bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrinsic Tone as Potential Vascular Reserve in Conductance and Resistance Vessels
Authors: Jain Mukesh , Dai Hai Bin , Carrozza Joseph P. , Sellke Frank W. , Morgan Kathleen G.
Published: June 2012

Background
The purpose of this study was to define the degree of intrinsic tone in conductance and resistance vessels, to define the calcium dependency of intrinsic tone in these vascular preparations, and to investigate the efficacy of vasodilatory agents on the level of intrinsic tone in these vascular preparations.

Methods and Results
All vessels were deendothelialized. Isometric force was recorded from strips of ferret aorta, ferret pulmonary artery, and human coronary artery. Vessel diameter was recorded from the ferret epicardial coronary artery and from ferret coronary microvessel in a pressurized no-flow state. Intrinsic tone was defined as the active increase in force or decrease in diameter with warming from 6°C to 37°C. Changes in force or diameter with various pharmacological agents were expressed as a percentage of intrinsic tone. Our results indicate that intrinsic tone accounts for ≈35% to 40% of total tone in all vascular preparations studied and is not dependent on extracellular calcium. Agents that increased cAMP levels (eg, forskolin, milrinone) and agents that decreased protein kinase C activity (eg, staurosporine) were partially effective in decreasing intrinsic tone. Nitroprusside, adenosine, hydralazine, and nifedipine had no significant effect.

Conclusions
Our results indicate that intrinsic tone represents a significant component of vascular tone that has not been previously recognized and remains largely unexploited by current pharmacological therapies.
Hirudin in Acute Myocardial Infarction
Authors: Antman Elliott M.
Published: June 2012

Background
The TIMI 9 trial evaluated whether the direct antithrombin hirudin is more effective than an indirect-acting antithrombin, heparin, as adjunctive therapy for thrombolysis in myocardial infarction.

Methods and Results
Patients (n=3002) with acute myocardial infarction were treated with aspirin and either accelerated-dose tissue plasminogen activator (TPA) or streptokinase. They were randomized within 12 hours of symptoms to receive either intravenous heparin (5000 U bolus followed by infusion of 1000 U/h) or hirudin (0.1 mg/kg bolus followed by infusion of 0.1 mg/kg per hour). The infusions of both antithrombins were titrated to a target activated partial thromboplastin time (aPTT) of 55 to 85 seconds and were administered for 96 hours. Patients randomized to hirudin were significantly more likely to have an aPTT measurement in the target range (
P
<.0001). The primary end point (death, recurrent nonfatal myocardial infarction, or development of severe congestive heart failure or cardiogenic shock by 30 days) occurred in 11.9% of the 1491 patients in the heparin group and 12.9% of the 1511 patients in the hirudin group (
P
=NS). Subgroup analyses did not reveal any profile of patients who benefited more from one of the antithrombins. The rate of major hemorrhage was similar in the heparin (5.3%) and hirudin (4.6%) groups; intracranial hemorrhage occurred in 0.9% of the heparin and 0.4% of the hirudin patients.

Conclusions
Heparin and hirudin have an equal effect as adjunctive therapy to TPA and streptokinase in preventing unsatisfactory outcome in patients with acute myocardial infarction. Similar rates of major bleeding were observed for patients in the heparin and hirudin groups.
Vulnerable Plaque
Authors: Mann Jessica M. , Davies Michael J.
Published: June 2012

Background
The microanatomic features of the atherosclerotic plaque at risk of disruption include a large lipid core, a high macrophage content, and a thin cap. The relation between lipid core size, plaque size, and cap thickness either with each other or with the degree of stenosis has yet to be evaluated in human coronary arteries.

Methods and Results
Atherosclerotic coronary plaques (n=160) were obtained from 31 subjects who died suddenly of ischemic heart disease. In coronary arteries perfused with formol saline at a pressure of 100 mm Hg, stenosis was measured by comparison of the minimal lumen size at the site of a plaque with that of the lumen in an adjacent normal segment of artery. Plaque size, the size of the lipid core, and the thickness of the cap were measured in histological sections. Lipid core size ranged from 0% to 82% of overall plaque size. Seventeen percent of plaques had a core size of >50%. Linear regression showed no relation of core size to stenosis (
r
=.21). Absolute plaque size bore no relation to core size (
r
=.14). Minimal cap thickness was not related to core size (
r
=.06). Ten percent of plaques predicted to be angiographically invisible had cores of >50%.

Conclusions
Two major determinants of plaque vulnerability, core size and cap thickness, are not statistically related. Neither of these two factors that confer vulnerability are related to absolute plaque size or to the degree of stenosis.
Avoidance of Immune Response Prolongs Expression of Genes Delivered to the Adult Rat Myocardium by Replication-Defective Adenovirus
Authors: Quin˜ones Manuel J. , Leor Jonathan , Kloner Robert A. , Ito Masamichi , Patterson Michael , Witke Werner F. , Kedes Larry
Published: June 2012

Background
Gene delivery is a rapidly expanding field with potential applications to every human organ system. Recently, adenoviruses have been used as efficient vectors for in vivo gene transfer into the myocardium. These methods, however, have shown a sharp decline of gene expression after 1 week. To test the hypothesis that an immune-effector mechanism is involved in this decline, we compared the results after injection of adenovirus-5 carrying the β-galactosidase gene (Adβ-gal) into the left ventricular myocardium of athymic nude rats (NDRs) versus immunocompetent Sprague-Dawley rats (SDRs).

