bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinically Silent Electrocardiographic Abnormalities and Risk of Primary Cardiac Arrest Among Hypertensive Patients
Authors: Siscovick David S. , Raghunathan T.E. , Rautaharju Pentti , Psaty Bruce M. , Cobb Leonard A. , Wagner Edward H.
Published: June 2012

Background
Whether continuous ECG indexes that reflect the severity of left ventricular hypertrophy (LVHI), myocardial injury (CIIS), and QT-interval prolongation (QTI) are associated with the risk of primary cardiac arrest among hypertensive patients, independent of conventional binary ECG criteria, remains unknown.

Methods and Results
We conducted a population-based case-control study among patients who were free of clinically recognized heart disease and who received care at a health maintenance organization. Cases (n=131) were treated hypertensive patients who had had a primary cardiac arrest between 1977 and 1990. Controls (n=562) were a stratified random sample of treated hypertensive patients. Resting ECGs were reviewed to estimate the severity of left ventricular hypertrophy, myocardial injury, and QT-interval prolongation on the basis of the algorithms of the Novacode ECG classification system. After adjustment for other risk factors and binary ECG criteria for the abnormalities, the LVHI, CIIS, and QTI scores were directly related to the risk of primary cardiac arrest. In a comparison of the 80th with the 20th percentile score for the LVHI, the risk was increased 40% (odds ratio, 1.4; 95% CI, 1.0 to 2.0); for the CIIS, the risk was increased 70% (odds ratio, 1.7; 95% CI, 1.2 to 2.5); and for the QTI, the risk was increased 80% (odds ratio, 1.8; 95% CI, 1.3 to 2.7).

Conclusions
Our findings suggest that continuous ECG indexes that reflect left ventricular hypertrophy, myocardial injury, and QT-interval prolongation are directly related to the risk of primary cardiac arrest among hypertensive patients without clinically recognized heart disease. Binary ECG criteria may underestimate the prognostic importance of these pathophysiological abnormalities.
Fetal Atrioventricular Flow-Velocity Waveforms and Their Relation to Arterial and Venous Flow-Velocity Waveforms at 8 to 20 Weeks of Gestation
Authors: van Splunder Paula , Stijnen Theo , Wladimiroff Juriy W.
Published: June 2012

Background
Doppler ultrasonography was used to determine the nature and gestational age-related changes of human fetal AV flow-velocity waveforms and to establish their relationship with arterial impedance indexes and venous flow velocities in normal human fetuses between 8 and 20 weeks of gestation.

Methods and Results
Flow-velocity waveform recordings were attempted in 318 singleton pregnancies. After the exclusion criteria were applied, data on 214 women were available for further analysis. Differentiation between E wave and A wave became possible at 9 weeks, whereas distinction between transmitral and transtricuspid valve flow velocities was first achieved at 10 to 11 weeks. A statistically significant nonlinear gestational age-dependent increase was established for all AV waveform parameters, which became linear when related to logarithmically estimated fetal crown-to-rump length. Transtricuspid valve flow velocities were significantly higher than transmitral valve flow velocities. Transmitral valve time-averaged flow velocities were positively correlated with peak diastolic velocities and time-velocity integral of late-diastolic reverse flow in the inferior vena cava. No correlation existed between AV time-averaged velocities and arterial impedance indexes.

Conclusions
Monophasic AV flow-velocity waveforms can be recorded as early as 8 weeks of gestation and become biphasic as early as 8 weeks. They demonstrate a linear increase relative to logarithmically estimated fetal crown-to-rump length, suggesting that fetal growth-related increase in volume flow plays a role in this velocity rise. Transtricuspid valve A-wave and E-wave velocities suggest right ventricular predominance as early as the late first trimester of pregnancy. AV flow velocities are not related to arterial downstream impedance.
Expression of an Estrogen Receptor by Human Coronary Artery and Umbilical Vein Endothelial Cells
Authors: Kim-Schulze Seunghee , McGowan Kelly A. , Hubchak Susan C. , Cid Maria C. , Martin Mary Beth , Kleinman Hynda K. , Greene Geoffrey L. , Schnaper H. William
Published: June 2012

Background
Premenopausal women have much lower susceptibility to coronary artery disease than do men or postmenopausal women. It has been proposed that estrogen plays a role in cardioprotection, but little information is available regarding the mechanism by which estrogen may help to protect the vasculature. Here, we describe an estrogen receptor (ER) in human coronary artery and umbilical vein endothelial cells.

Methods and Results
Human umbilical vein endothelial cells and human coronary artery endothelial cells were cultured in hormone-free medium for 48 hours before experiments. Estradiol (3.7 nmol/L) added to cultures promoted proliferation by a mechanism that is inhibited by the specific ER antagonist ICI182,780. Estradiol-treated cells incorporated twice the [
3
H]thymidine of hormone-free cells; this increase was prevented by ICI182,780. Endothelial cells from both sources stained in a nuclear pattern with an ER-specific antibody. Ribonuclease protection assay detected mRNA for the ER. Ligand-binding studies estimated 2×10
4
to 8×10
4
receptors per cell and a
K
d
of ≈5 nmol/L. Interaction of ERs with a consensus estrogen response element was shown by an electrophoretic mobility shift assay. In addition, an antibody against the ER supershifted the protein-DNA complex.

Conclusions
These studies define the presence of an ER in human coronary artery and umbilical vein endothelial cells. They support the hypothesis that cardioprotective effects of estrogen are mediated, at least in part, through a classic steroid hormone receptor mechanism.
Contractile Versus Microvascular Reserve for the Determination of the Extent of Myocardial Salvage After Reperfusion
Authors: Sklenar Jiri , Camarano Gustavo , Goodman N. Craig , Ismail Suad , Jayaweera Ananda R. , Kaul Sanjiv
Published: June 2012

Background
We hypothesized that microvascular reserve is a better indicator of the extent of viable myocardium postinfarction than contractile reserve, especially in the presence of a residual stenosis of the infarct-related artery.

