conclusions
—The data indicate that ET-1 exacerbates ischemic contracture and worsens ventricular and coronary reperfusion dysfunction by activating ET
A
receptors via a mechanism likely involving activation of Na
+
/H
+
exchange in this model.
Prevention of Restenosis After Angioplasty in Small Coronary Arteries With Probucol
Authors: Rodés Josep , Côté Gilles , Lespérance Jacques , Bourassa Martial G. , Doucet Serge , Bilodeau Luc , Bertrand Olivier F. , Harel François , Gallo Richard , Tardif Jean-Claude
Published: June 2012

Background
—Restenosis remains the major limitation of coronary angioplasty. Coronary stents have reduced the incidence of restenosis in selected patients with relatively large vessels. No strategies to date have demonstrated a beneficial effect in vessels < 3.0 mm in diameter. We have shown in the MultiVitamins and Probucol (MVP) Trial that probucol, a potent antioxidant, reduces restenosis after balloon angioplasty. The purpose of this study was to determine whether the benefit of probucol therapy is maintained in the subgroup of patients with smaller coronary vessels.

Methods and Results
—We studied a subgroup of 189 patients included in the MVP trial who underwent successful balloon angioplasty of at least one coronary segment with a reference diameter < 3.0 mm. One month before angioplasty, patients were randomly assigned to one of four treatments: placebo, probucol (500 mg), multivitamins (beta-carotene 30 000 IU, vitamin C 500 mg, and vitamin E 700 IU), or probucol plus multivitamins twice daily. The treatment was maintained until follow-up angiography was performed at 6 months. The mean reference diameter of this study population was 2.49±0.34 mm. Lumen loss was 0.12±0.34 mm for probucol, 0.25±0.43 mm for the combined treatment, 0.35±0.56 mm for vitamins, and 0.38±0.51 mm for placebo (
P
=.005 for probucol). Restenosis rates per segment were 20.0% for probucol, 28.6% for the combined treatment, 45.1% for vitamins, and 37.3% for placebo (
P
=.006 for probucol).

Conclusions
—Probucol reduces lumen loss and restenosis rate after balloon angioplasty in small coronary arteries.
Regular Physical Activity and Coronary Risk Factors in Japanese Men
Authors: Hsieh Shiun Dong , Yoshinaga Hideyo , Muto Takashi , Sakurai Yutaka
Published: June 2012

Background
—Physical activity decreases the risk of coronary heart disease (CHD), but its effects on risk factors require further exploration.

Methods and Results
—The study included 3331 adult Japanese men in whom health benefits, especially CHD risk factors, were compared among those who were sedentary and those who were engaged in continuous physical activity of 30 minutes or more per day for 1, 2 and ≥3 days per week. Significantly higher HDL cholesterol values; lower triceps, scapula, and iliac subcutaneous fat thickness; and lower smoking rates were noted in all physically active groups compared with the sedentary group, whereas body mass index did not differ significantly. Waist-to-height ratios and the prevalence of fatty liver were significantly lower in the groups who exercised 2 or ≥3 days per week than in the sedentary group. The lowest triglyceride values were noted in the group who exercised ≥3 days per week. Multiple regression analysis revealed both the frequency of physical activity and smoking status to be independent positive and negative factors, respectively, for the HDL cholesterol value. The sum of the risk factor scores for hypertension, abnormal glucose tolerance, hypertriglyceridemia, hypercholesterolemia, and low HDL cholesterol level (one point for each if present) was highest in the sedentary group (1.38, 1.19, 1.19, 0.99 for the sedentary group and the groups who exercised 1, 2, and ≥3 days per week).

Conclusions
—Those who engaged in regular physical activity ≥3 days per week appeared to have the fewest coronary risk factors. However, even those engaged in physical activity once per week had fewer CHD risk factors than sedentary individuals.
Arginine Vasopressin Enhances Sympathetic Constriction Through the V
1
Vasopressin Receptor in Human Saphenous Vein
Authors: Medina Pascual , Acuña Antonio , Martínez-León Juan B. , Otero Eduardo , Vila José M. , Aldasoro Martín , Lluch Salvador
Published: June 2012

Background
—Arginine vasopressin (AVP) not only acts directly on blood vessels through V
1
receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vivo and in vitro. The aim of the present study was to investigate whether AVP can contribute to an abnormal adrenergic constrictor response of human saphenous veins.