Methods and Results
Adβ-gal (5.0×10
9
PFU/mL) was injected into the left ventricle of NDRs (n=16) and SDRs (n=22). Hearts were harvested, embedded in paraffin, and sectioned and stained for β-gal activity, hematoxylin and eosin and picrosirius red at 4, 21, 35, 85, and 120 days. Representative samples were immunostained with antibodies directed at inflammatory markers. β-gal activity was quantified by digital planimetry and expressed as area of staining (%±SEM). Peak β-gal activity was highest at 4 days, with NDRs displaying significantly greater staining (83±3.0% versus 54±8.0%;
P
=.03). SDRs sustained a rapid drop in activity, such that at 35 (1±0.19%) and 85 (1±0.4%) days, only occasional cells stained positive and by 120 days (0.3±0.0%), activity had been extinguished. NDRs continued to show transgene expression at all time periods (35 and 85 days, 25±7.1% and 7.4±2.7%, respectively) and was still readily detected at 120 days. An inflammatory response was limited in NDRs compared with SDRs, in which there was intense mononuclear cell infiltration, with collagen deposition and scar formation. Immunostaining identified the majority of these inflammatory cells as not being of lymphocyte lineage, although small numbers of lymphocytes and phagocytic and activated plasma cells were identified.

Conclusions
Our data suggest that immune-effector mechanisms can severely affect the expression of genes delivered by adenovirus. The present model provides efficient gene expression for at least 120 days without significant inflammatory reaction.
Overexpression of Heat Shock Protein 72 in Transgenic Mice Decreases Infarct Size In Vivo
Authors: Hutter Jonathan J. , Mestril Ruben , Tam Eunice K.W. , Sievers Richard E. , Dillmann Wolfgang H. , Wolfe Christopher L.
Published: June 2012

Background
Previous studies have demonstrated that induction of heat shock protein (HSP) 72 by whole-body hyperthermia reduces infarct size in an in vivo model of ischemia and reperfusion. Furthermore, hearts obtained from transgenic mice that overexpress HSP72 demonstrate improved functional recovery and decreased infarct size in vitro after global ischemia and reperfusion.

Methods and Results
To test the hypothesis that overexpression of HSP72 in transgenic mice reduces infarct size in vivo, transgenic mice that were heterozygous for a rat HSP70i gene ([+]HSP72) and transgene-negative littermate controls ([−]HSP72) were subjected to 30 minutes of left coronary artery occlusion followed by 120 minutes of reperfusion. Core body temperature was monitored with a rectal thermometer and maintained between 36.5°C and 37.0°C with a heating pad. Infarct size, determined by dual staining with triphenyltetrazolium chloride and phthalocyanine blue dye, was smaller in [+]HSP72 mice compared with [−]HSP72 mice (12.7±2.8% [n=7] versus 33.4±4.5% [n=6], infarct size/risk area, respectively;
P
<.05; mean±SEM).

Conclusions
Overexpression of HSP72 reduces infarct size in this in vivo transgenic mouse model of myocardial ischemia and reperfusion.
Zones of Atrial Vulnerability
Authors: Friedman Howard S. , Sinha Bindeshwari , Tun Aung , Pasha Rizwan , Sharafkhaneh Amir , Bharadwaj Anoopendra
Published: June 2012

Background
Bradycardia is commonly found in individuals at risk for paroxysmal atrial fibrillation (AF). However, a clear relationship between lengthening of basic cyclic length (BCL) and AF has not been demonstrated.

Methods and Results
In 20 open-chest dogs, atrial refractoriness, AF vulnerability, and atrial activation times (ACTs) were determined in sinus rhythm and at BCLs of 400, 300, and 200 ms, and the findings at the same coupling intervals and stimulus strengths were compared. As BCL increased, AFV zone lengthened, and its outer limit occurred later in diastole. The outer limit of the AF vulnerability zone for a BCL was its relative refractory period; the inner limit, however, was not its effective refractory period. A border zone, defined by the inner limit of the AF vulnerability zone and the effective refractory period for a BCL, decreased as BCL lengthened, offsetting the increase in the AF vulnerability zone. The border zone was characterized by paradoxical stimulus current strength propagation relations and features suggesting supernormal conduction. ACT also increased with BCL lengthening. When AF induced by rapid atrial burst pacing was contrasted with AF induced by an extrastimulus, it tended to have a more disorganized pattern and lasted longer.

Conclusions
Lengthening of BCL increases the AF vulnerability zone, extending its outer limit later in diastole and comprising an increasing component of the total duration of the relative refractory period. Very short BCLs create conditions that also favor AF vulnerability.
Effect of Radiofrequency Catheter Ablation on Health-Related Quality of Life and Activities of Daily Living in Patients With Recurrent Arrhythmias
Authors: Bubien Rosemary S. , Knotts-Dolson Susan M. , Plumb Vance J. , Kay G. Neal
Published: June 2012

Background
Although radiofrequency catheter ablation can be used to effectively treat a variety of arrhythmias, the effects of this procedure on health-related quality of life have not been systematically studied.

Methods and Results
The SF-36 (a measure of general health status), the Symptom Checklist—Frequency and Severity Scale (an instrument specific for cardiac arrhythmias), and an Activities of Daily Living questionnaire were used to assess quality of life in 161 patients before radiofrequency catheter ablation. These same instruments were used to measure quality of life 1 and 6 months after ablation with complete data in 159 of the original 161 patients. Before ablation, SF-36 scores of the study population were low compared with the US normative data base reflecting significant impairment in physical functioning and well-being. The lowest scores were reported by patients with atrial fibrillation and atrial flutter. Catheter ablation was associated with significant improvement in quality of life that was sustained over the 6 months after ablation. Improvements were measured in both the generic SF-36 health status questionnaire and the disease-specific Symptom Checklist—Frequency and Severity Scale. Catheter ablation was followed by improved performance of activities of daily living and a marked decrease in the number of visits to physicians and emergency rooms in the 6 months after ablation compared with the 6 months before ablation.

