bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-Related Differences in Autonomic Modulation of Heart Rate in Middle-aged Subjects
Authors: Huikuri Heikki V. , Pikkuja¨msa¨ Sirkku M. , Airaksinen K.E. Juhani , Ika¨heimo Markku J. , Rantala Asko O. , Kauma Heikki , Lilja Mauno , Kesa¨niemi Y. Antero
Published: June 2012

Background
Women have worse outcomes when they experience acute myocardial infarction (MI), but the reasons for this sex-related difference are not well understood. Because cardiovascular neural regulation plays an important role in cardiac mortality, we studied possible sex-related differences in the autonomic modulation of heart rate (HR) in middle-aged subjects without known heart disease.

Methods and Results
Baroreflex sensitivity (BRS) and HR variability were studied in randomly selected, age-matched populations of middle-aged women (n=186; mean age, 50±6 years) and men (n=188; mean age, 50±6 years) without hypertension, diabetes, or clinical or echocardiographic evidence of heart disease. BRS measured from the overshoot phase of the Valsalva maneuver was significantly lower in women (8.0±4.6 ms/mm Hg, n=152) than in men (10.5±4.6 ms/mm Hg, n=151) (
P
<.001), and the low-frequency component of HR variability measured from ECG recordings also was lower in women (
P
<.001), whereas the high-frequency component was higher in women than in men (
P
<.001). The ratio between the low- and high-frequency oscillations also was lower in the women (
P
<.001). The increase of HR and decrease of high-frequency component of HR variability in response to an upright posture were smaller in magnitude in women than in men (
P
<.01 for both). After adjustment for differences in the baseline variables, such as blood pressure, HR, smoking, alcohol consumption, and psychosocial score, the sex-related differences in BRS and HR variability still remained significant (
P
<.001 for all). Women with estrogen replacement therapy (n=46) had significantly higher BRS and total HR variance than the age-matched women without hormone treatment (
P
<.01 for both), and the BRS and HR variability of the women with estrogen therapy did not differ from those of the age-matched men.

Conclusions
Baroreflex responsiveness is attenuated in middle-aged women compared with men, but the tonic vagal modulation of HR is augmented. Hormone replacement therapy appears to have favorable effects on the cardiovascular autonomic regulation in postmenopausal women.
In Vitro Flow Mapping of Regurgitant Jets
Authors: Diebold Benoit , Delouche Annie , Delouche Philippe , Guglielmi Jean-Paul , Dumee Philippe , Herment Alain
Published: June 2012

Background
Color Doppler and magnetic resonance imaging give pictures of abnormal jets within which the respective contribution of fluid mechanics and image artifacts are difficult to establish because of current technical limitations of these modalities. We conducted the present study to provide numerical descriptions of the velocity fields within regurgitant free jets.

Methods and Results
Laser Doppler measurements were collected in rigid models with pulsatile flow conditions, giving several series of two-dimensional flow images. The data were studied with the use of two-dimensional or M-mode flow images as well as regular plots. Numerical descriptions validated in steady flow conditions were tested at the various times of the cycle. In these free jets, the momentum was conserved throughout the cycle. The transverse velocity profiles were approximately similar. A central laminar core was found at peak ejection and during the deceleration. Its length (
l
=4.08
d
−0.036 mm,
r
=.99) and its diameter (
d
) were proportional to the orifice diameter. At peak ejection, the velocity decay was hyperbolic, and the transverse velocity profiles were clearly gaussian. The different relations that were tested could be combined in a single formula describing the velocity field:

\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathit{V}(\mathit{x},\mathit{y},\mathit{t}_{\mathit{peak}}){=}\mathit{V}(0,0,\mathit{t}_{\mathit{peak}}){\cdot}4{\cdot}(\mathit{d}/\mathit{x}){\cdot}10^{{-}45(\mathit{y}/\mathit{x})^{2}}\ (\mathit{r}{=}.92).\) \end{document}

Conclusions
These in vitro measurements demonstrated the presence of a central laminar core and similar transverse velocity profiles in free turbulent jets. This allowed us to validate a series of numerical relations that can be combined to describe the velocity fields at peak ejection. On the other hand, further studies are needed to describe the various singularities often encountered in pathology.
Recombinant Staphylokinase Variants With Altered Immunoreactivity
Authors: Collen De´sire´ , Moreau Huberte , Stockx Luc , Vanderschueren Steven
Published: June 2012

Background
The substitution variants K35A,E38A,K74A,E75A,R77A (SakSTAR.M38) and K74A,E75A,R77A,E80A,D82A (SakSTAR.M89) of recombinant staphylokinase (SakSTAR) with reduced antibody reactivity were assayed for thrombolytic potency and antibody induction in animal models and in patients.