Methods and Results
—Saphenous vein rings were obtained from 32 patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. AVP (3×10
−9
mol/L) enhanced the contractions elicited by electrical field stimulation at 1, 2, and 4 Hz (by 80%, 70%, and 60%, respectively) and produced a leftward shift of the concentration-response curve to norepinephrine (half-maximal effective concentration decreased from 6.87×10
−7
to 1.04×10
−7
mol/L;
P
<.05). The V
1
vasopressin receptor antagonist d(CH
2
)
5
Tyr(Me)AVP (10
−6
mol/L) prevented the potentiation evoked by AVP. The selective V
1
receptor agonist [Phe,
2
Orn
8
]-vasotocin (3×10
−9
mol/L) induced potentiation of electrical stimulation–evoked responses, which was also inhibited in the presence of the V
1
receptor antagonist (10
−6
mol/L). In contrast, the V
2
receptor agonist desmopressin (10
−9
to 10
−7
mol/L) did not modify neurogenic responses, and the V
2
receptor antagonist [d(CH
2
)
5
, D-Ile,

2

Ile,

4

Arg
8
]-vasopressin (10
−8
to 10
−6
mol/L) did not prevent the potentiation induced by AVP. The dihydropyridine calcium antagonist nifedipine (10
−6
mol/L) did not affect the potentiating effect of AVP.

Conclusions
—The results suggest that low concentrations of AVP facilitate sympathetic neurotransmission and potentiate constrictor effects of norepinephrine in human saphenous veins. These effects appear to be mediated by V
1
receptor stimulation and are independent of calcium entry through dihydropyridine calcium channels. Thus, AVP may contribute to vascular mechanisms involved in acute ischemic syndromes associated with venous grafts, particularly if the sympathetic nervous system is activated.
β
3
Integrins Are Upregulated After Vascular Injury and Modulate Thrombospondin- and Thrombin-Induced Proliferation of Cultured Smooth Muscle Cells
Authors: Stouffer George A. , Hu Zhaoyong , Sajid Mansoor , Li Husong , Jin Guifang , Nakada Marian T. , Hanson Stephen R. , Runge Marschall S.
Published: June 2012

Background
—Treatment with an antibody that binds β
3
integrins (abciximab; c7E3 Fab) at the time of coronary angioplasty decreases the need for repeat revascularization. Two potential mechanisms have been proposed to explain this effect: (1) inhibition of platelet aggregation or (2) interruption of ligand binding to β
3
integrins on the smooth muscle cell (SMC) surface. We examined the latter hypothesis by determining (1) if β
3
integrin expression is upregulated after vascular injury in the baboon, (2) if 7E3 binds β
3
integrins on cultured SMC, and (3) if β
3
integrin activation plays a role in proliferation of cultured SMC.

Methods and Results
—Results demonstrated that immunostaining for β
3
integrins was present in the neointima 1 week after balloon withdrawal injury of baboon brachial arteries and that β
3
integrin expression colocalized with α-actin–positive cells. In contrast, staining for β
3
integrins was undetectable in contralateral uninjured brachial arteries. 7E3 bound to cultured human aortic SMC with an affinity (
K
D
=3.3 nmol/L) similar to 7E3 binding to endothelial cells or platelets. Cotreatment with 7E3 partially inhibited thrombospondin-induced or α-thrombin–induced proliferation but not PDGF-induced or serum-induced proliferation.

Conclusions
—In summary, these studies demonstrate that vascular cell β
3
integrin expression is increased after injury, that 7E3 binds to cultured SMC with high affinity, and that β
3
activation is important for thrombospondin-induced or α-thrombin–induced proliferation. These results support the hypothesis that β
3
integrins play a role in SMC growth responses after balloon injury.
Coronary Side-Effect Potential of Current and Prospective Antimigraine Drugs
Authors: MaassenVanDenBrink Antoinette , Reekers Marije , Bax Willem A. , Ferrari Michel D. , Saxena Pramod R.
Published: June 2012

Background
—The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan).