Conclusions
Radiofrequency catheter ablation improves the health-related quality of life for patients with a variety of cardiac arrhythmias.
Functional Upregulation of the Vascular Endothelial Growth Factor Receptor KDR by Hypoxia
Authors: Waltenberger Johannes , Mayr Ulrike , Pentz Siegwald , Hombach Vinzenz
Published: June 2012

Background
Vascular endothelial growth factor (VEGF) is a specific endothelial mitogen and chemoattractant that has been shown to be useful for inducing therapeutic angiogenesis in ischemic myocardium and found to stimulate mitogenicity and chemotaxis of endothelial cells through the receptor tyrosine kinase KDR. Although VEGF expression is upregulated by hypoxic stimuli, regulation of KDR remained unknown under these conditions.

Methods and Results
With the use of human umbilical vein endothelial cells and transfected porcine aortic endothelial cells, KDR protein was found to be upregulated under hypoxic conditions (2% O
2
) in both cell types. This process of KDR upregulation was found to be reversible, was maximal after 24 hours of hypoxia, and was regulated on a posttranscriptional level. Furthermore, the susceptibility for VEGF-induced mitogenicity was enhanced under hypoxic conditions as shown by [
3
H]-thymidine incorporation assay. The activated state of increased VEGF function in hypoxic endothelial cells was associated with elevated tyrosine phosphorylation of KDR as demonstrated by anti-phosphotyrosine blot.

Conclusions
These data indicate that hypoxia stimulates VEGF-dependent signaling not only by upregulation of VEGF ligand but also by functional upregulation of a specific signaling receptor. Therefore, these data provide evidence that the endothelium plays an active role in hypoxia-induced angiogenesis.
Orally Effective CVS-1123 Prevents Coronary Artery Thrombosis in the Conscious Dog
Authors: Cousins Geoffrey R. , Friedrichs Gregory S. , Sudo Yuji , Rebello Sam S. , Rote William E. , Vlasuk George P. , Nolan Thomas G. , Mendoza Christine , Lucchesi Benedict R.
Published: June 2012

Background
We examined the oral efficacy of a direct thrombin inhibitor, CVS-1123 [(CH
3
CH
2
CH
2
)
2
-CH-CO-Asp(OCH
3
)-Pro-Arg-CHO; MW, 575]. The object was to determine whether thrombin inhibition could reduce the incidence of occlusive coronary artery thrombosis in response to arterial wall injury.

Methods and Results
Arterial wall injury was induced in conscious dogs by a 150-μA anodal current applied to the intimal surface of the circumflex coronary artery 30 minutes after oral CVS-1123 (20 mg/kg every 8 hours for three doses; n=11) or placebo containing diluent (n=10). Dogs were monitored for 8 hours and at 24 hours. The coronary artery remained patent for 24 hours in 8 of 11 CVS-1123–treated dogs. All dogs (n=10) in the placebo group developed a sustained, occlusive arterial thrombus. Two hours after the initial oral dose, the plasma CVS-1123 concentration was 13±1 μg/mL, reaching a maximum of 15±1 μg/mL after the second dose and 4.4±0.5 μg/mL at 24 hours. Ex vivo platelet aggregation to γ-thrombin was inhibited and activated partial thromboplastin time was increased after treatment with CVS-1123 (
P
<.05).

Conclusions
The direct thrombin inhibitor CVS-1123 is effective after oral administration in reducing the incidence of primary thrombus formation in an experimental model of arterial wall injury. Thrombin-specific inhibitors, such as CVS-1123, may be alternative antithrombotic agents in clinical settings in which heparin-associated thrombosis is a complicating factor or when long-term anticoagulation is required.
Phospholipase D Plays a Role in Ischemic Preconditioning in Rabbit Heart
Authors: Cohen Michael V. , Liu Yongge , Liu Guang S. , Wang Peipei , Weinbrenner Christof , Cordis Gerald A. , Das Dipak K. , Downey James M.
Published: June 2012

Background
Activation of protein kinase C (PKC) is thought to be a critical step in ischemic preconditioning. Many receptor agonists activate PKC via stimulation of phospholipase C (PLC), which degrades membrane phospholipids to diacylglycerol (DAG), an important PKC cofactor. However, adenosine receptors, critical components of the prototypical preconditioning pathway, are not thought to couple to PLC in the cardiomyocyte. We therefore tested whether ischemic preconditioning or adenosine might instead activate phospholipase D (PLD) to produce DAG.

Methods and Results
PLD activity was measured in isolated rabbit hearts. Ischemic injury was evaluated in either isolated rabbit hearts or dispersed myocytes. PLD activity doubled from a control level of 74.8±10.0 to 140.0±11.5 μmol·min
−1
·g
−1
(
P
<.025) after two 5-minute periods of global ischemia separated by 5 minutes of reperfusion. A similar increase was noted after the heart had been exposed to (R)-
N
6
-(2-phenylisopropyl)-adenosine [(R)-PIA] for 20 minutes. When sodium oleate, which activates PLD, was administered to isolated hearts before a 30-minute coronary occlusion, infarct size (15.6±2.0% of the risk zone) was significantly smaller than in untreated hearts (30.4±2.2%;
P
<.01). Exposure to sodium oleate significantly prolonged the rate of isolated myocyte survival during simulated ischemia. Propranolol 100 μmol/L, which blocks DAG production from metabolites produced by PLD catalysis, completely abolished the protective effects of both metabolic preconditioning and (R)-PIA exposure in myocytes.