Methods and Results
In a
125
I-fibrin–labeled pulmonary embolism model in the hamster, the doses giving 50% clot lysis in 90 minutes were 25 μg/kg for SakSTAR, 85 μg/kg for SakSTAR.M38, and 90 μg/kg for SakSTAR.M89. In rabbits with
125
I-fibrin–labeled plasma clots incorporated into extracorporeal arteriovenous loops, lysis within 2 hours was 76±18% (mean±SD, n=28) with 400 μg/kg SakSTAR, 53±13% (n=8) with 1000 μg/kg SakSTAR.M38, and 39±13% (n=6) with 800 μg/kg SakSTAR.M89. When groups of eight rabbits were immunized by intravenous administration of 0.2 to 1.0 mg/kg compound followed by subcutaneous injection of 0.4 mg in Freund's adjuvant at 2, 3, and 5 weeks, SakSTAR.M38 and SakSTAR.M89 elicited markedly less circulating neutralizing activity, compared with SakSTAR, when determined at 6 weeks (neutralizing 6.1±3.0 and 4.9±1.3 μg compound/mL plasma, respectively, versus 20±17 μg/mL;
P
=.02 and
P
=.01, respectively) and induced significantly less resistance to thrombolysis (residual thrombolytic potency producing 59±25% and 39±12% lysis, respectively, versus 8.5±5.7%;
P
=.008 and
P
=.006, respectively). In patients with peripheral arterial occlusion, intra-arterial administration of SakSTAR.M38 (n=4) or SakSTAR.M89 (n=4) induced significantly fewer circulating neutralizing antibodies (
P
=.03) and specific IgG (
P
=.01) at 2 to 3 weeks than SakSTAR (n=8).

Conclusions
SakSTAR.M38 and SakSTAR.M89 induce less antibody formation and might constitute preferred agents for thrombolytic therapy in humans.
Platelet Activation and Coronary Stent Implantation
Authors: Gawaz Meinrad , Neumann Franz-Josef , Ott Ilka , May Andreas , Scho¨mig Albert
Published: June 2012

Background
Platelet activation and surface expression of adhesive glycoproteins play a key role in ischemic thrombotic complications after coronary intervention. The purpose of this case-control study was to evaluate the effects of two different antithrombotic regimens on platelet function after coronary Palmaz-Schatz stent implantation.

Methods and Results
The study group consisted of 46 “low-risk” patients who were treated with ticlopidine (250 mg BID) and aspirin (100 mg BID) after stenting. The control group was derived from a cohort of 151 patients receiving conventional anticoagulation therapy, including phenprocoumon (target international normalized ratio, 3.5), heparin (activated partial thromboplastin time, 80 to 120 seconds), and aspirin (100 mg BID) after stenting. Criteria for matching were indication for stenting, target vessel, balloon size, inflation pressure, and number of inserted stents. Matches were obtained for 38 patients. Platelet function was evaluated before and daily for 12 days after stenting in venous blood samples with immunologic activation markers. Patients receiving anticoagulation therapy showed a significantly increased surface exposure of LIBS1 (activated fibrinogen receptor;
P
<.05) and CD62P (P-selectin;
P
<.001) above prestent values, peaking days 3 to 6 after stenting. In contrast, in patients receiving ticlopidine, expression of LIBS1 decreased (
P
<.01) and expression of CD62P remained basically unchanged after stenting. Platelet count significantly decreased after stenting in patients treated by anticoagulation (day 3;
P
<.01), whereas no significant changes were found in the ticlopidine group.

Conclusions
Significant platelet activation occurs in patients receiving anticoagulation therapy after stenting, while platelet deactivation is found in patients treated with combined antiplatelet therapy. This may contribute to a lowering of the incidence of subacute stent thrombosis.
Determinants of Increased Regional Left Atrial Coagulation Activity in Patients With Mitral Stenosis
Authors: Peverill Roger E. , Harper Richard W. , Gelman John , Gan T. Eng , Harris Geoff , Smolich Joseph J.
Published: June 2012

Background
Recent evidence suggests that regional left atrial coagulation activity may be increased in mitral stenosis and perhaps contribute to the pathophysiology of left atrial thrombus. However, the relation of left atrial coagulation activity to factors that predispose to left atrial thrombus formation is unknown, and the relation between left atrial and systemic coagulation activities is unresolved.

Methods and Results
Left atrial and peripheral venous levels of the coagulation marker prothrombin fragment 1+2 (F1+2) were measured in 32 patients with mitral stenosis with normal clotting times and no left atrial thrombus who were undergoing percutaneous balloon mitral valvuloplasty. Baseline peripheral venous F1+2 levels, measured at the beginning of the valvuloplasty procedure, did not differ from those of 30 age-matched control patients. Prevalvuloplasty left atrial F1+2 levels, obtained immediately after transseptal puncture, were similar to femoral venous levels in patients without left atrial spontaneous echo contrast (LASEC) (0.81±0.32 versus 0.81±0.27 nmol/L, n=7) but greater than femoral venous levels in patients with LASEC and either sinus rhythm (1.57±0.86 versus 0.99±0.38 nmol/L, n=16,
P
<.001) or atrial fibrillation (1.52±0.69 versus 0.85±0.33 nmol/L, n=9,
P
<.003). Furthermore, LASEC emerged as the only significant predictor of increased regional left atrial coagulation activity (
P
=.005) on stepwise multivariate logistic regression analysis.

Conclusions
Increased regional left atrial coagulation activity in mitral stenosis occurs in the presence of LASEC, is evident in either sinus rhythm or atrial fibrillation, and is associated with normal systemic coagulation activity.
A Meta-analysis of the Association of the Deletion Allele of the Angiotensin-Converting Enzyme Gene With Myocardial Infarction
Authors: Samani Nilesh J. , Thompson John R. , O'Toole Laurence , Channer Kevin , Woods Kent L.
Published: June 2012

Background
The
ACE
gene is characterized by a polymorphism based on the presence (insertion [
I
]) or absence (deletion [
D
]) within intron 16 of a 287-basepair
alu
repeat sequence, resulting in three genotypes. Subsequent studies have produced conflicting findings. To further evaluate the association of the
ACE
I/D
genotype with MI risk, we carried out a meta-analysis of all the published studies.