Methods and Results
—Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (E
max
) and the concentration eliciting 50% of E
max
(EC
50
). The EC
50
values were related to maximum plasma concentrations (C
max
) reported in patients, obtaining C
max
/EC
50
ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the receptor biophase. Compared with sumatriptan, all drugs were more potent (lower EC
50
values) in contracting the coronary artery but had similar efficacies (E
max
<25% of K
+
-induced contraction). The C
max
of avitriptan was 7- to 11-fold higher than its EC
50
value, whereas those of the other drugs were <40% of their respective EC
50
values. The contractile responses to ergotamine and dihydroergotamine persisted even after repeated washings, but those to the other drugs declined rapidly after washing.

Conclusions
—All current and prospective antimigraine drugs contract the human coronary artery in vitro, but in view of low efficacy, these drugs are unlikely to cause myocardial ischemia at therapeutic plasma concentrations in healthy subjects. In patients with coronary artery disease, however, these drugs must remain contraindicated. The sustained contraction by ergotamine and dihydroergotamine seems to be an important disadvantage compared with sumatriptan-like drugs.
High-Resolution, Three-dimensional Fluorescent Imaging Reveals Multilayer Conduction Pattern in the Atrioventricular Node
Authors: Efimov Igor R. , Mazgalev Todor N.
Published: June 2012

Background
—The atrioventricular node (AVN) is the only normal electrical link between the upper and lower chambers of the heart. The AVN modulates transmission of impulses, thus coordinating the contraction of the atria and ventricles.

Methods and Results
—Structural and functional complexity, combined with the absence of adequate experimental techniques, has complicated attempts to directly evaluate the three-dimensional electrical activity of the AVN. Thus, despite a century of research by conventional electrophysiologic and histologic methods, even the existence of conduction through AVN is still debated.

Conclusions
—Using a novel combination of microelectrode recordings and high resolution fluorescent imaging with voltage-sensitive dyes, we have for the first time clearly demonstrated three-dimensional conduction through the AVN.
Magnitude and Time Course of Microvascular Obstruction and Tissue Injury After Acute Myocardial Infarction
Authors: Rochitte Carlos E. , Lima João A. C. , Bluemke David A. , Reeder Scott B. , McVeigh Elliot R. , Furuta Toshiya , Becker Lewis C. , Melin Jacques A.
Published: June 2012

Background
—Microvascular obstruction within an area of myocardial infarction indicates worse functional recovery and a higher risk of postinfarction complications. After prolonged coronary occlusion, contrast-enhanced MRI identifies myocardial infarction as a hyperenhanced region containing a hypoenhanced core. Because the time course of microvascular obstruction after infarction/reperfusion is unknown, we examined whether microvascular obstruction reaches its full extent shortly after reperfusion or shows significant progression over the following 2 days.

Methods and Results
—Seven dogs underwent 90-minute balloon occlusion of the left anterior descending coronary artery (LAD) followed by reflow. Gadolinium-DTPA–enhanced MRI performed at 2, 6, and 48 hours after reperfusion was compared with radioactive microsphere blood flow (MBF) measurements and myocardial staining to define microvascular obstruction (thioflavin S) and infarct size (triphenyltetrazolium chloride, TTC). The MRI hypoenhanced region increased 3-fold during 48 hours after reperfusion (3.2±1.8%, 6.7±4.4%, and 9.9±3.2% of left ventricular mass at 2, 6, and 48 hours, respectively,
P
<0.03) and correlated well with microvascular obstruction (MBF <50% of remote region,
r
=0.99 and thioflavin S,
r
=0.93). MRI hyperenhancement also increased (21.7±4.0%, 24.3±4.6%, and 28.8±5.1% at 2, 6, and 48 hours,
P
<0.006) and correlated well with infarct size by TTC (
r
=0.92). The microvascular obstruction/infarct size ratio increased from 13.0±4.8% to 22.6±8.9% and to 30.4±4.2% over 48 hours (
P
=0.024).