Methods and Results
Fifteen dogs with various infarct sizes were studied after reperfusion. Contractile reserve, studied by use of dobutamine echocardiography, and microvascular reserve, studied by use of myocardial contrast echocardiography, were measured both before and after creation of a stenosis. In the absence of a stenosis, the relation between infarct size, expressed as percent of risk area, and wall thickening improved with increasing doses of dobutamine (
r
=.41, .71, and .90 for 5, 10, and 15 μg·kg
−
1
·min
−
1
, respectively;
P
<.01 for dobutamine 15 μg·kg
−
1
·min
−
1
). In the presence of a stenosis, however, the relation was poor for all doses of dobutamine (
r
=.22, .57, and .32 for 5, 10, and 15 μg·kg
−
1
·min
−
1
, respectively;
P
<.01 for 15 μg·kg
−
1
·min
−
1
dobutamine in the absence of a stenosis). There was a fair correlation between infarct size and perfusion defect size on myocardial contrast echocardiography after reperfusion (
r
=.82), with the defect size underestimating infarct size by approximately 20%. This relationship improved (
P
<.01) during infusions of both adenosine (
r
=.99) and dobutamine (
r
=.94) in the absence of a stenosis. The correlations between infarct size and perfusion defect on myocardial contrast echocardiography also remained good in the presence of a stenosis (
r
=.95 and .81 for adenosine and dobutamine, respectively;
P
=NS compared with stenosis).

Conclusions
Microvascular reserve is superior to contractile reserve for definition of the spatial topography of necrosis and hence the extent of viable myocardium within the infarct bed after reperfusion, particularly when a residual stenosis is present in the infarct-related artery.
Sex Hormones Prolong the QT Interval and Downregulate Potassium Channel Expression in the Rabbit Heart
Authors: Drici Milou D. , Burklow Thomas R. , Haridasse Vedanandam , Glazer Robert I. , Woosley Raymond L.
Published: June 2012

Background
Sex hormones are known to exert direct and indirect effects on cardiovascular function, but their effects on cardiac repolarization have not been elucidated. The repolarization phase of the cardiac action potential or QT interval of the ECG is regulated largely by potassium channels such as the delayed rectifier currents HK2 and I
sK
.

Methods and Results
The effects of ovariectomy (OVX) and estradiol (E2) or dihydrotestosterone (DHT) treatment were evaluated on HK2,
HERG
, and I
sK
mRNA levels, QT duration, and quinidine-induced changes in QT interval in isolated rabbit hearts. HK2 and 0.7-kilobase I
sK
mRNA were downregulated in cardiac ventricular tissue from OVX rabbits treated with either E2 or DHT. The QT interval was prolonged in E2- and DHT-treated animals (OVX+vehicle, 223±6 ms; OVX+DHT, 236±10 ms; and OVX+DHT, 245±6 ms;
P
<.05).

Conclusions
The association between hormone-induced changes in baseline QT interval and the mRNA level for these channels suggests that sex hormones may play a critical role in regulating cardiac repolarization. However, the changes in baseline QT and potassium channel mRNA after hormone treatment were not concordant with the changes in QT interval after the infusion of quinidine, after which E2-treated animals responded similarly to controls (18.4±4.6% and 19.3±4.6% increase in QT interval, respectively) and DHT-treated animals exhibited less QT prolongation (11.4±3.8% increase;
P
<.03).
Are Heart-Lung Transplant Recipients Protected From Developing Transplant Coronary Artery Disease?
Authors: Lim Tai Tian , Botas Javier , Ross Heather , Liang David H. , Theodore James , Hunt Sharon A. , Oesterle Stephen N. , Yeung Alan C.
Published: June 2012

Background
Accelerated coronary artery disease is a major cause of mortality in heart transplant recipients; however, it does not appear to play a major role in the clinical outcome of heart-lung transplant recipients. The purpose of this study was to determine whether the incidence and severity of transplant coronary artery disease as detected by intracoronary ultrasound in heart-lung transplant recipients are less than those encountered in heart transplant recipients.

Methods and Results
We studied the left anterior descending coronary artery with the use of intracoronary ultrasound imaging in 22 heart-lung transplant recipients at the time of their routine annual coronary angiogram. Twenty-two heart transplant recipients were case matched for number of years after transplant at ultrasound study, recipient age, donor age, and diagnosis of nonischemic cardiomyopathy. Mean intimal area, intimal index, Stanford class, and incidence of at least moderate disease (Stanford class ≥3) were measured and calculated in each group and then compared between the two groups. Mean intimal area (1.6±2.5 versus 3.8±2.8 mm
2
), mean intimal index (0.07±0.10 versus 0.22±0.14), mean Stanford class (1.7±1.0 versus 2.7±1.2), and incidence of Stanford class ≥3 (14% versus 45%) were significantly lower in the heart-lung transplant recipient group.

Conclusions
The incidence and severity of transplant coronary artery disease are much less in patients receiving heart-lung transplants than in those receiving heart transplants alone.
Human Pulmonary Circulation Is an Important Site for Both Clearance and Production of Endothelin-1
Authors: Dupuis Jocelyn , Stewart Duncan J. , Cernacek Peter , Gosselin Gilbert
Published: June 2012

Background
Animal studies suggest a major role of the pulmonary circulation in the clearance of circulating endothelin-1 (ET-1). The contribution of the human pulmonary circulation to plasma ET-1 clearance, however, has never been quantified. The absence of an AV gradient in plasma ET-1 has previously been interpreted as evidence that the lungs do not have a role in modulating circulating ET-1 levels. This study was designed to quantify and discern between pulmonary ET-1 clearance and production in humans.