Methods and Results
In total, 15 studies containing 3394 MI cases and 5479 control subjects were analyzed. The overall distribution of genotypes in the control subjects was 22.7%
II,
49.0%
ID,
and 28.3%
DD
. The mean odds ratio for MI for
DD
versus
ID/II
genotypes across all studies was 1.26 (95% CI, 1.15, 1.39;
P
<.0001). Pairwise odds ratios were 1.36 (95% CI, 1.19, 1.55) for
DD
and
II,
1.24 (95% CI, 1.11, 1.38) for
DD
and
ID,
and 1.09 (95% CI, 0.96, 1.23) for
ID
and
II.
The relative risk appeared to be increased in Japanese populations (2.55; 95% CI, 1.75, 3.70).

Conclusions
Within the limitations of the available data, the meta-analysis therefore supports an association of the
ACE D
allele with MI risk and strengthens the justification for further evaluation in appropriately powered studies.
Experimental Model for an Ectopic Focus Coupled to Ventricular Cells
Authors: Kumar Rajiv , Wilders Ronald , Joyner Ronald W. , Jongsma Habo J. , Verheijck E. Etienne , Golod David A. , van Ginneken Antoni C.G. , Goolsby William N.
Published: June 2012

Background
We used a mathematical model of a sinoatrial nodal cell (SAN model) electrically coupled to real ventricular cells (VCs) to investigate action potential conduction from an automatic focus.

Methods and Results
Since input resistance of a VC is less than that of an SAN cell, coupling of the SAN model, with a size factor of 1, to a VC produced either (1) spontaneous pacing at the slower rate of the SAN model but without driving (activation) of the VC for lower values of coupling conductance (G
j
) or (2) inhibition of pacing of the SAN model by electrical coupling to the VC for higher values of G
j
. When the SAN model was adjusted in size to be 3 to 5 times larger than a sinoatrial nodal cell, thus making effective SAN model capacitance 3 to 5 times larger and input resistance 3 to 5 times smaller, the SAN model propagated activity to the coupled VC for G
j
above a critical value. When the VC was paced at 1 Hz, the coupled cell pair demonstrated a stable rhythm of alternating cycle lengths and alternating conduction directions. By increasing pacing frequency to 2 Hz, we converted this rhythm to a regular 2-Hz frequency in which each action potential originated in the VC. More complex periodic interactions were observed at intermediate cycle lengths and lower or higher values of G
j
.

Conclusions
The phenomena we observed demonstrate the critical role of the size of an automatic focus as well as the coupling in the propagation of activity from the focus into surrounding myocardium.
Respiratory Sinus Arrhythmia
Authors: Hayano Junichiro , Yasuma Fumihiko , Okada Akiyoshi , Mukai Seiji , Fujinami Takao
Published: June 2012

Background
The primary mechanisms of respiratory sinus arrhythmia (RSA) are understood to be the modulation of cardiac vagal efferent activity by the central respiratory drive and the lung inflation reflex, and the degree of RSA increases with cardiac vagal activity. However, it is unclear whether RSA serves an active physiological role or merely reflects a passive cardiovascular response to respiratory input. We hypothesized that RSA benefits pulmonary gas exchange by matching perfusion to ventilation within each respiratory cycle.

Methods and Results
In seven anesthetized dogs, a model simulating RSA was made. After elimination of endogenous autonomic activities, respiration-linked heartbeat fluctuations were generated by electrical stimulation of the right cervical vagus during negative pressure ventilation produced by phrenic nerve stimulation (diaphragm pacing). The vagal stimulation was performed in three conditions: phasic stimulation during expiration (artificial RSA) and during inspiration (inverse RSA) and constant stimulation (control) causing the same number of heartbeats per minute as the phasic stimulations. Although tidal volume, cardiac output, and arterial blood pressure were unchanged, artificial RSA decreased the ratio of physiological dead space to tidal volume (V
d
/V
t
) and the fraction of intrapulmonary shunt (Q
sp
/Q
t
) by 10% and 51%, respectively, and increased O
2
consumption by 4% compared with control. Conversely, reverse RSA increased V
d
/V
t
and Q
sp
/Q
t
by 14% and 64%, respectively, and decreased O
2
consumption by 14%.

Conclusions
These results support our hypothesis that RSA benefits the pulmonary gas exchange and may improve the energy efficiency of pulmonary circulation by “saving heartbeats.”
Response of Type I Atrial Fibrillation to Atrial Pacing in Humans
Authors: Daoud Emile G. , Pariseau Brett , Niebauer Mark , Bogun Frank , Goyal Rajiva , Harvey Mark , Man K. Ching , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
High-density mapping studies of atrial fibrillation (AF) have suggested the presence of an excitable gap. The purpose of this study was to assess the local and left atrial response to pacing at the high right atrium during type I AF in humans.

Methods and Results
Pacing was performed at the high right atrium during type I AF in 24 patients in the electrophysiology laboratory. The response to pacing was assessed at cycle lengths 10, 20, 30, 40, and 50 ms less than the mean baseline atrial cycle length. Digitized tracings of the baseline tachycardia and the response to pacing were recorded from the high right atrium and from the distal coronary sinus. Computer analysis of these signals was used to calculate a left atrial electrogram density before, during, and after pacing. Two hundred eighty-eight segments of AF with a duration of 3.9±0.5 seconds (mean±SD) were analyzed. Local capture of the right atrium during AF was demonstrated for at least one pacing cycle length in each patient. The left atrial electrogram density was significantly greater than baseline at each pacing cycle length that resulted in local capture, except when pacing at 50 ms less than the mean AF cycle length. There was no significant change in the baseline left atrial electrogram density compared with baseline when pacing did not result in local capture of AF.