Conclusions
—The extent of microvascular obstruction and the infarct size increase significantly over the first 48 hours after myocardial infarction. These results are consistent with progressive microvascular and myocardial injury well beyond coronary occlusion and reflow.
Complex Demodulation of Cardiorespiratory Dynamics Preceding Vasovagal Syncope
Authors: Lipsitz Lewis A. , Hayano Junichiro , Sakata Seiichiro , Okada Akiyoshi , Morin Raymond J.
Published: June 2012

Background
—The dynamic autonomic processes leading to vasovagal syncope are poorly understood.

Methods and Results
—We used complex demodulation to continuously assess changes in respiration, R-R interval, and arterial pressure (blood pressure) variability during 60 degree head-up tilt in 25 healthy subjects with tilt-induced vasovagal syncope and 25 age-matched nonsyncopal control subjects. Coherence and transfer function analyses were used to examine the relation between respiration and R-R interval variability before syncope. Baseline blood pressure, R-R, and ventilation were similar between syncope subjects and control subjects. Syncope subjects experienced an increase in tidal volume and decrease in BP beginning 3 minutes before impending syncope (systolic blood pressure <80 mm Hg) necessitated termination of tilt. Approximately 90 seconds before syncope there was a sudden prolongation of R-R interval and increase in amplitude of high and low frequency R-R interval variability, indicating an abrupt enhancement of vagal tone. The increase in respiratory amplitude between 180 and 90 seconds before syncope was not accompanied by changes in R-R interval or R-R variability, suggesting a dissociation between respiration and the respiratory sinus arrhythmia. The coherence analysis showed fewer syncope subjects with coherence between respiratory and R-R interval variabilities and lower transfer magnitudes in syncope subjects compared with control subjects. Nonsyncopal subjects had no change in respiratory, R-R interval, or blood pressure dynamics during matched time periods before the time of syncope.

Conclusions
—Vasovagal syncope is preceded by a period of hyperpnea and cardiorespiratory decoupling followed by an abrupt increase in cardiovagal tone. Respiratory pumping without inspiratory cardiac slowing may partially counteract preload reduction until sudden bradycardia precipitates syncope.
Presence of Tissue Factor Pathway Inhibitor in Human Atherosclerotic Plaques Is Associated With Reduced Tissue Factor Activity
Authors: Caplice Noel M. , Mueske Cheryl S. , Kleppe Laurel S. , Simari Robert D.
Published: June 2012

Background
—Plaque disruption and exposure of subendothelial procoagulants such as tissue factor (TF) to circulating factor VII/VIIa (FVII/VIIa) lead to intravascular thrombosis. Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of TF-induced coagulation that binds to factor Xa and the TF-FVIIa catalytic complex in a two-step process. The aim of this study was to determine the expression of TFPI within human atherosclerotic plaque and its role in modulation of TF activity.

Methods and Results
—We measured the level of TFPI antigen in human carotid plaque and determined the relationship between TFPI and TF activity within plaque. Furthermore, we examined the biological activity and immunolocalization patterns of TFPI within carotid plaque. TFPI was detectable (TFPI+ group) in 22 of 34 specimens (mean±SEM, 404.4±91.8 pg/mg) and undetectable (TFPI− group) in 12 of 34 specimens. In the TFPI− group, normalized TF activity was significantly greater than that in the TFPI+ group (0.28±0.04 vs 0.14±0.02 U/pg,
P
=0.002). Furthermore, neutralization of TFPI activity using a polyclonal antibody resulted in an 8-fold increase in TF activity in the TFPI+ group (
P
=0.001) but had no effect in the TFPI− group. Immunostaining for TFPI showed localization to endothelial cells, vascular smooth muscle cells within the fibrous cap region of the plaque, and macrophages within the shoulder region of the plaque.