Methods and Results
We studied 13 subjects by combining the multiple indicator-dilution technique with the measurement of immunoreactive ET-1 (irET-1). All patients had normal left ventricular ejection fractions (61±7%, mean±SD) and baseline hemodynamics. Mean pulmonary ET-1 extraction was 47±7%. The ET-1 extracted does not return to circulation and can be characterized by a sequestration rate constant:
K
seq
=0.048±0.019 s
−1
. There was no significant difference between irET-1 levels from the pulmonary artery and aorta (0.61±0.29 and 0.68±0.33 pg/mL, respectively;
P
=.22); the normal lung consequently produces an amount of ET-1 that is quantitatively similar to the amount that has been extracted.

Conclusions
The human lung is an important site for both clearance and production of ET-1. There is a normal physiological balance of ET-1 across the pulmonary circulation, which explains the absence of difference in AV ET-1 levels despite a 47±7% clearance. Reduced pulmonary clearance or increased production of this peptide may contribute to the increase in circulating levels found in various cardiovascular conditions.
Fibrous Matrix of Ventricular Myocardium in Tricuspid Atresia Compared With Normal Heart
Authors: Ho Siew Yen , Jackson Mark , Kilpatrick Lucienne , Smith Audrey , Gerlis Leon M.
Published: June 2012

Background
The collagen matrix is a small component of the myocardium, but it provides a supportive framework. An increase in collagen in the pressure-overloaded ventricle is known to cause myocardial stiffness. However, little is known about the collagen matrix in the volume-overloaded ventricle, particularly in relation to congenital heart disease.

Methods and Results
We examined a total of 53 hearts with tricuspid atresia and 58 normal hearts matched for age. Using a microscopic-morphometric method, we analyzed the percentage per field area occupied by interstitial fibrous tissue in four sites in the ventricular mass for each specimen. A comparison of sampling sites showed no significant variations between normal and malformed hearts. Results from a homogeneity of regression coefficients analysis suggested that the two groups shared the same basic relation of proportion of fibrosis with age. The use of ANCOVA, however, revealed a clear separation between the extents of fibrous tissue in the two groups of hearts.

Conclusions
The myocardium of hearts with tricuspid atresia is consistently more fibrotic than normal heart and is probably an inherent part of the malformation. This difference could explain, at least in part, the clinical observation that the left ventricle is frequently abnormal, even at an early age.
Postischemic Antiarrhythmic Effects of Angiotensin-Converting Enzyme Inhibitors
Authors: Brunner Friedrich , Kukovetz Walter R.
Published: June 2012

Background
ACE inhibitors improve reperfusion function in several animal models. We tested the hypothesis that ACE inhibitor–induced coronary protection and inhibition of reperfusion arrhythmias are mediated by suppression of cardiac endothelin-1 (ET-1) secretion and action.

Methods and Results
The effects of two ACE inhibitors on ET-1 secretion and mechanical function during ischemia and reperfusion were studied in perfused rat hearts. Drugs were infused during the control (60 minutes), ischemic (60 minutes), and reperfusion (30 minutes) period. ET-1 appearing in coronary effluents and the interstitium was analyzed by radioimmunoassay. We observed (1) in hearts treated with ramiprilat (100 nmol/L) or captopril (5 μmol/L), a significant reduction of ET-1 secretion under all three experimental conditions and fewer ventricular extrasystoles during reperfusion; (2) increased ET-1 secretion and numerous tachyarrhythmic events in the presence of ACE inhibitor and a bradykinin B
2
receptor antagonist, icatibant (100 nmol/L); (3) an almost-complete suppression of reperfusion arrhythmias when an ET receptor antagonist, ie, SB 209670 (5 μmol/L) or PD 142893 (200 nmol/L), was infused together with ACE inhibitor and icatibant; and (4) SB 209670 alone to be equally antiarrhythmic as ACE inhibitors. Exogenous ET-1 (40 pmol/L) was proarrhythmic, whereas exogenous bradykinin (100 nmol/L) reduced ET-1 secretion and improved cardiac rhythm.

Conclusions
ACE inhibitors suppress endogenous ET-1 secretion, which results in improved coronary function and stabilization of cardiac rhythm after ischemia in this model. Suppression of ET-1 results from both removal of endogenous angiotensin II and accumulation of endogenous bradykinin/nitric oxide. ET receptor antagonists may be prime antiarrhythmic drugs worthy of testing in cardiac patients, either alone or together with ACE inhibitors.
Large Change in Voltage at Phase Reversal Improves Biphasic Defibrillation Thresholds
Authors: Yamanouchi Yoshio , Mowrey Kent A. , Nadzam George R. , Hills Donald G. , Kroll Mark W. , Brewer James E. , Donohoo Ann M. , Wilkoff Bruce L. , Tchou Patrick J.
Published: June 2012

Background
Multiple factors contribute to an improved defibrillation threshold of biphasic shocks. The leading-edge voltage of the second phase may be an important factor in reducing the defibrillation threshold.