Conclusions
Local right atrial capture is often possible by pacing during type I AF and consistently influences the left atrial electrograms recorded in the coronary sinus. These results confirm the presence of excitable tissue in the right and left atria in type I AF.
Differential Dose-Response to Oral Xemilofiban After Antecedent Intravenous Abciximab
Authors: Kereiakes Dean J. , Runyon John Paul , Kleiman Neal S. , Higby Nancy A. , Anderson Linda C. , Hantsbarger Gary , McDonald Shawn , Anders Robert J.
Published: June 2012

Background
Placebo-controlled randomized trials of parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated reduced ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers are being developed to allow more sustained receptor antagonism with potential for long-term secondary prevention. Sequential therapy with abciximab followed by an oral IIb/IIIa antagonist has not previously been reported. The clinical safety and pharmacodynamics of a sequential therapeutic strategy are unknown.

Methods and Results
Of 74 consecutive patients enrolled in a placebo-controlled, dose-ranging pharmacokinetic/pharmacodynamic study of xemilofiban, a new oral nonpeptide GP IIb/IIIa antagonist, after elective intracoronary stent placement, 17 patients received abciximab during stent deployment as a weight-adjusted intravenous bolus and 12-hour infusion at the discretion of the investigator. Ex vivo platelet aggregation in response to 20 μmol/L ADP and 4 μg/mL collagen was measured over time after the first dose of either xemilofiban (5, 10, 15, or 20 mg) or placebo (ticlopidine) administered 8 to 18 hours after termination of abciximab and again after 1 week of twice-daily oral administration of study drug. At baseline, patients who had received abciximab had lower platelet aggregation in response to both agonists (
P
<.001). A significant dose-response relationship to xemilofiban was observed. Patients who had received abciximab had lower ADP-induced (
P
≤.010) and collagen-induced (
P
≤.029) platelet aggregation after xemilofiban. This pharmacodynamic interaction was no longer evident at 1 week. No significant clinical bleeding events or blood product transfusions were observed in this trial.

Conclusions
Both the magnitude and the duration of pharmacodynamic response to xemilofiban were enhanced by prior abciximab treatment. The potentiated pharmacodynamic response was not evident after 1 week. This observation has implications for the safety and efficacy of sequential parenteral-oral GP IIb/IIIa blockade therapy and may be useful in deriving dose regimens for orally administered compounds.
Hospital Readmission in Patients Treated With Tiered-Therapy Implantable Defibrillators
Authors: Fahy Gerard J. , Sgarbossa Elena B. , Tchou Patrick J. , Pinski Sergio L.
Published: June 2012

Background
We wished to determine the incidence, reasons, costs, and predictors of cardiac-related hospital readmission in patients with tiered-therapy implantable defibrillators. Hospital readmission in patients with defibrillators reduces their quality of life and increases the cost associated with such therapy.

Methods and Results
We retrospectively studied 65 consecutive local patients (median age, 67 years; median ejection fraction, 0.34) who underwent tiered-therapy defibrillator implantation at this institution. Patients were followed for a median of 19 months (interquartile range, 10 to 27 months). The cause, duration, costs, and predictors of cardiac-related rehospitalizations were analyzed. There were 76 cardiac admissions for 34 patients. The rate of cardiac-related hospital readmission was 0.72 per patient-year of follow-up. Arrhythmia-related admissions accounted for 43 of such admissions in 24 patients. Actuarial freedom from cardiac-related admissions was 0.57 and 0.40 at 1 and 2 years, respectively. The median length of stay for hospital readmissions was 5 days (interquartile range, 3 to 8 days). The median cost per admission was $5842 (interquartile range, $3549 to $12 170). The time to first readmission and the total rehospitalization time per year of follow-up were associated with a poor preimplant New York Heart Association functional class. Readmission for cardiac arrhythmias was not predicted by clinical parameters.

Conclusions
Rehospitalization for cardiac reasons is common in patients receiving implantable defibrillators and is responsible for substantial resource consumption. The need for readmission for arrhythmia-related reasons cannot be predicted by clinical parameters at the time of device implantation.
Transcatheter Subendocardial Infusion
Authors: Goette Andreas , Hartung Wolfgang , Lesh Michael , Honeycutt Clegg , Fleischman Sidney , Swanson David , Langberg Jonathan
Published: June 2012

Background
Catheter ablation with radiofrequency energy is feasible in a limited subset of patients with ventricular tachycardia. The purpose of this study was to evaluate a technique for mapping and ablation of ventricular myocardium with the use of transcatheter subendocardial infusion.