Conclusions
We conclude that PLD stimulation is involved in the protection of ischemic preconditioning in the rabbit heart.
Failure to Detect
connexin43
Mutations in 38 Cases of Sporadic and Familial Heterotaxy
Authors: Gebbia Marinella , Towbin Jeffrey A. , Casey Brett
Published: June 2012

Background
Heterotaxy results from failure to establish normal left/right asymmetry during embryonic development. Typical manifestations include complex heart defects and malpositioning of abdominal organs. Missense base substitutions clustered in a 150–base pair region of the gap-junction gene
connexin43 (cx43)
have been implicated in the pathogenesis of heterotaxy.

Methods and Results
cx43
was studied in 38 cases of sporadic and familial heterotaxy. A 400–base pair region containing the previously reported mutation sites was amplified and directly sequenced in 19 patients. Nineteen additional patients were tested for restriction fragments predicted by two of the previously reported missense substitutions. No difference from normal control subjects was detected in any of the patients.

Conclusions
Randomly selected cases of heterotaxy are unlikely to be the result of mutations in
cx43
.
Importance of Pressure Recovery for the Assessment of Aortic Stenosis by Doppler Ultrasound
Authors: Niederberger Julia , Schima Heinrich , Maurer Gerald , Baumgartner Helmut
Published: June 2012

Background
Pressure recovery has been shown to occur distal to aortic stenoses in experimental and clinical studies. However, its clinical relevance in this setting has not yet been evaluated.

Methods and Results
To address the hypothesis that pressure recovery can cause significant differences between Doppler and catheter gradients in aortic stenosis and to examine the effects of aortic size, aortic valve area, and direction of the stenotic jet on these differences, stenoses with valve areas from 0.5 to 1.25 cm
2
and aortic diameters from 1.8 to 5.0 cm were studied in a pulsatile flow model. Jets entered the aorta centrally or eccentrically with angles of 15°, 30°, or 45°. Overall, good correlation was found between Doppler and catheter gradients. However, when the various combinations of orifices and aortas were analyzed separately, slopes varied from 1.0 to 1.86, and the Doppler-catheter gradient differences ranged from −2 (small valve area with a large aorta) to 66 mm Hg (80% overestimation by Doppler echocardiography) when the stenosis was moderate and the aorta was small. Mild eccentricity of the jet did not significantly alter the results. However, overestimation by Doppler decreased with increasing jet eccentricity. Finally, differences between Doppler and catheter gradients could be predicted by estimating pressure recovery from Doppler measurements.

Conclusions
Significant pressure recovery can occur in aortic stenosis and can cause differences between Doppler and catheter gradients. These differences may reach clinical relevance, particularly when the stenosis is moderate and the aorta is small and can be predicted from Doppler measurements.
Inhibition of Tissue Angiotensin-Converting Enzyme With Quinapril Reduces Hypoxic Pulmonary Hypertension and Pulmonary Vascular Remodeling
Authors: Nong Zengxuan , Stassen Jean-Marie , Moons Lieve , Collen De´sire´ , Janssens Stefan
Published: June 2012

Background
Angiotensin II may contribute to hypoxic pulmonary hypertension via its vasoconstrictor and growth-stimulatory effects on vascular smooth muscle cells (VSMCs). Therefore, the use of ACE inhibitors might reduce hypoxic pulmonary hypertension by decreasing pulmonary vasomotor tone or vascular remodeling.

Methods and Results
Pulmonary hemodynamics and vascular remodeling were compared in chronically hypoxic (F
io
2
=0.10) rats treated with 0, 1, and 10 mg·kg
−1
·d
−1
quinapril, a potent tissue ACE inhibitor, both during and after the development of pulmonary hypertension. Quinapril reduced the development of pulmonary hypertension after 12 days of hypoxia from 26±1 to 19±1 mm Hg (
P
<.05). When started in established pulmonary hypertension, quinapril reduced pulmonary artery pressure and total pulmonary resistance index from 29±1 to 25±1 mm Hg and from 0.136±0.01 to 0.101±0.005 mm Hg·mL
−1
·min
−1
per kg, respectively (
P
<.05). Chronically hypoxic rats showed a small pulmonary vasoconstrictor response that was not affected by quinapril. In contrast, percent medial thickness in alveolar duct blood vessels was reduced by quinapril treatment both in developing and in established pulmonary hypertension (10.0±0.2% versus 8.9±0.1% [
P
<.05] and 11.2±0.2% versus 9.1±0.2% [
P
<.05], respectively). 5′-Bromo-deoxyuridine–positive VSMCs were detected in 56±3% of hypoxic control pulmonary resistance vessels versus 41±3% of vessels after quinapril treatment (
P
<.05).

Conclusions
Pulmonary ACE and angiotensin II contribute to the development and maintenance of hypoxic pulmonary hypertension in rats. ACE inhibition with quinapril reduces the development of hypoxic pulmonary hypertension and in part reverses established pulmonary hypertension, most likely via inhibition of pulmonary VSMC proliferation and/or growth.
Association of Heparin-Resistant Thrombin Activity With Acute Ischemic Complications of Coronary Interventions
Authors: Oltrona Luigi , Eisenberg Paul R. , Lasala John M. , Sewall David J. , Shelton Marc E. , Winters Kenneth J.
Published: June 2012

Background
Acute thrombosis is thought to contribute to abrupt coronary occlusion during percutaneous coronary revascularization despite the administration of heparin and aspirin. This study was designed to detect the presence of heparin-resistant thrombin activity and to define its relationship to the acute ischemic complications of coronary interventions.