Methods and Results
We tested two experimental biphasic waveforms with large voltage changes at phase reversal. The phase 2 leading-edge voltage was twice the phase 1 trailing-edge voltage. This large voltage change was achieved by switching two capacitors from parallel to series mode at phase reversal. Two capacitors were tested (60/15 microfarads [μF] and 90/22.5 μF) and compared with two control biphasic waveforms for which the phase 1 trailing-edge voltage equaled the phase 2 leading-edge voltage. The control waveforms were incorporated into clinical (135/135 μF) or investigational devices (90/90 μF). Defibrillation threshold parameters were evaluated in eight anesthetized pigs by use of a nonthoracotomy transvenous lead to a can electrode system. The stored energy at the defibrillation threshold (in joules) was 8.2±1.5 for 60/15 μF (
P
<.01 versus 135/135 μF and 90/90 μF), 8.8±2.4 for 90/22.5 μF (
P
<.01 versus 135/135 μF and 90/90 μF), 12.5±3.4 for 135/135 μF, and 12.6±2.6 for 90/90 μF.

Conclusions
The biphasic waveform with large voltage changes at phase reversal caused by parallel-series mode switching appeared to improve the ventricular defibrillation threshold in a pig model compared with a currently available biphasic waveform. The 60/15-μF capacitor performed as well as the 90/22.5-μF capacitor in the experimental waveform. Thus, smaller capacitors may allow reduction in device size without sacrificing defibrillation threshold energy requirements.
Evidence for the Existence of a Functional Cardiac Renin-Angiotensin System in Humans
Authors: Serneri Gian Gastone Neri , Boddi Maria , Coppo Mirella , Chechi Tania , Zarone Nicoletta , Moira Martelli , Poggesi Loredana , Margheri Massimo , Simonetti Ignazio
Published: June 2012

Background
The presence of mRNA for the essential components of the renin-angiotensin system (RAS) has been found in animal and human hearts. The present study was designed to provide evidence for the existence of a (functional) cardiac RAS.

Methods and Results
Twenty-four patients with atypical chest pain undergoing coronary angiography for diagnostic purposes were investigated. The cardiac production rate of angiotensins was estimated by measurement of the cardiac extraction of
125
I-angiotensin I and
125
I-angiotensin II associated with the determination of endogenous angiotensins in aortic and coronary sinus blood in normal, low, or high sodium diets. In a normal sodium diet, angiotensin I and II aorta–coronary sinus gradients were tendentially negative (−1.8±2.5 and −0.9±1.7 pg/mL, respectively), and the amounts of angiotensin I and II added by cardiac tissues were 6.5±3.1 and 2.7±1.3 pg/mL, respectively. The low sodium diet caused a significant increase in both plasma renin activity (PRA) and angiotensin I concentration in aortic but not in coronary sinus blood, resulting in a more negative aorta–coronary sinus gradient (−9.7±3.1 pg/mL,
P
<.01). Angiotensin formation by PRA in blood during transcardiac passage increased (
P
<.001), whereas angiotensin I formed by cardiac tissues decreased dramatically. Accordingly, in the low sodium diet,
125
I-angiotensin II extraction did not change, the cardiac fractional conversion rate of
125
I-angiotensin I to
125
I-angiotensin II notably decreased (
P
<.01), and angiotensin II formation by cardiac tissues was undetectable. The high sodium diet caused a decrease in PRA and no changes in cardiac extraction of radiolabeled angiotensins; conversely, angiotensin I formed by cardiac tissues, cardiac Ang I fractional conversion rate, and angiotensin II formed during transcardiac passage significantly (
P
<.01 for all) increased.

Conclusions
These results provide evidence for the existence of a functional cardiac RAS independent of but related to the circulating RAS.
Inhaled Nitric Oxide Increases Coronary Artery Patency After Thrombolysis
Authors: Adrie Christophe , Bloch Kenneth D. , Moreno Pedro R. , Hurford William E. , Guerrero J. Luis , Holt Robert , Zapol Warren M. , Gold Herman K. , Semigran Marc J.
Published: June 2012

Background
Nitric oxide (NO) and nitrosovasodilators that release NO inhibit platelet aggregation. The antithrombotic effect of intravenously infused nitrosovasodilators is usually accompanied by systemic vasodilation. Inhaled NO is a pulmonary vasodilator that does not produce systemic hemodynamic effects. This study examines the antithrombotic effect of inhaled NO in a canine model of platelet-mediated coronary artery reocclusion after thrombolysis.

Methods and Results
In 25 anesthetized dogs, a segment of the left anterior descending coronary artery was traumatized and a high-grade stenosis created. Thrombus was injected at this site, and tissue plasminogen activator was administered, producing cyclic flow variations (CFVs) in 24 of 25 dogs. CFV frequency was unchanged in dogs not breathing NO but decreased by 35±9% (
P
<.05) and 53±7% (
P
<.01) while dogs breathed 20 and 80 parts per million (ppm) NO, respectively. The coronary artery patency ratio (fraction of time during which the coronary artery was patent; CAPR) was unchanged in dogs not treated with NO but increased from 51±7% to 64±8% while breathing 20 ppm NO (
P
<.01) and from 49±3% to 75±7% while breathing 80 ppm NO (
P
<.01). The increased CAPR during 80 ppm NO administration persisted during a 45-minute posttreatment period (70±7%,
P
<.05 versus baseline). NO inhalation did not change systemic hemodynamics. In a pharmacological model of coronary vasoconstriction, inhaled NO did not reverse the effect of the thromboxane A
2
agonist U-46619. In vitro ADP-induced platelet aggregation was inhibited by NO gas.

Conclusions
Inhaled NO at concentrations of 20 and 80 ppm increases coronary patency and decreases CFV frequency in a canine model of platelet-mediated coronary reocclusion after thrombolysis without producing systemic hemodynamic effects.
Inducible Nitric Oxide Synthase and the Regulation of Central Vessel Caliber in the Fetal Rat
Authors: Bustamante Sergio A. , Pang Ying , Romero Silvia , Pierce Maria R. , Voelker Cynthia A. , Thompson Jane H. , Sandoval Manuel , Liu Xiaoping , Miller Mark J.S.
Published: June 2012

Background
The purpose of this study was to evaluate the possibility that inducible nitric oxide synthase (iNOS) regulates the fetal circulation.