Conclusions
—Taken together, these data suggest that biologically active TFPI is present within human atherosclerotic plaque and is associated with attenuated TF activity.
Pharmacodynamic Efficacy, Clinical Safety, and Outcomes After Prolonged Platelet Glycoprotein IIb/IIIa Receptor Blockade With Oral Xemilofiban
Authors: Kereiakes Dean J. , Kleiman Neal S. , Ferguson James J. , Masud A. R. Zaki , Broderick Thomas M. , Abbottsmith Charles W. , Runyon John Paul , Anderson Linda C. , Anders Robert J. , Dreiling Roger J. , Hantsbarger Gary L. , Bryzinski Brian , Topol Eric J.
Published: June 2012

Background
—Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention. The pharmacodynamic efficacy, clinical safety, and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled, randomized trial of xemilofiban, an oral platelet GP IIb/IIIa blocking agent, administered to patients after percutaneous coronary intervention.

Methods and Results
—After successful elective percutaneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in a dose of 15 or 20 mg. Stented patients randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary intervention and who were randomized to receive xemilofiban were administered a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients received 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 μmol/L ADP and 4 μg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients. All patients were followed clinically for 90 days. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events. Although this study was not powered to evaluate differences in clinical outcomes, a trend (
P
=0.04) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose (20 mg) of xemilofiban studied.

Conclusions
—Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress.
Effects of Short-Term Treatment of Hyperlipidemia on Coronary Vasodilator Function and Myocardial Perfusion in Regions Having Substantial Impairment of Baseline Dilator Reverse
Authors: Huggins Gordon S. , Pasternak Richard C. , Alpert Nathaniel M. , Fischman Alan J. , Gewirtz Henry
Published: June 2012

Background
—We tested the hypothesis that correction of hyperlipidemia improves coronary vasodilator response and maximal perfusion in myocardial regions having substantial impairment of pretreatment vasodilator capacity.

Methods and Results
—Measurements of myocardial blood flow were made with PET [
13
N]ammonia in 12 patients with ischemic heart disease (11 men; age, 65±8 years [mean±SD]) at rest and during adenosine at 70 and then 140 μg · kg
−1
· min
−1
for 5 minutes each before and ≈4 months after simvastatin treatment (40 mg daily). Simvastatin reduced LDL (171±13 before versus 99±18 mg/dL after simvastatin,
P
<0.001) and increased HDL (39±8 versus 45±9 mg/dL,
P
<0.05). Myocardial segments were classified on the basis of pretreatment blood flow response to 140 μg · kg
−1
· min
−1
adenosine as normal (flow ≥2 mL · min
−1
· g
−1
) or abnormal (flow <2 mL · min
−1
· g
−1
). In normal segments, baseline myocardial blood flow (0.95±0.32) increased (
P
<0.001) at both low- (1.62±0.81) and high- (2.63±0.41) dose adenosine and was unchanged both at rest and with adenosine after simvastatin. In abnormal segments, myocardial blood flow at rest (0.73±0.19) increased at low- (1.06±0.59,
P
<0.02) and high- (1.29±0.33,
P
<0.01) dose adenosine. After simvastatin, myocardial blood flow increased more compared with pretreatment at both low- (1.37±0.66,
P
<0.05 versus pretreatment) and high- (1.89±0.79,
P
<0.01 versus pretreatment) dose adenosine.

Conclusions
—Short-term lipid-lowering therapy increases stenotic segment maximal myocardial blood flow by ≈45%. The mechanism involves enhanced, flow-mediated dilation of stenotic epicardial conduit vessels and may account at least in part for the efficacy of lipid lowering in secondary prevention trials and in reducing ischemic episodes in ambulatory patients.
Echocardiography-Guided Ethanol Septal Reduction for Hypertrophic Obstructive Cardiomyopathy
Authors: Lakkis Nasser M. , Nagueh Sherif F. , Kleiman Neal S. , Killip Donna , He Zuo-Xiang , Verani Mario S. , Roberts Robert , Spencer William H.
Published: June 2012

Background
—Left ventricular outflow tract (LVOT) obstruction is frequently responsible for symptoms in hypertrophic obstructive cardiomyopathy (HOCM). Medical therapy is often not sufficient to control these symptoms, and surgical myotomy-myomectomy is required.