Methods and Results
A needle-tipped deflectable electrode catheter was used to deliver reagents to endocardial target sites. This was equipped with two central lumens to allow sequential administration of mapping and ablation injectants with minimal admixture. The mapping injectant consisted of a mixture of lidocaine, iohexal, and glycerin; the ablation injectant contained ethanol, iohexal, and glycerin. Infusion of the mapping injectant (1 cm
3
over 3 or 5 seconds, n=14) produced a stain on fluoroscopy and increased local capture threshold by 61%. No lesions resulted from mapping infusions. Infusion of the ethanol-containing injectant (n=48) produced discrete lesions, with a mean volume ranging from 0.6 to 1.5 cm
3
. There was a direct relationship between infusion volume, infusion duration, and resultant lesion volume. Fibrosis in a region of healed myocardial infarction did not impair diffusion of the injectant or affect lesion dimensions. Microscopic analysis of chronic lesions showed a sharply demarcated border zone between fibrotic and normal myocardium.

Conclusions
Transcatheter subendocardial infusion can be used to reversibly impair local excitability and mark an injection site fluoroscopically. Subendocardial injection of ethanol can predictably ablate a large volume of ventricular myocardium. Additional study of this system in an arrhythmia model will help to define its potential for mapping and ablation of hypotensive ventricular tachycardia.
Rapid Shortening During Relaxation Increases Activation and Improves Systolic Performance
Authors: Watkins Matthew W. , Higashiyama Akihiro , Chen Zengyi , LeWinter Martin M.
Published: June 2012

Background

Previous studies in cardiac muscle and isolated heart preparations generally have attributed positive effects of ejection to greater length-dependent activation. However, there have been some reports of an ejection-related increase in contractile function that is independent of end-diastolic volume (EDV) history. The present study was designed to more fully characterize the mechanoenergetic results of the latter effect in the intact ventricle.

Methods and Results
A servomotor was used to initiate left ventricular volume reduction (VR) at end systole, with EDV kept constant. Seven isolated, red blood cell-perfused rabbit hearts were studied at constant EDV during isovolumic contraction, slow VR (5.0±0.9 EDV/s), and rapid VR (26.8±5.1 EDV/s). Compared with isovolumic beats, VR caused an enhancement in contractility. This effect was greater for rapid VR and required >50 beats to attain steady state. Rapid VR increased developed pressure by 15% (92.2±23.7 [mean±SD] versus 105.9±27.6 mm Hg), maximum dP/dt by 17% (1223±401 versus 1435±505 mm Hg·s
−
1
), and E
max
(slope of the end-systolic pressure-volume relation) by 13% (69.4±19.9 versus 78.6±23.0 mm Hg/mL) (all
P
<.01). Left ventricular oxygen consumption (V̇
o
2
) was unchanged with slow VR and decreased by 8% with rapid VR (0.0744±0.0194 versus 0.0683±0.0141 mL O
2
·beat
−
1
·100 g
−
1
;
P
<.05). In separate hearts (n=8), costs (basal metabolism and excitation-contraction coupling) were estimated by use of 2,3-butanedione monoxime. Compared with control, rapid VR was associated with a 26% increase in nonmechanical V̇
o
2
(0.0248±0.0021 versus 0.0312±0.0022 mL O
2
·beat
−
1
·100 g
−
1
;
P
<.01), consistent with an increase in calcium cycled per beat.

Conclusions
Ejection after end systole has a positive effect on ventricular performance that cannot be ascribed to length-dependent activation and is likely related to an increase in calcium available for activation. Similarly, an increase in nonmechanical V̇
o
2
associated with ejection suggests a positive interaction between myofilament shortening and activator calcium cycling.
Asymptomatic Cardiac Ischemia Pilot (ACIP) Study
Authors: Stone Peter H. , Chaitman Bernard R. , McMahon Robert P. , Andrews Thomas C. , MacCallum Gail , Sharaf Barry , Frishman William , Deanfield John E. , Sopko George , Pratt Craig , Goldberg A. David , Rogers William J. , Hill James , Proschan Michael , Pepine Carl J. , Bourassa Martial G. , Conti C. Richard
Published: June 2012

Background
We investigated whether the presence and frequency of asymptomatic ischemic episodes recorded during ambulatory ECG (AECG) monitoring could be predicted on the basis of clinical characteristics or exercise treadmill test (ETT) performance in patients with stable coronary disease and whether the estimate of ischemia severity was similar between the AECG and ETT.

Methods and Results
Patients screened for the Asymptomatic Cardiac Ischemia Pilot (ACIP) study were selected for the current analysis if data were available from 48-hour AECG monitoring as well as from an ETT during which the patient developed ≥1-mm ST-segment depression. Exercise ECG data were available for 143 of the 910 patients without ischemic episodes and for 659 of the 910 patients with ischemic episodes during AECG monitoring. Angina was more frequent among patients with ambulatory ischemic episodes than among patients without such ischemia (
P
<.001). Patients with AECG ischemia had a consistently more marked ischemic response on the ETT than patients without AECG ischemia; patients likely to have AECG ischemia could be predicted on the basis of ETT performance characteristics. However, the correlation coefficients between the severity of ischemia estimated by ETT and by AECG were small.

Conclusions
There are significant relations between ischemia detected by AECG monitoring and by ETT, but the relations are limited, indicating that the two tests are not redundant to characterize coronary patients. A larger study investigating the prognostic significance of the ischemia identified by each modality, with follow-up for clinical events, will be necessary to determine the most appropriate methods to evaluate patients with stable coronary disease.
Fluid Flow Inhibits Endothelial Adhesiveness
Authors: Tsao Philip S. , Buitrago Ricardo , Chan Jason R. , Cooke John P.
Published: June 2012

Background
In the arterial tree, regions exposed to reduced shear stress (low and/or disturbed flow) are predisposed to atherogenesis. Fluid flow is a potent stimulus for the release of endothelium-derived nitric oxide (NO). Because NO inhibits monocyte–endothelial cell interaction, we speculated that the effects of flow in inhibiting atherogenesis might be mediated in part by NO.