Methods and Results
Positive evidence for iNOS gene expression was noted in heart central vessels and placenta of untreated rat fetuses. Rats in the last week of pregnancy were treated for 5 days with
l
-
N
G
-(1-Iminoethyl)lysine (L-NIL), a selective inhibitor of iNOS, at 1, 10, and 100 μg/mL in the drinking water. To raise NO levels, lipopolysaccharide (LPS) 30 μg/kg was given by intraperitoneal injection, and sodium nitroprusside (SNP) was placed in mini-osmotic pumps to deliver 10 μg/kg per minute. Control animals were undisturbed. On day 21 of gestation, dams were anesthetized and fetuses were delivered by cesarean section and rapidly frozen in isopentane chilled in liquid nitrogen. Frozen sections (10 μm) were used to reconstruct a computer-generated three-dimensional image of the great vessels and ductus arteriosus. Significant constriction of the great vessels and ductus arteriosus was observed with L-NIL, whereas both LPS and SNP dilated these vessels. The vasorelaxant effect of LPS was blocked by L-NIL. NO release from placental explants was 633±41 nmol/L under basal conditions, increasing to 4.0±0.4 μmol/L with LPS administration, although placental iNOS message and protein levels were unchanged.

Conclusions
We suggest that nitric oxide, generated by iNOS, plays a significant role in control of major vessel and ductus arteriosus caliber in the rat fetus. In regard to the nitrergic regulation of the circulation, the fetus is clearly different from the adult.
Recombinant Mitotoxin Basic Fibroblast Growth Factor–Saporin Reduces Venous Anastomotic Intimal Hyperplasia in the Arteriovenous Graft
Authors: Chen Changyi , Mattar Samer G. , Hughes John D. , Pierce Glenn F. , Cook Jennifer E. , Ku David N. , Hanson Stephen R. , Lumsden Alan B.
Published: June 2012

Background
The plant cytotoxin saporin (SAP) is a potent ribosome-inactivating protein. When conjugated to basic fibroblast growth factor (FGF2), it selectively kills proliferating cells that have upregulated FGF receptors. In this study, we evaluated the effect of the recombinant chimeric mitotoxin rFGF2-SAP on venous anastomotic intimal hyperplasia, a major cause of failure of arteriovenous (AV) grafts.

Methods and Results
Recently designed expanded polytetrafluoroethylene–based local infusion devices were implanted bilaterally as femoral AV conduits in six dogs. The venous anastomoses were the sites of continuous delivery of rFGF2-SAP (2.7 μg·kg
−1
·d
−1
) to one side and vehicle (4.6 μL·kg
−1
·d
−1
) as control to the contralateral side for 14 days. All animals survived, and all grafts were patent. Liver enzyme levels and histological analyses of liver, kidneys, and brain were normal, indicating the absence of systemic toxicity. Morphometric measurements and measurements of cell proliferation by bromodeoxyuridine index analysis were performed at both arterial and venous anastomoses. There were no significant differences between the treated grafts and the control grafts in intimal hyperplasia and intimal cell proliferation at the arterial anastomoses. In contrast, rFGF2-SAP reduced intimal thickness by 32%, intimal area by 40%, and cell proliferation index by 33% at the treated venous anastomoses compared with the control venous anastomoses (
P
<.05).

Conclusions
These data demonstrate that local infusion of rFGF2-SAP significantly reduces venous anastomotic intimal hyperplasia and cell proliferation without systemic toxicity. This study suggests a new strategy for reducing intimal hyperplasia by the selective killing of proliferating smooth muscle cells with a potent chimeric mitotoxin through a novel local infusion device.
Immediate Results of Percutaneous Mitral Commissurotomy
Authors: Iung Bernard , Cormier Bertrand , Ducimetie`re Pierre , Porte Jean-Marc , Nallet Olivier , Michel Pierre-Louis , Acar Jean , Vahanian Alec
Published: June 2012

Background
The wide use of percutaneous mitral commissurotomy (PMC) underlines the need to identify the predictive factors of the results. Using a large series allowed us to develop a multivariate model that can be applied to improve patient selection.

Methods and Results
Between 1986 and 1995, PMC was undertaken in 1514 patients. Mean age was 45±15 years. Echocardiography showed that 245 patients (16%) had pliable valves and mild chordal thickening (group 1), 886 (59%) had extensive subvalvular disease (group 2), and 383 (25%) had calcified valves (group 3). PMC failed in 22 patients; it was performed with a single balloon in 30 patients, a double balloon in 586, and the Inoue balloon in 876. Good immediate results were defined as a valve area ≥1.5 cm
2
with mitral regurgitation Sellers' grade ≤2 and were obtained in 1348 patients (89%). A logistic model developed from the first 1088 cases identified the following predictors of immediate results: age (
P
=.004), echocardiographic group (
P
<.0001), valve area (
P
<.0001), and effective balloon dilating area (EBDA) (
P
=.03). Two interactions were significant: age at previous commissurotomy (
P
=.013) and EBDA by initial mitral regurgitation (
P
=.034). The type of balloon was of borderline significance (
P
=.09). The model was validated on an independent sample comprising the subsequent 426 procedures. For a threshold of probability of good results of .75, sensitivity was 92%, specificity 25%, and predictive accuracy 87%.