Methods and Results
Plasma levels of fibrinopeptide A (FPA) and prothrombin fragment 1.2 (F1.2), markers of thrombin and factor Xa activity, respectively, were measured in the coronary sinus with heparin-bonded catheters in 58 patients undergoing coronary interventions. Activated coagulation times were maintained >300 seconds by the Hemochron method. Mean FPA levels decreased significantly, from 7.0±0.9 nmol/L before the procedure to 5.2±0.5 nmol/L after the heparin bolus and to 2.9±0.2 nmol/L after the procedure (
P
=.0001). In 26 patients (45%), FPA levels remained above the threshold for suppression of thrombin activity determined during angiography in 7 patients without coronary artery disease (>3.0 nmol/L). FPA concentrations after coronary interventions were increased in patients with intracoronary thrombus (
P
=.01), abrupt coronary occlusion (
P
=.06), postprocedural non–Q-wave myocardial infarction (
P
=.04), and clinically unsuccessful procedures (
P
=.04). F1.2 levels were relatively low before the procedures and did not change significantly.

Conclusions
Heparin administration suppresses thrombin activity in most but not all patients undergoing coronary interventions. Heparin-resistant thrombin activity is associated with angiographic evidence of intracoronary thrombus and ischemic complications of coronary interventions.
Effects of Integrelin, a Platelet Glycoprotein IIb/IIIa Receptor Antagonist, in Unstable Angina
Authors: Schulman Steven P. , Goldschmidt-Clermont Pascal J. , Topol Eric J. , Califf Robert M. , Navetta Frank I. , Willerson James T. , Chandra Nisha C. , Guerci Alan D. , Ferguson James J. , Harrington Robert A. , Lincoff A. Michael , Yakubov Steven J. , Bray Paul F. , Bahr Raymond D. , Wolfe Christopher L. , Yock Paul G. , Anderson H. Vernon , Nygaard Thomas W. , Mason Steven J. , Effron Mark B. , Fatterpacker Anil , Raskin Stephen , Smith Jack , Brashears Lori , Gottdiener Patricia , du Mee Charles , Kitt Michael M. , Gerstenblith Gary
Published: June 2012

Background
Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina.

Methods and Results
Patients received intravenous heparin and standard anti-ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin, 45 μg/kg bolus followed by a 0.5-μg·kg
−1
·min
−1
continuous infusion; or placebo aspirin and high-dose Integrelin, 90 μg/kg bolus followed by a 1.0-μg·kg
−1
·min
−1
constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24±0.11 ischemic episodes (mean±SEM) on Holter lasting 8.41±5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0±0.33,
P
<.05) and longer duration (26.2±9.8 minutes,
P
=.01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms.

Conclusions
Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.
Assessment of Left Ventricular Filling Pressures by Doppler in the Presence of Atrial Fibrillation
Authors: Nagueh Sherif F. , Kopelen Helen A. , Quin˜ones Miguel A.
Published: June 2012

Background
Although Doppler echocardiography can be used to estimate left ventricular filling pressures (LVFPs) in patients in sinus rhythm, its utility in atrial fibrillation is unknown.

Methods and Results
An initial training population of 30 patients (17 men, 13 women; mean age, 69±9 years; range, 48 to 87 years) was studied. Measurements of LVFP were obtained simultaneously with pulsed Doppler recordings of mitral and pulmonary venous flow velocities and color M-mode recording of the flow propagation velocity of the mitral inflow. Measurements were averaged over 10 cardiac cycles. In addition, left atrial volume was derived from the apical four-chamber view. Significant relations were observed between LVFP and several parameters derived from the transmitral and pulmonary venous velocity and left atrial volume. The best relations were observed with the peak acceleration (PkAcc) of the mitral velocity (
r
=.84), isovolumic relaxation time (IVRT) (
r
=−.76), mean early (E) velocity (
r
=.6), and the ratio of peak E velocity to color M-mode flow propagation velocity (
r
=.65). The best model obtained by multilinear regression analysis (
r
=.88) included PkAcc and IVRT. The equation

\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(LVFP{=}22{+}0.005(PkAcc){-}0.183(IVRT)\) \end{document}

was tested in 30 additional patients (12 women and 18 men; mean age, 65±10.6 years; range, 43 to 87 years) with similar results (
r
=.87). When all 60 patients were combined, the mean±1SD difference between predicted and observed pressure was −0.88±3.6 mm Hg.

Conclusions
LVFPs can be estimated with Doppler echocardiography in patients with atrial fibrillation.
Anorexic Agents Aminorex, Fenfluramine, and Dexfenfluramine Inhibit Potassium Current in Rat Pulmonary Vascular Smooth Muscle and Cause Pulmonary Vasoconstriction
Authors: Weir E. Kenneth , Reeve Helen L. , Huang James M.C. , Michelakis Evangelos , Nelson Daniel P. , Hampl Vaclav , Archer Stephen L.
Published: June 2012

Background
The appetite suppressant aminorex fumarate is thought to have caused an epidemic of pulmonary hypertension in Europe in the 1960s. More recently, pulmonary hypertension has been described in some patients taking other amphetamine-like, anorexic agents: fenfluramine and its
d
-isomer, dexfenfluramine. No mechanism has been demonstrated that might account for the association between anorexic drugs and pulmonary hypertension.