Methods and Results
Confluent monolayers of human aortic endothelial cells were exposed to static or fluid flow conditions for 4 hours. The medium was replaced, and cells were then incubated with native LDL (50 μg/mL), oxidized LDL (30 μg/mL), or lipopolysaccharide (LPS) (10 ng/mL) + tumor necrosis factor-α (TNF-α) (10 U/mL) for an additional 4 hours. Functional binding assays using THP-1 monocytes were then performed. Superoxide production by human aortic endothelial cells was monitored by lucigenin chemiluminescence, and expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 were quantified by flow cytometry. Whereas native LDL had little effect, incubation with either oxidized LDL or LPS/TNF-α significantly increased superoxide production, nuclear factor-κB activity, VCAM-1 expression, and endothelial adhesiveness for monocytes. Previous exposure to fluid flow inhibited these sequelae of exposure to cytokines or oxidized lipoprotein. The effect of fluid flow appears to be due in part to shear-induced release of NO, because coincubation with nitro-
l
-arginine completely abolished these effects of flow. Furthermore, the NO donor PAPA-NONOate and 8-Br-cGMP (but not 8-Br-cAMP) mimicked the effects of flow.

Conclusions
Previous exposure to fluid flow decreased cytokine- or lipoprotein-stimulated endothelial cell superoxide production, VCAM-1 expression, and monocyte binding; the effects of flow appear to be due to NO. Flow-mediated NO-dependent regulation of oxidant-responsive transcription may influence the site of a lesion.
Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries
Authors: van der Giessen Willem J. , Lincoff A. Michael , Schwartz Robert S. , van Beusekom Heleen M.M. , Serruys Patrick W. , Holmes David R. , Ellis Stephen G. , Topol Eric J.
Published: June 2012

Background
With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery.

Methods and Results
Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90° of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79±0.22, 1.12±0.01, 2.36±0.60, 1.24±0.36, and 1.43±0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46±0.18 and 0.61±0.23 mm, respectively) and for the nonbiodegradable PETP (0.46±0.11 mm).

Conclusions
An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.
Reduced Arrhythmogenicity of Biphasic Versus Monophasic T-Wave Shocks
Authors: Behrens Steffen , Li Cuilan , Kirchhof Paulus , Fabritz F. Larissa , Franz Michael R.
Published: June 2012

Background
Biphasic waveforms defibrillate more effectively than monophasic waveforms; however, the mechanism remains unknown. The “upper-limit-of-vulnerability” hypothesis of defibrillation suggests that unsuccessful defibrillation is due to reinduction of ventricular fibrillation (VF). Thus, VF induction mechanisms may be important for the understanding of defibrillation mechanisms. We therefore compared myocardial VF vulnerability for monophasic versus biphasic shocks.

Methods and Results
In 10 Langendorff-perfused rabbit hearts, monophasic and biphasic T-wave shocks were randomly administered over a wide range of shock coupling intervals and shock strengths, and the two-dimensional coordinates within which VF was induced were used to calculate the area of vulnerability (AOV) for both shock waveforms. The arrhythmic response to biphasic shocks differed from that to monophasic shocks in three distinct ways: (1) the AOV was smaller (8.9±4.2 versus 13.9±6.0 area units,
P
<.02), (2) the transition zone between VF-inducing and nonarrhythmogenic shocks was narrower (14.7±4.8 versus 29.9±6.4 area units,
P
<.001), and (3) the entire AOV shifted toward longer coupling intervals (by 11.0±8.8 ms at the left border [
P
<.005] and 6.0±5.2 ms at the right border [
P
=.005] of the AOV).

Conclusions
Biphasic shocks encounter a smaller AOV than monophasic shocks, a narrower transition zone from VF to no arrhythmia induction, and a lesser effectiveness in inducing VF at short coupling intervals. In keeping with the upper-limit-of-vulnerability hypothesis, these waveform-dependent differences in VF inducibility might help explain the lower defibrillation threshold for biphasic shocks.
Antiviral Treatment With WIN 54 954 Reduces Mortality in Murine Coxsackievirus B3 Myocarditis
Authors: Fohlman J. , Pauksen K. , Hyypia¨ T. , Eggertsen G. , Ehrnst A. , Ilba¨ck N.G. , Friman G.
Published: June 2012

Background
Coxsackieviruses B (CBVs) are dominant causative agents in myocarditis and are associated with pathogenesis in some cases of dilated cardiomyopathy, a clinical entity with a poor survival without heart transplantation.

Methods and Results
In vitro, the antiviral agent WIN 54 954 was shown to inhibit replication of CBV3 at a minimal inhibitory concentration value of 0.02 mg/L. Administration of WIN 54 954, 100 mg/kg BID PO, beginning on the day of infection resulted in complete protection from enteroviral mortality (
P
<.01). WIN 54 954 treatment did not abrogate the inflammatory reaction in the myocardium. No difference was found in the expression of surface lymphocyte subset markers. At 3 weeks, macrophages seemed to dominate the inflammatory reaction, regardless of treatment. There was no difference in CBV3 antibody titers, indicating that WIN 54 954 does not interfere with the development of protective immunity. Complement factors C3 and B were synthesized at a higher level during infection and correlated well with the degree of inflammatory reaction.