Conclusions
Prediction of the immediate results of PMC is multifactorial. The predictive model developed and validated can be contributive in decision making for individual patients.
Potential Gene Therapy for Lecithin-Cholesterol Acyltransferase (LCAT)–Deficient and Hypoalphalipoproteinemic Patients With Adenovirus-Mediated Transfer of Human LCAT Gene
Authors: Se´guret-Mace´ Sandrine , Latta-Mahieu Martine , Castro Graciela , Luc Ge´rald , Fruchart Jean-Charles , Rubin Edward , Dene`fle Patrice , Duverger Nicolas
Published: June 2012

Background
Overexpression of human lecithin-cholesterol acyltransferase (LCAT) in transgenic mice results in an increase of the antiatherogenic HDLs.

Methods and Results
To investigate the potential use of LCAT for gene therapy, a recombinant adenovirus was constructed in which the human LCAT cDNA was expressed under the control of the human cytomegalovirus immediate/early promoter followed by a chimeric intron (AdCMV human LCAT). Human apolipoprotein (apo) A-I transgenic mice infected with AdCMV human LCAT by intravenous injection accumulated reactive LCAT in the plasma. LCAT activity was increased 201-fold in the plasma of mice infected with 1×10
9
pfu AdCMV human LCAT, from 45±2 to 9068±812 nmol·mL
−1
·h
−1
, in comparison with basal LCAT activity measured in control mice, 5 days after injection. Plasma HDL cholesterol levels rose from 117±12 to 797±48 mg/dL, and plasma human apo A-I concentrations increased from 247±14 to 616±17 mg/dL, in AdCMV human LCAT–infected mice compared with control mice. HDL particles were larger and had a different electrophoretic mobility. Studies of cholesterol efflux by incubation of serum with cholesterol-loaded Fu5AH cells showed that serum from AdCMV human LCAT–infected mice promoted a significantly higher efflux than did that of the controls.

Conclusions
These data establish the potential of this approach for treatment of subjects with LCAT gene defects as well as patients with low plasma levels of apo A-I and HDL cholesterol.
Myocardial Protection by Brief Ischemia in Noncardiac Tissue
Authors: Gho Ben C.G. , Schoemaker Regien G. , van den Doel Mirella A. , Duncker Dirk J. , Verdouw Pieter D.
Published: June 2012

Background
Brief coronary artery occlusions (CAOs) protect both the artery's own perfusion territory (“myocardial preconditioning”) and adjacent “virgin” myocardium. Whether ischemia in remote organs protects myocardium is unknown. We examined whether brief occlusion of the anterior mesenteric artery (MAO) or left renal artery (RAO) protects against myocardial infarction.

Methods and Results
Area at risk (AR) and infarcted area (IA) were determined in anesthetized rats after 180 minutes of reperfusion following a 60-minute CAO. At normothermia (body temperature, 36.5°C to 37.5°C), IA/AR was 68±2% (mean±SEM, n=11) in control rats and 50±3% (n=9,
P
<.001) in rats preconditioned by 15-minute CAO 10 minutes before 60-minute CAO. A 15-minute MAO was equally protective (IA/AR=50±3%, n=10,
P
<.001), whereas 15-minute RAO failed to limit IA/AR (72±5%, n=8). Hypothermia (body temperature, 30°C to 31°C) did not affect IA/AR (67±3%, n=11) in control animals but enhanced protection by 15-minute CAO (IA/AR=22±3%, n=8), whereas protection by 15-minute MAO (IA/AR=44±5%, n=11,
P
<.001) was minimally enhanced. Hypothermia unmasked protection by 15-minute RAO (IA/AR=46±6%, n=9,
P
<.01). Hexamethonium (20 mg/kg IV) did not alter protection by 15-minute CAO, but it abolished protection by 15-minute MAO. When MAO was sustained throughout the study, cardioprotection was absent.

Conclusions
Brief ischemia in “remote” organs protects myocardium against infarction as effectively as myocardial preconditioning. The mechanism of protection by MAO differs from that of CAO, because ganglion blockade abolished protection by MAO but not by CAO. The neurogenic pathway is activated during reperfusion after 15-minute MAO, because sustained MAO failed to produce cardioprotection.
Spatial Heterogeneity of Myocardial Blood Flow Presages Salvage Versus Necrosis With Coronary Artery Reperfusion in Conscious Baboons
Authors: Ghaleh Bijan , Shen You-Tang , Vatner Stephen F.
Published: June 2012

Background
Myocardial blood flow distribution is known to be heterogeneous. It is also known that not all of the area at risk (AAR) infarcts with coronary artery occlusion (CAO) and coronary artery reperfusion (CAR). The goal of the present study was to determine whether the proportion of AAR that is salvaged or infarcted can be predicted by the pre-CAO level of myocardial blood flow, which varies considerably in individual samples as a result of natural heterogeneity.

Methods and Results
The effects of 90-minute CAO followed by 5- to 7-day CAR were examined in six conscious baboons instrumented with aortic and left atrial catheters and coronary artery occluders. AAR was determined by dual perfusion. Myocardial blood flow was measured by radioactive microspheres before and after CAO and CAR. The AAR was cut into small pieces (0.21±0.01 g) and separated into two categories: salvaged (n=252) or infarcted (n=133). Analysis of myocardial blood flow distribution revealed two distinct populations (
P
<.01); infarcted tissues demonstrated higher pre-CAO myocardial blood flow than salvaged tissues. Importantly, 50% of the salvaged tissue samples were characterized by pre-CAO myocardial blood flows of <0.90 mL·min
−1
·g
−1
compared with 29% for infarcted samples, whereas 51% of infarcted samples were characterized by pre-CAO myocardial blood flows of >1.12 mL·min
−1
·g
−1
compared with 22% of salvaged samples. Endocardial analyses were qualitatively similar to transmural analyses.