Methods and Results
Using the whole-cell, patch-clamp technique, we found that aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung. Dexfenfluramine causes reversible membrane depolarization in these cells. These actions are similar to those of hypoxia, which initiates pulmonary vasoconstriction by inhibiting a potassium current in pulmonary vascular smooth muscle. In the isolated, perfused rat lung, aminorex, fenfluramine, and dexfenfluramine induce a dose-related increase in perfusion pressure. When the production of endogenous NO is inhibited by
N
-nitro-
l
-arginine methyl ester, the pressor response to dexfenfluramine is greatly enhanced.

Conclusions
These observations indicate that anorexic agents, like hypoxia, can inhibit potassium current, cause membrane depolarization, and stimulate pulmonary vasoconstriction. They suggest one mechanism that could be responsible for initiating pulmonary hypertension in susceptible individuals. It is possible that susceptibility is the result of the reduced production of an endogenous vasodilator, such as NO, but this remains speculative.
Charge-Burping Theory Correctly Predicts Optimal Ratios of Phase Duration for Biphasic Defibrillation Waveforms
Authors: Swerdlow Charles D. , Fan Wei , Brewer James E.
Published: June 2012

Background
For biphasic waveforms, it is accepted that the ratio of the duration of phase 2 to the duration of phase 1 (phase-duration ratio) should be ≤1. The charge-burping theory postulates that the beneficial effects of phase 2 are maximal when it completely removes the charge delivered by phase 1. It predicts that the phase-duration ratio should be <1 when the time constant of the defibrillation system (τ
s
) exceeds the time constant of the cell membrane (τ
m
) but >1 when τ
s
<τ
m
. This study tested the hypothesis that the optimal phase-duration ratio depends on τ
s
(the product of the defibrillator capacitance and pathway resistance).

Methods and Results
In a canine model of transvenous defibrillation (n=8), we determined stored-energy defibrillation thresholds (DFTs) for biphasic waveforms from conventional capacitors (140 μF, τ
s
=7.1±0.8 ms) and very small capacitors (40 μF, τ
s
=2.0±0.2 ms). Each capacitance was tested with phase-duration ratios of 0.5, 1, 2, and 3. The duration of phase 1 approximated the optimal monophasic waveform, 6.3±0.7 ms for 140-μF waveforms and 2.8±0.2 ms for 40-μF waveforms. For 140-μF waveforms, the DFT was lower for phase-duration ratios ≤1 than for phase-duration ratios >1 (
P
=.0003). The reverse was true for 40-μF capacitors (
P
=.0008). There was a significant interaction between the effects of capacitance and phase-duration ratio on DFT (
P
=.0002). The lowest DFT for 40-μF waveforms was less than the lowest DFT for 140-μF waveforms (4.9±2.5 versus 6.4±2.4 J,
P
<.05).

Conclusions
The optimal phase-duration ratio is ≤1 for conventional capacitors and >1 for small capacitors. This supports the predictions of the charge-burping theory.
Coronary Vascular Nitric Oxide Activity in Hypertension and Hypercholesterolemia
Authors: Quyyumi Arshed A. , Mulcahy David , Andrews Neil P. , Husain Syed , Panza Julio A. , Cannon Richard O.
Published: June 2012

Background
Whether the abnormal responses of the human coronary circulation to acetylcholine in patients with hypertension and hypercholesterolemia extend to other, nonmuscarinic stimulators of the endothelium and whether this signifies a specific abnormality of NO is not known.

Methods and Results
We studied 26 patients with angiographically normal coronary arteries, 10 without risk factors, and 16 with either hypertension (n=9) and/or hypercholesterolemia (n=10). Dose-response curves were performed with acetylcholine, substance P, and sodium nitroprusside before and after
N
G
-monomethyl-
l
-arginine (L-NMMA). Substance P produced predominantly epicardial coronary dilation, whereas the dilating effect of acetylcholine was mainly microvascular. There was no correlation between the responses to the two drugs. L-NMMA did not affect the response to sodium nitroprusside, but it suppressed dilation in response to both substance P and acetylcholine, suggesting that the latter promote bioavailability of NO from the coronary vascular endothelium. Compared with patients without risks, those with hypercholesterolemia and hypertension had significantly reduced vasodilation with substance P: 21% versus 12.6% (
P
=.004) increase in epicardial coronary diameter and 35% versus 19% (
P
<.05) decrease in vascular resistance. Similar differences were noted with acetylcholine but not with sodium nitroprusside or adenosine. Epicardial and microvascular dilations with substance P or acetylcholine after L-NMMA were similar in patients with and without risk factors, indicating that the reduced effect of endothelium-dependent vasodilators in those with hypertension and hypercholesterolemia is due to diminished NO activity.

Conclusions
(1) Substance P– and acetylcholine-induced coronary vasodilation, like that to acetylcholine, is at least partly due to stimulation of NO activity, indicating that the dysfunction of the coronary vascular endothelial cell layer is not restricted to muscarinic receptors. (2) Hypertension and hypercholesterolemia are associated with depression of both basal and pharmacologically stimulated bioavailability of NO.
Noninvasive Assessment of the Ventricular Relaxation Time Constant (τ) in Humans by Doppler Echocardiography
Authors: Scalia Gregory M. , Greenberg Neil L. , McCarthy Patrick M. , Thomas James D. , Vandervoort Pieter M.
Published: June 2012

Background
The time constant of ventricular relaxation (τ) is a quantitative measure of diastolic performance requiring intraventricular pressure recording. This study validates in humans an equation relating τ to left ventricular pressure at peak −dP/dt (P
0
), pressure at mitral valve opening (P
MV
), and isovolumic relaxation time (IVRT
inv
). The clinically obtainable parameters peak systolic blood pressure (P
s
), mean left atrial pressure (P
LA
), and Doppler-derived IVRT (IVRT
Dopp
) are then substituted into this equation to obtain τ
Dopp
noninvasively.