Conclusions
The results show that WIN 54 954 is a potent antiviral agent with a highly significant effect on survival in CBV-induced myocarditis in the A/J mouse if treatment is started early. It is suggested that the reduction in mortality seen with WIN 54 954 administration is due to an inhibitory effect on virus replication in affected organs that does not interfere with cellular or humoral immunity.
Long-term Implications of Reocclusion on Left Ventricular Size and Function After Successful Thrombolysis for First Anterior Myocardial Infarction
Authors: Nijland Francisca , Kamp Otto , Verheugt Freek W.A. , Veen Gerrit , Visser Cees A.
Published: June 2012

Background
Successful thrombolysis can prevent left ventricular dilatation after acute myocardial infarction. However, in almost 30% of patients, reocclusion occurs. The aim of this study was to assess the long-term implications of reocclusion on left ventricular size and function.

Methods and Results
Fifty-six patients were studied with two-dimensional echocardiography at baseline (2±1.6 days) and 5.0±1.4 years after first anterior myocardial infarction. All patients (a subset of those enrolled in the APRICOT trial) had a patent infarct-related artery when studied <48 hours after thrombolysis and underwent repeat coronary angiography at 3 months. Baseline characteristics were comparable in patients with (n=17) and without reocclusion (n=39). Left ventricular volume indexes were stable in patients without reocclusion. Patients with reocclusion, however, showed a significant increase in end-diastolic volume index (EDVI;
P
=.008) and end-systolic volume index (ESVI;
P
=.039). Furthermore, patients without reocclusion demonstrated improvement in wall motion score index (WMSI;
P
=.0001) and ejection fraction (EF;
P
=.016), whereas patients with reocclusion did not. After 5 years, patients with reocclusion had significantly larger volume indexes (EDVI, 99±41 versus 76±22 mL/m
2
,
P
=.007; ESVI, 59±40 versus 39±20 mL/m
2
,
P
=.017) and more compromised left ventricular function (WMSI, 1.63±0.33 versus 1.39±0.32,
P
=.013; EF, 45±13% versus 51±11%,
P
=.077) than patients without reocclusion. Multivariate analysis identified baseline WMSI and reocclusion as significant independent predictors of left ventricular dilatation.

Conclusions
Reocclusion of the infarct-related artery within 3 months of successful thrombolysis is associated with left ventricular dilatation and is detrimental to functional recovery of left ventricular function 5 years after first anterior myocardial infarction.
ACE Inhibitors Promote Nitric Oxide Accumulation to Modulate Myocardial Oxygen Consumption
Authors: Zhang Xiaoping , Xie Yi-Wu , Nasjletti Alberto , Xu Xiaobin , Wolin Michael S. , Hintze Thomas H.
Published: June 2012

Background
ACE inhibitors potentiate kinin–nitric oxide (NO)–dependent coronary vascular dilation, and NO can modulate myocardial oxygen consumption. Whether ACE inhibitors also affect myocardial O
2
consumption has not been established.

Methods and Results
Production of nitrite, a metabolite of NO in aqueous solution, in coronary microvessels and O
2
consumption in myocardium were quantified with the use of in vitro tissue preparations, the Greiss reaction, and a Clark-type O
2
electrode. In coronary microvessels, kininogen (the precursor of kinin; 10 μg/mL) and three ACE inhibitors (captopril, enalaprilat, or ramiprilat; 10
−8
mol/L) increased nitrite production from 76±6 to 173±15, 123±12, 125±12, and 153±12 pmol/mg, respectively (all
P
<.05). In myocardium, kininogen (10 μg/mL) and captopril, enalaprilat, or ramiprilat (10
−4
mol/L) reduced cardiac O
2
consumption by 41±2%, 19±3%, 25±2%, and 35±2%, respectively. The changes in both nitrite release and O
2
consumption in vitro were blocked by
N
ω
-nitro-
l
-arginine methyl ester or
N
ω
-nitro-
l
-arginine, inhibitors of endogenous NO formation. The effects were also blocked by HOE 140, which blocks the bradykinin B
2
-kinin receptor, and serine protease inhibitors, which inhibit local kinin formation.

Conclusions
Our data indicate that stimulation of local kinin formation by use of a precursor for kinin formation or inhibition of kinin degradation by use of ACE inhibitors increases NO formation and is important in the control of cardiac O
2
consumption. Vasodilation and control of myocardial O
2
consumption by NO may contribute importantly to the therapeutic actions of ACE inhibitors in cardiac disease states.
Adhesion Molecule P-Selectin and Vascular Cell Adhesion Molecule–1 in Enhanced Heart Allograft Arteriosclerosis in the Rat
Authors: Koskinen Petri K. , Lemstro¨m Karl B.
Published: June 2012

Background
The increase of P-selectin on endothelial cells (EC) overlying human atherosclerotic plaques in classic atherosclerosis was recently established. We have previously shown that vascular cell adhesion molecule–1 (VCAM-1) is extensively expressed on EC of occluded arteries during accelerated transplant arteriosclerosis. In the present study, with the use of rat heart allografts under different doses of cyclosporine A (CsA), we investigated whether the expression of P-selectin is increased during chronic rejection and possibly coexpressed with VCAM-1 on EC.