Conclusions
This study suggests that heterogeneity of pre-CAO myocardial blood flows can predict the proportion of myocardium salvaged by CAR and can further explain the spatial heterogeneity of infarction that occurs after CAR, potentially independent of CAR injury.
Medroxyprogesterone Attenuates Estrogen-Mediated Inhibition of Neointima Formation After Balloon Injury of the Rat Carotid Artery
Authors: Levine Ronald L. , Chen Shi-Juan , Durand Joan , Chen Yiu-Fai , Oparil Suzanne
Published: June 2012

Background
Estrogen blunts the neointimal proliferative response to balloon injury of the carotid artery in intact female rats and gonadectomized rats of both sexes. This study tested whether, in gonadectomized rats of both sexes, (1) progestin (medroxyprogesterone acetate, MPA) alters neointima formation in injured carotid arteries, (2) addition of MPA alters the antiproliferative effects of estrogen, and (3) an interaction between MPA and estrogen can be accounted for by MPA-induced alterations in serum 17β-estradiol levels.

Methods and Results
Male and female Sprague-Dawley rats were subjected to gonadectomy, then were randomly divided into four subgroups and treated with either (1) 17β-estradiol, (2) MPA, (3) 17β-estradiol+MPA, or (4) vehicle, and balloon injury of the right common carotid artery was carried out. Two weeks later, rats were killed by overdose of pentobarbital, and the carotid arteries were subjected to morphometric analysis for evaluation of myointimal thickening. Estradiol inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes (
P
<.05). MPA alone did not alter neointima formation, but addition of MPA to estradiol completely blocked the antiproliferative effects of estrogen without altering serum 17β-estradiol levels.

Conclusions
These data indicate that exogenous progestin given alone does not alter the vascular injury response in the rat carotid injury model but that addition of a progestin blocks the antiproliferative effects of estrogen in this model. These effects are seen in gonadectomized rats of both sexes. These findings have direct implications for postmenopausal hormone replacement therapy in humans.
Assessing the Excitable Gap in Reentry by Resetting
Authors: Fei Hailing , Hanna Michael S. , Frame Lawrence H.
Published: June 2012

Background
The shortest excitable gap during reentry may determine responses to pacing and antiarrhythmic drugs. The resetting response has been used clinically to assess the excitable gap, but it cannot directly indicate the shortest excitable gap.

Methods and Results
We studied resetting in the in vitro canine atrial tricuspid ring using an adjustable reentry preparation in which the ring was cut and reconnected electronically with an adjustable delay to vary the cycle length and excitable gap. We reset the tachycardias using 31 delays in 12 experiments. Tachycardias were terminated by premature stimuli in 16 delays. The reset window overestimated the shortest excitable gap by 25±14 ms, and the maximum degree of advancement of tachycardia underestimated the shortest excitable gap by 22±11 ms. The slope of the increasing portion of the resetting response curve was steeper in tachycardias terminated by premature stimuli than in those not terminated (−0.69±0.2 versus −0.37±0.2,
P
<.01). The effective refractory period difference between the sites of pacing and of block correlated with the slope of the resetting response curve. Damped cycle length oscillation after a long return cycle during resetting was always present when there was a partially excitable gap.

Conclusions
The reset window during pacing within the circuit and the maximum degree of advancement provided equally good estimates bracketing the shortest excitable gap. The slope of the resetting response curve predicted the likelihood of termination by premature stimuli. Damped cycle length oscillation after resetting detected a partially excitable gap.
Endothelin-Converting Enzyme Expression in the Rat Vascular Injury Model and Human Coronary Atherosclerosis
Authors: Minamino Tohru , Kurihara Hiroki , Takahashi Masaaki , Shimada Kohei , Maemura Koji , Oda Hideaki , Ishikawa Takatoshi , Uchiyama Takashi , Tanzawa Kazuhiko , Yazaki Yoshio
Published: June 2012

Background
Endothelin 1 has been implicated in various human diseases, including atherosclerosis. In this study, we examined the expression and localization of endothelin-converting enzyme-1 (ECE-1), the final key enzyme of endothelin 1 processing, in rat carotid arteries after balloon injury and in human coronary atherosclerotic lesions.

Methods and Results
ECE-1 mRNA levels and ECE activity in rat balloon-injured arteries started to increase between 2 and 5 days after injury. The endothelin 1 content of tissue in injured arteries was concomitantly increased. Immunohistochemical staining located ECE-1 signals in endothelial cells in uninjured arteries, whereas ECE-1 immunoreactivity was detected in neointimal smooth muscle cells in injured arteries 5 to 14 days after balloon denudation. The size of the neointima was effectively reduced by phosphoramidon, an inhibitor of neutral metalloproteases, including ECE-1. In human coronary atherosclerotic lesions, intense ECE-1 immunoreactivity was detected in subsets of cells embedded in atheromatous plaque that correspond to smooth muscle cells and macrophages, as identified by staining for smooth muscle α-actin and CD68 surface marker, respectively.

Conclusions
The present study ascertained that ECE-1 is expressed in neointimal smooth muscle cells in rat balloon-injured arteries and in both smooth muscle cells and macrophages in human coronary atherosclerotic lesions. Blockade of ECE-1 was effective in reducing neointimal formation after balloon injury. Thus, ECE-1 may contribute to the process of injury-induced neointimal formation and atherosclerosis through the autocrine/paracrine effects of endothelin 1.
Sustained Prognostic Value of Dobutamine Stress Echocardiography for Late Cardiac Events After Major Noncardiac Vascular Surgery
Authors: Poldermans Don , Arnese Mariarosaria , Fioretti Paolo M. , Boersma Eric , Thomson Ian R. , Rambaldi Riccardo , van Urk Hero
Published: June 2012

Background
Late cardiac events after major noncardiac vascular surgery are an important cause of morbidity and mortality. We studied the prognostic value of preoperative dobutamine stress echocardiography, relative to clinical risk assessment, in predicting late cardiac events.