Methods and Results
High-fidelity left atrial and left ventricular pressure recordings with simultaneous Doppler by transesophageal echocardiography were obtained from 11 patients during cardiac surgery. Direct curve fitting to the left ventricular pressure trace by Levenberg-Marquardt regression assuming a zero asymptote generated τ
LM
, the “gold standard” against which τ
calc
{IVRT
inv
/[ln(P
0
)−ln(P
MV
)]} and τ
Dopp
{IVRT
Dopp
/[ln(P
s
)−ln(P
LA
)]} were compared. For 123 cycles analyzed in 18 hemodynamic states, mean τ
LM
was 53.8±12.9 ms. τ
calc
(51.5±11 ms) correlated closely with this standard (
r
=.87, SEE=5.5 ms). Noninvasive τ
Dopp
(43.8±11 ms) underestimated τ
LM
but exhibited close linear correlation (n=88,
r
=.75, SEE=7.5 ms). Substituting P
LA
=10 mm Hg into the equation yielded τ
10
(48.7±15 ms), which also closely correlated with the standard (
r
=.62, SEE=11.6 ms).

Conclusions
The previously obtained analytical expression relating IVRT, invasive pressures, and τ is valid in humans. Furthermore, a more clinically obtainable, noninvasive method of obtaining τ also closely predicts this important measure of diastolic function.
Methylenetetrahydrofolate Reductase Gene and Coronary Artery Disease
Authors: van Bockxmeer Frank M. , Mamotte Cyril D.S. , Vasikaran Samuel D. , Taylor Roger R.
Published: June 2012

Background
Hyperhomocysteinemia has been substantiated as a risk factor for occlusive vascular disease. A common mutation (nucleotide 677 C→T) has been described recently in the 5,10-methylenetetrahydrofolate reductase (
MTHFR
) gene, which results in a valine for alanine substitution, a thermolabile enzyme, and a tendency to elevate plasma homocysteine levels and which has been proposed to contribute importantly to coronary artery disease.

Methods and Results
To study the potential influence of the mutation on ischemic heart disease, we screened 555 whites with angiographically documented coronary artery disease and 143 unrelated control subjects without a history of angina or myocardial infarction randomly selected from the community. The patients were in two groups: group 1 comprised 358 prospectively recruited individuals younger than 50 years, and group 2, 197 patients investigated prospectively for restenosis 6 months after coronary angioplasty. The frequency of homozygosity for the mutation was 10.5% in control subjects, 10.6% in group 1, and 9.1% in group 2 patients. There was no relationship between
MTHFR
genotype and number of coronary vessels with >50% diameter obstruction, prior myocardial infarction, or restenosis after coronary angioplasty. Plasma folate concentrations in control subjects (n=90) and patients (n=208) showed closely similar distributions.

Conclusions
Although it is accepted that moderate hyperhomocysteinemia significantly increases the risk for coronary, cerebrovascular, and peripheral vascular diseases, our data suggest that a mutation of the
MTHFR
gene, which has been associated with a thermolabile form of the enzyme and with hyperhomocysteinemia in subjects with plasma folate below the median, does not appear to be significantly associated with risk for premature coronary artery disease or for restenosis after coronary angioplasty.
C-Reactive Protein Colocalizes With Complement in Human Hearts During Acute Myocardial Infarction
Authors: Lagrand Wim K. , Niessen Hans W.M. , Wolbink Gert-Jan , Jaspars Lies H. , Visser Cees A. , Verheugt Freek W.A. , Meijer Chris J.L.M. , Hack C. Erik
Published: June 2012

Background
Rises in circulating C-reactive protein (CRP), the prototypical acute-phase protein in humans, correlate with clinical outcome in patients with myocardial ischemia and infarction. We hypothesized that these correlations might reflect active participation of CRP in the local inflammatory response ensuing in the jeopardized myocardium because on binding to a ligand, CRP is able to activate the classic pathway of complement, and in addition, complement activation has been shown to occur locally in infarcted myocardium.

Methods and Results
To verify our hypothesis, we investigated localization of CRP in relation to deposition of complement in tissue specimens of infarcted and healthy heart tissue obtained from 17 patients who had died after acute myocardial infarction. CRP was found to be deposited only in infarcted regions and not in normal-appearing areas of the myocardium, being colocalized with depositions of C4 and C3 activation fragments of the complement system. Deposition of CRP and complement in infarcted myocardium appeared to be time dependent, because it was found in all infarctions except for one of young age (<12 hours old) and two of greater age (>1 year old), whereas another tissue specimen of an infarct <12 hours old showed only moderate but positive staining for both CRP and complement in comparison with older infarctions.

Conclusions
We conclude that in humans, CRP may localize in infarcted heart tissue and suggest that this acute-phase protein promotes local complement activation, and hence tissue damage, in acute myocardial infarction.
Enhanced Expression of Hepatocyte Growth Factor/c-Met by Myocardial Ischemia and Reperfusion in a Rat Model
Authors: Ono Koh , Matsumori Akira , Shioi Tetsuo , Furukawa Yutaka , Sasayama Shigetake
Published: June 2012

Background
Hepatocyte growth factor (HGF) is a multifunctional factor implicated in tissue regeneration, wound healing, and angiogenesis. Circulating HGF is reportedly elevated during the early stage of myocardial infarction. However, its precise effect on the heart is unknown. To evaluate the regulation of HGF in ischemically damaged myocardium, the production of HGF and its high-affinity receptor, c-Met, was studied in a rat model of myocardial ischemia and reperfusion.