Methods and Results
Rat cardiac allografts from DA donors to WF recipients were used. Without immunosuppression, these allografts show an irreversible rejection 7 days after transplantation. In the acute rejection model, syngeneic and allogeneic grafts were harvested 5 days after transplantation. In the chronic rejection model, allograft recipients received triple-drug immunosuppression, including azathioprine, methylprednisolone, and CsA in different doses. The grafts were removed 3 months after transplantation. During acute rejection, a significant expression of P-selectin (
P
<.01) and VCAM-1 (
P
<.05) on microvascular endothelia, but not on arteries, was noticed. During intense chronic rejection (5 mg/kg CsA), arterial EC expressed P-selectin (
P
<.01) and VCAM-1 (
P
<.05) extensively. The expression of tumor necrosis factor–α, a cytokine inducing both P-selectin and VCAM-1 expression, was upregulated in vascular medial cells (
P
<.05), in intimal cells (
P
<.01), and in interstitial mononuclear cells (
P
<.05). Linear regression analysis revealed a significant correlation between arterial P-selectin (
P
<.01) and VCAM-1 (
P
<.01) expression and the intensity of intimal thickening. Also, a significant correlation and coexpression of P-selectin and VCAM-1 in epicardial arteries was demonstrated (
P
<.05).

Conclusions
The early expression of P-selectin on microvascular EC during acute rejection may be the basis of cell adhesion and infiltration into the site of inflammation. During chronic rejection, the intensity of arterial intimal thickening was significantly correlated with the intensity of P-selectin expression on EC, in addition to that of previously reported VCAM-1 expression. Thus, P-selectin may have a crucial role in the pathogenesis of chronic rejection in the vascular wall, augmenting the immune-mediated injury against the allograft.
Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women
Authors: Schunkert Heribert , Danser A.H. Jan , Hense Hans-Werner , Derkx Frans H.M. , Ku¨rzinger Susanne , Riegger Gu¨nter A.J.
Published: June 2012

Background
Oral estrogen replacement therapy (ERT) is known to stimulate the synthesis of angiotensinogen. The effects of such therapy on renin, ACE, and aldosterone are less clear. This seems noteworthy, however, since further activation of the system could be disadvantageous to postmenopausal women who replace estrogen in the context of heart failure, coronary artery disease, or hypertension.

Methods and Results
Estrogen status and components of the renin-angiotensin system were examined in a population-based sample of postmenopausal women and age-matched men. Renin was quantified immunoradiometrically, ie, independent of substrate abundance; aldosterone, angiotensinogen, and ACE activity were determined by standard methods. Renin levels were lower in women with ERT (n=107; 12.0±0.7 mU/L) compared with women without ERT (n=223; 16.6±0.9 mU/L;
P
=.001) or men (n=342, 20.5±1.5 mU/L,
P
<.0001). In contrast, angiotensinogen was higher in women with ERT (1.36±0.08 mg/L) compared with women without ERT (1.03±0.02 mg/L;
P
<.0001) or compared with men (0.97±0.01 mg/L;
P
<.0001). Renin suppression was seen with either oral or transdermal estrogen replacement (−30% and −31%, respectively; both
P
<.001). In contrast, the increase of angiotensinogen was limited to women taking oral estrogens (+58%,
P
<.001). Multivariate analysis revealed that these estrogen effects were independent of age, body mass index, blood pressure, and/or antihypertensive medication. Finally, only marginal differences between groups were observed for serum ACE activity and aldosterone.

Conclusions
Aside from a well-documented induction of angiotensinogen, ERT is related to a substantial suppression of renin, a phenomenon that might have received little attention because of widely used indirect measurements of the hormone.
Dobutamine Enhances Cardiodepressant Effects of Receptor-Mediated Coronary Endothelial Stimulation
Authors: Bartunek Jozef , Shah Ajay M. , Vanderheyden Marc , Paulus Walter J.
Published: June 2012

Background
In humans, intracoronary infusion of substance P reduces left ventricular end-systolic pressure and left ventricular peak systolic pressure because of earlier onset of left ventricular relaxation induced by paracrine myocardial action of mediators released from the coronary endothelium. The present study investigated in humans the effects of β-adrenergic stimulation, which also induces earlier left ventricular relaxation, on the left ventricular myocardial contractile response to intracoronary infusion of substance P.

Methods and Results
Data were obtained in 13 patients after cardiac transplantation and in 3 patients with dilated nonischemic cardiomyopathy. Microtip left ventricular pressure recordings were obtained during a 5-minute intracoronary infusion of substance P (20 pmol/min) under control conditions and then repeated during concurrent intravenous administration of dobutamine. In the presence of dobutamine, intracoronary substance P caused a greater fall in left ventricular end-systolic pressure (transplantation control, −9±11 versus transplantation dobutamine, −20±18 mm Hg [
P
<.05]; cardiomyopathy control, −4±1 versus cardiomyopathy dobutamine, −10±3 mm Hg [
P
<.05]) and in left ventricular peak systolic pressure (transplantation control, −14±10 versus transplantation dobutamine, −30±22 mm Hg [
P
<.01]; cardiomyopathy control, −9±7 versus cardiomyopathy dobutamine, −15±6 mm Hg [
P
=.1]).

Conclusions
Dobutamine enhances the cardiodepressant effect on myocardial contractile performance of receptor-mediated coronary endothelial stimulation in transplant recipients and in patients with dilated nonischemic cardiomyopathy. This enhancement could result from a potentiating interaction of the relaxation-hastening effect exerted by β-adrenergic stimulation and by mediators released from the coronary endothelium, such as nitric oxide.