Methods and Results
—We enrolled 33 symptomatic patients with HOCM and obstruction (≥40 mm Hg gradient at rest or ≥60 mm Hg dobutamine-provoked). By contrast echocardiography, the bulging septum was localized and infarcted by injection of 2 to 5 mL of absolute ethanol into the septal artery(ies) supplying the hypertrophied area. Baseline echocardiograms with Doppler, myocardial perfusion tomograms, and treadmill exercise or pharmacological testing were compared with those at 6 weeks and 6 months. The mean rise in creatine kinase was 1964±796 U. All patients experienced symptomatic relief; NYHA class decreased from 3.0±0.5 to 0.9±0.6 (
P
<0.001). Exercise time increased from 286±193 to 421±181 seconds (
P
=0.03). The resting and dobutamine-provoked gradient decreased from 49±33 and 96±34 mm Hg to 9±19 (
P
<0.001) and 24±31 mm Hg (
P
<0.001), respectively. Echocardiograms repeated at 6 weeks after the procedure showed a 28% reduction in septal thickness and 17% reduction in left ventricular mass. Myocardial perfusion imaging showed a “septal amputation pattern,” with scarring in the upper and middle septal areas. Complete heart block developed in 11 patients, who then required permanent pacemaker implantation.

Conclusions
—Echocardiography-guided ethanol septal reduction in patients with HOCM is a safe, minimally invasive procedure that provides symptomatic relief with improved hemodynamic and left ventricular parameters.
Myocardial Contractility Is Not Constant During Spontaneous Atrial Fibrillation in Patients
Authors: Brookes Carl I. O. , White Paul A. , Staples Maurice , Oldershaw Paul J. , Redington Andrew N. , Collins Peter D. , Noble Mark I. M.
Published: June 2012

Background
—The variation in stroke volume and pulse pressure characteristic of atrial fibrillation is usually ascribed to time-dependent ventricular filling, implying a single positive relationship between end-systolic pressure and volume, which defines a single state of myocardial contractility. We tested the hypothesis that contractility also varies.

Methods and Results
—We measured the left ventricular pressure and volume continuously with a conductance catheter with catheter-tip micromanometer introduced retrogradely into the left ventricle. The end-systolic pressure-volume relationship was determined in 6 patients in atrial fibrillation undergoing cardiac catheterization for diagnostic purposes and 4 control patients in sinus rhythm undergoing coronary artery bypass graft surgery. The normal positive relationship between end-systolic pressure and volume was found in the control patients, but no such positive relationship was found in any patient in atrial fibrillation. In the latter, the slopes of the linear regressions were either not significantly different from zero or significantly negative (
r
values <0.08), both results indicating a change in contractility from beat to beat. Significantly negative relationships were found between end-systolic volume and preceding R-R interval (−0.82<
r
<−0.24), indicating the presence of mechanical restitution. Significantly positive relationships were found between end-systolic volume and the R-R interval before the preceding R-R interval (0.35<
r
<0.74), indicating the presence of postextrasystolic potentiation.

Conclusions
—Myocardial contractility is constantly changing from beat to beat in atrial fibrillation because of the influence of the force-interval relationships.
Assessment of Transmural Distribution of Myocardial Perfusion With Contrast Echocardiography
Authors: Linka Andre Z. , Sklenar Jiri , Wei Kevin , Jayaweera Ananda R. , Skyba Danny M. , Kaul Sanjiv
Published: June 2012

Background
—We hypothesized that by using our newly defined method of destroying microbubbles and measuring their rate of tissue replenishment, we could assess the transmural distribution of myocardial perfusion.

Methods and Results
—We studied 12 dogs before and after creation of left anterior descending coronary artery stenoses both at rest and during hyperemia (n=62 stages). Microbubbles were administered as a constant infusion, and myocardial contrast echocardiography (MCE) was performed with the use of different pulsing intervals. The video intensity versus pulsing interval plots derived from each myocardial pixel were fitted to an exponential function: y=
A
(1−e
βt
), where
A
reflects microvascular cross-sectional area (or myocardial blood volume), and
β
reflects mean myocardial microbubble velocity. The product
A · β
represents myocardial blood flow (MBF). Average values for these parameters were derived from the endocardial and epicardial regions of interest placed over the left anterior descending coronary artery bed. Radiolabeled microsphere–derived MBF was also measured from the same regions. There was poor correlation between radiolabeled microsphere–derived MBF and
A
-endocardial/epicardial ratios (EER) (
r
=0.46). The correlation with
β
-EER was better (
r
=0.69,
P
<0.01). The best correlation with radiolabeled microsphere–derived MBF-EER was noted with
A · β
-EER (
r
=0.88,
P
<0.01).