Methods and Results
The plasma concentration of HGF began to increase within 1 hour of reperfusion after 1 hour of ischemia. The peak level was reached at 3 hours after reperfusion. Northern blotting revealed that HGF mRNA expression in the heart was augmented threefold at 24 and 48 hours and remained elevated by twofold at 120 hours after the myocardium was reperfused. The signal for c-
met
, high-affinity HGF receptor mRNA, was also upregulated parallel to upregulation for HGF. In the kidney, liver, lung, and spleen, HGF mRNA was also maximally increased at 12 hours after reperfusion. However, c-
met
was not upregulated in these organs. Immunohistochemical studies disclosed that capillary endothelial and interstitial cells, including infiltrating macrophages, were intensely stained for HGF, whereas capillary endothelial cells in the reperfused myocardium were positive for c-Met.

Conclusions
This study is the first to show that myocardial ischemia and reperfusion induced HGF expression in various organs in vivo. These results indicate that HGF/c-Met plays a role in capillary endothelial cell regeneration in the ischemically injured heart.
Mapping of Familial Primary Pulmonary Hypertension Locus
(PPH1)
to Chromosome 2q31-q32
Authors: Morse Jane H. , Jones Alison C. , Barst Robyn J. , Hodge Susan E. , Wilhelmsen Kirk C. , Nygaard Torbjoern G.
Published: June 2012

Background
The pathogenesis of primary pulmonary hypertension (PPH) is unknown, although in some instances families with multiple affected members suggest a genetic etiology.

Methods and Results
We used microsatellite markers and linkage analysis in a large family with PPH to determine the chromosomal location of their disease gene. We tested a second, ethnically distinct, family for cosegregation of disease with markers from the linked region. We mapped the disease locus
PPH1
; GDB/HUGO designation (GDB:1381541; July 1996), approved when this work was accepted for publication in abstract form (
Circulation
. 1996;94[suppl I]:I-49.), in these families to a 27-cM region on chromosome 2q31-q32, with a maximum lod score of 3.87 associated with markers D2S350 and D2S364.

Conclusions
Cosegregation of this region with disease in different ethnic groups suggests that we mapped an important locus in familial PPH. Careful study of additional families and sporadic cases will be required to confirm this localization of PPH1 and characterize its overall role.
Load-Induced Growth Responses in Isolated Adult Rat Hearts
Authors: Thienelt Christiane D. , Weinberg Ellen O. , Bartunek Jozef , Lorell Beverly H.
Published: June 2012

Background
Stimulation of the angiotensin II type 1 (AT
1
) receptor by angiotensin II appears to be mandatory for the acute load-induced hypertrophic response of cultured neonatal rat cardiocytes, but its role in the adult heart is controversial. We tested the hypothesis that AT
1
receptor blockade will inhibit the acute induction of proto-oncogenes and protein synthesis by the elevation of systolic wall stress in isolated beating adult rat hearts.

Methods and Results
Using the established isovolumic perfused heart preparation under constant coronary flow, we found that an increment in left ventricular balloon volume generated an increase in systolic wall stress. The induction of left ventricular c-
fos
and c-
myc
mRNA (Northern blotting) was assessed in hearts subjected to increased systolic load without AT
1
blockade (No AT
1
, n=11) and with AT
1
blockade (AT
1
, n=11, losartan 40 mg·kg
−1
·d
−1
×5 days followed by 10
−5
mol/L infusion during perfusion). Flaccid hearts (no left ventricular balloon) served as controls (C, n=9). The stimulation of new protein synthesis in response to increased systolic load was measured by incorporation of [
3
H]phenylalanine into cardiac proteins. Elevation of systolic load was associated with a twofold (
P
<.05) increase in c-
fos
and c-
myc
mRNA levels that was not blocked by losartan. The rate of [
3
H]phenylalanine incorporation into cardiac proteins was increased 2.7-fold (
P
<.01) in hearts subjected to increased systolic load compared with control hearts. However, AT
1
receptor blockade with losartan did not prevent the stimulation of [
3
H]phenylalanine incorporation (881±97 versus 923±82 nmol·g protein
−1
·h
−1
,
P
=NS).

Conclusions
In contrast with immature myocytes subjected to stretch, the acute growth responses induced by systolic pressure overload in adult rat hearts do not depend on AT
1
receptor activation.
Sympathetic Alternans
Authors: Ando Shin-ichi , Dajani Hilmi R. , Senn Beverley L. , Newton Gary E. , Floras John S.
Published: June 2012

Abstract
Alternation in the amplitude of muscle sympathetic nerve activity (MSNA) was documented in three patients with severe heart failure. In the index patient with pulsus alternans, the amplitude of MSNA was inversely related to changes in the preceding diastolic pressure with a lag time of 1.2 to 1.3 seconds, indicating that oscillations in burst amplitude are determined primarily by changes in this component of blood pressure. Spectral analysis of the blood pressure and MSNA signals identified two spectral peaks, one at the cardiac frequency and a second peak, with greater spectral power, at the alternans frequency (ie, at half the heart rate). The latter peak for both blood pressure and MSNA disappeared when alternans was abolished by nitroglycerin. The presence of sympathetic alternans in synchrony with pulsus alternans and the rapid transduction of changes in the diastolic blood pressure afferent signal to the amplitude of sympathetic outflow indicate that the arterial baroreflex control of MSNA must be active and rapidly responsive in human heart failure.