Methods and Results
Three hundred sixteen patients undergoing major vascular surgery were studied. All patients underwent clinical evaluation for the presence of cardiac risk factors (smoking, hypertension, angina, diabetes, history of heart failure, previous infarction, and age >70 years) and dobutamine stress echocardiography. Left ventricular wall motion was evaluated at rest, and the extent and severity of stress-induced new wall motion abnormalities were quantified. The heart rate threshold at which new wall motion abnormalities occurred was noted. Patients were followed perioperatively and for 19±11 months postoperatively, and the occurrence of cardiac events was noted. Univariate and multivariate Cox proportional hazards regression models were used to identify predictors of late cardiac events. Thirty-two cardiac events occurred (11 cardiac deaths, 11 nonfatal myocardial infarctions, and 10 incidents of unstable angina). By multivariate regression analysis, the occurrence of extensive (three or more segments) or limited (one or two segments) stress-induced new wall motion abnormalities and previous infarction independently predicted late cardiac events, elevating the risk by 6.5-, 2.9-, and 3.8-fold, respectively. The severity of ischemia during stress and the heart rate threshold for ischemia were not independently predictive.

Conclusions
Patients with a history of myocardial infarction or stress-induced ischemia have a high risk of fatal and nonfatal cardiac events after vascular surgery. Patients with both a history of infarction and extensive stress-induced ischemia are at especially high risk and deserve intensive management.
Short-Acting Nifedipine and Diltiazem Do Not Reduce the Incidence of Cardiac Events in Patients With Healed Myocardial Infarction
Authors: Ishikawa Kinji , Nakai Shoji , Takenaka Toshihiko , Kanamasa Ken , Hama Junkichi , Ogawa Iwao , Yamamoto Tadahiko , Oyaizu Miki , Kimura Akio , Yamamoto Kentaro , Yabushita Hiroshi , Katori Ryo
Published: June 2012

Background
The administration of calcium antagonists to patients with healed myocardial infarction is a controversial treatment. This study was conducted to elucidate the effect of short-acting nifedipine and diltiazem on cardiac events in patients with healed myocardial infarction.

Methods and Results
A controlled clinical open trial of 1115 patients with healed myocardial infarction was carried out between 1986 and 1994. The patients included 595 who received no calcium antagonist, 341 who received short-acting nifedipine 30 mg/d, and 179 who received short-acting diltiazem 90 mg/d. The primary end points were cardiac events, which were defined as fatal or nonfatal recurrent myocardial infarction; death from congestive heart failure; sudden death; and hospitalization because of worsening angina, congestive heart failure, or premature ventricular contractions. Cardiac events occurred in 51 patients (8.6%) in the no-calcium-antagonist group and 54 (10.4%) in the calcium-antagonist group (odds ratio, 1.24; 95% CI, 0.83 to 1.85), demonstrating that the calcium antagonists did not reduce the incidence of cardiac events. Subgroup analysis revealed no beneficial effects of these drugs for reducing cardiac events in patients with such complications as hypertension or angina pectoris.

Conclusions
This study showed that use of short-acting nifedipine and diltiazem in this postmyocardial infarction population was associated with a 24% higher cardiac event rate, but this strong adverse trend did not reach statistical significance.
Fibrinolytic Variables and Cardiovascular Prognosisin Patients With Stable Angina Pectoris Treated With Verapamil or Metoprolol
Authors: Held Claes , Hjemdahl Paul , Rehnqvist Nina , Wallén N. Håkan , Björkander Inge , Eriksson Sven V. , Forslund Lennart , Wiman Björn
Published: June 2012

Background
Disturbed fibrinolytic function may influence the progression of coronary atherosclerosis and contribute to thrombotic cardiovascular (CV) events.

Methods and Results
In the Angina Prognosis Study In Stockholm (APSIS), patients with stable angina pectoris were studied prospectively during double-blind treatment with metoprolol or verapamil. Various measures of fibrinolytic function were studied in 631 (of 809) patients. During a median follow-up time of 3.2 years (2132 patient-years), 32 patients suffered a CV death, 21 had a nonfatal myocardial infarction (MI), and 77 underwent revascularization. Plasma levels of tissue plasminogen activator (TPA) activity and antigen (ag), plasminogen activator inhibitor (PAI-1) activity at rest, and TPA responses to exercise were determined at baseline and after 1 month's treatment and were related to subsequent fatal and nonfatal CV events. Univariate Cox regression analysis revealed that elevated levels of TPA-ag at rest (
P
<.05), high PAI-1 activity (
P
<.05), and low TPA-ag responses to exercise (
P
<.05) were associated with increased risk of subsequent CV death. After adjustment for baseline risk factors, TPA-ag independently predicted CV death or MI. In addition, PAI-1 activity independently predicted CV death or MI in male patients. Verapamil treatment was associated with a 10% decrease of TPA-ag levels and metoprolol treatment with a 2% increase (
P
<.001 for treatment difference).

Conclusions
Plasma TPA-ag levels at rest, and among male patients PAI-1 activity as well, independently predict subsequent CV death or MI in patients with stable angina pectoris. Impaired fibrinolytic reactivity to exercise is a novel factor related to CV prognosis. Effects of verapamil or metoprolol treatment on fibrinolytic function did not importantly influence CV prognosis.