Conclusions
—The transmural distribution of myocardial perfusion can be accurately assessed with MCE with the use of our newly described method of tissue replenishment of microbubbles after their ultrasound-induced destruction. In the model studied, an uncoupling of the transmural distribution of MBF and myocardial blood volume was observed during reversal of the MBF-EER.
Distribution of Inflammatory Cells in Atherosclerotic Plaques Relates to the Direction of Flow
Authors: Dirksen Maurits T. , van der Wal Allard C. , van den Berg Frank M. , van der Loos Chris M. , Becker Anton E.
Published: June 2012

Background
—The distribution of macrophages and smooth muscle cells (SMCs) within atherosclerotic plaques is highly variable. This is clinically relevant because these cell types have opposite effects on the stability of atherosclerotic plaques. The present study was designed to investigate whether local variations in arterial flow over the plaque surface could relate to differences in the distribution of SMCs and macrophages in plaques.

Methods and Results
—Thirty-three entire carotid plaques were collected at autopsy and marked at their proximal (in relation to the direction of the blood flow) ends, and the cell composition of upstream parts (where high flow and high shear prevail) was compared with that of downstream parts (low flow and low shear stress). Seventy percent of plaques showed more SMCs in their downstream part, and 67% of plaques contained more macrophages in the upstream part. Immunostained macrophage areas were larger in upstream parts (
P
=0.011). Immunostained SMC areas were larger in downstream parts (
P
=0.031). Rupture sites of 6 of 9 ruptured plaques were in the upstream part.

Conclusions
—Significant differences in cell composition between upstream and downstream parts of plaques indicate a role for arterial flow in the distribution of different cell types. The low-flow/low-shear downstream areas of plaques contain significantly more SMCs, which could provide the background for slowly progressive growth at distal ends of plaques. The significantly high number of macrophages in the upstream areas suggests a relationship between high flow/high shear and plaque instability.
Very Early Risk Stratification Using Combined ECG and Biochemical Assessment in Patients With Unstable Coronary Artery Disease (A Thrombin Inhibition in Myocardial Ischemia [TRIM] Substudy)
Authors: Holmvang Lene , Lüscher Michael S. , Clemmensen Peter , Thygesen Kristian , Grande Peer
Published: June 2012

Background
—The diagnostic capability of troponin T (TnT), troponin I (TnI), myoglobin, and creatine kinase (CK)-MB mass for detection of myocardial injury seems evident. Newer studies have found these sensitive markers to carry independent prognostic information in patients with unstable coronary artery disease as well. ST-segment depression in the admission ECG is known to be an important indicator of poor outcome in these patients. The present study investigates the prognostic capacities of the ECG in combination with biochemical admission measurements in 516 patients admitted to hospital with unstable coronary artery disease.

Methods and Results
—Baseline ECG recordings and blood samples were collected for central analysis. The patients were followed up for 30 days, and predefined end points, ie, death, myocardial infarction, and refractory angina, were registered as end points. By univariate analysis, ST-segment depression, inverted T waves in ≥5 leads, TnT ≥0.1 μg/L, TnI ≥0.5 μg/L, myoglobin ≥40 μg/L, female sex, and age ≥65 years were predictors of death and myocardial infarction at 30 days. By multivariate analysis, female sex, ST-segment depression at randomization, or inverted T-waves in ≥5 leads were the only independent predictors of death or myocardial infarction. On the basis of baseline ECG ST-T changes and CK-MB mass/TnT/TnI/myoglobin levels, the patients were divided into 3 subgroups at high (14% event rate), intermediate (6%), and low (3%) risk of early death/myocardial infarction.

Conclusions
—The present study found the combination of baseline values of TnT, TnI, CK-MB mass, and ST-T changes in the ECG to be effective for early risk stratification in patients with unstable coronary artery disease.