bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrogen Receptors α and β
Authors: Hodges Yvonne K. , Tung Lin , Yan Xiang-Dong , Graham J. Dinny , Horwitz Kathryn B. , Horwitz Lawrence D.
Published: June 2012

Background
—Estrogens have vascular effects through the activation of estrogen receptors (ERs). In addition to ERα, the first ER to be cloned, a second subtype called ERβ has recently been discovered.

Methods and Results
—Using a reverse-transcriptase polymerase chain reaction assay that employs the same primer pair to simultaneously amplify ERα and ERβ transcripts, we found that ERβ is the ER form that is predominantly expressed in human vascular smooth muscle, particularly in women. The transcriptional effects of the 2 ERs in transfected HeLa cells differed. In response to 17β-estradiol, ERα is a stronger transactivator than ERβ at low receptor concentrations. However, at higher receptor concentrations, ERα activity self-squelches, and ERβ is a stronger transactivator. Tamoxifen has partial agonist effects with ERα but not with ERβ.

Conclusions
—The protective effects of estrogens in the cardiovascular system of women may be due to the genomic effects of ERβ in vascular tissue.
Enzymatically Degraded, Nonoxidized LDL Induces Human Vascular Smooth Muscle Cell Activation, Foam Cell Transformation, and Proliferation
Authors: Klouche Mariam , Rose-John Stefan , Schmiedt Walther , Bhakdi Sucharit
Published: June 2012

Background
—Enzymatic, nonoxidative modification transforms LDL to an atherogenic molecule (E-LDL) that activates complement and macrophages and is present in early atherosclerotic lesions.

Methods and Results
—We report on the atherogenic effects of E-LDL on human vascular smooth muscle cells (SMC). E-LDL accumulated in these cells, and this was accompanied by selective induction of monocyte chemotactic protein-1 in the absence of effects on the expression of interleukin (IL)-8, RANTES, or monocyte inflammatory proteins-1α and -β). Furthermore, E-LDL stimulated the expression of gp130, the signal-transducing chain of the IL-6 receptor (IL-6R) family, and the secretion of IL-6. E-LDL invoked mitogenic effects on SMC through 2 mechanisms. First, an autocrine mitogenic circuit involving platelet-derived growth factor and fibroblast growth factor-β was induced. Second, upregulation of gp130 rendered SMC sensitive to transsignaling through the IL-6/sIL-6R activation pathway. Because E-LDL promoted release of both IL-6 and sIL-6R from macrophages, application of macrophage cell supernatants to prestimulated SMC provoked a pronounced and sustained proliferation of the cells.

Conclusions
—E-LDL can invoke alterations in SMC that are characteristic of the evolving atherosclerotic lesion.
Matrix Metalloproteinase-2 Contributes to Ischemia-Reperfusion Injury in the Heart
Authors: Cheung Po-Yin , Sawicki Grzegorz , Wozniak Mieczyslaw , Wang Wenjie , Radomski Marek W. , Schulz Richard
Published: June 2012

Background
—Matrix metalloproteinases (MMPs) contribute to collagen degradation and remodeling of the extracellular matrix after myocardial infarction; however, their role in myocardial dysfunction immediately after ischemia and reperfusion is unknown.

Methods and Results
—We measured the release of MMPs into the coronary effluent of isolated, perfused rat hearts during aerobic perfusion and reperfusion after ischemia. Aerobically perfused control hearts expressed pro-MMP-2 and MMP-2, as well as an unidentified 75-kDa gelatinase. These enzymes were also detected in the coronary effluent. After 20 minutes of global no-flow ischemia, there was a marked increase in pro-MMP-2 in the coronary effluent that peaked within the first minute of reperfusion. The release of pro-MMP-2 into the coronary effluent during reperfusion was enhanced with increasing duration of ischemia and correlated negatively with the recovery of mechanical function during reperfusion (
r
2
=0.99). MMP-2 antibody (1.5 to 15 μg/mL) and the inhibitors of MMPs doxycycline (10 to 100 μmol/L) and
o
-phenanthroline (3 to 100 μmol/L) improved whereas MMP-2 worsened the recovery of mechanical function during reperfusion.

Conclusions
—These results show that acute release of MMP-2 during reperfusion after ischemia contributes to cardiac mechanical dysfunction. The inhibition of MMPs may be a novel pharmacological strategy for the treatment of ischemia-reperfusion injury.
Pressure-Derived Fractional Flow Reserve to Assess Serial Epicardial Stenoses
Authors: De Bruyne Bernard , Pijls Nico H. J. , Heyndrickx Guy R. , Hodeige Dominique , Kirkeeide Richard , Gould K. Lance
Published: June 2012

Background
—Fractional flow reserve (FFR) is an index of stenosis severity validated for isolated stenoses. This study develops the theoretical basis and experimentally validates equations for predicting FFR of sequential stenoses separately.

Methods and Results
—For 2 stenoses in series, equations were derived to predict FFR (FFR
pred
) of each stenosis separately (ie, as if the other one were removed) from arterial pressure (P
a
), pressure between the 2 stenoses (P
m
), distal coronary pressure (P
d
), and coronary occlusive pressure (P
w
). In 5 dogs with 2 stenoses of varying severity in the left circumflex coronary artery, FFR
pred
was compared with FFR
app
(ratio of the pressure just distal to that just proximal to each stenoses) and to FFR
true
(ratio of the pressures distal to proximal to each stenosis but after removal of the other one) in case of fixed distal and varying proximal stenoses (n=15) and in case of fixed proximal and varying distal stenoses (n=20). The overestimation of FFR
true
by FFR
app
was larger than that of FFR
true
by FFR
pred
(0.070±0.007 versus 0.029±0.004,
P
<0.01 for fixed distal stenoses, and 0.114±0.01 versus 0.036±0.004,
P
<0.01 for fixed proximal stenoses). This overestimation of FFR
true
by FFR
app
was larger for fixed proximal than for fixed distal stenoses.

Conclusions
—The interaction between 2 stenoses is such that FFR of each lesion separately cannot be calculated by the equation for isolated stenoses (P
d
/P
a
during hyperemia) applied to each separately but can be predicted by more complete equations taking into account P
a
, P
m
, P
d
, and P
w
.
Social Support, Depression, and Mortality During the First Year After Myocardial Infarction
Authors: Frasure-Smith Nancy , Lespérance François , Gravel Ginette , Masson Aline , Juneau Martin , Talajic Mario , Bourassa Martial G.
Published: June 2012

Background
—We previously reported that depression after myocardial infarction (MI) increases the long-term risk of cardiac mortality. Other research suggests that social support may also influence prognosis. This article examines the interrelationships between baseline depression and social support in terms of cardiac prognosis and changes in depression symptoms over the first post-MI year.

Methods and Results
—For this study, 887 patients completed the Beck Depression Inventory (BDI) and the Perceived Social Support Scale (PSSS) at about 7 days after MI. Some 32% had BDIs ≥10, indicating mild to moderate depression. One-year survival status was determined for all patients. Follow-up interviews, including the BDI, were conducted with 89% of survivors. There were 39 deaths (35 cardiac). Elevated BDI scores were related to cardiac mortality (
P
=0.0006), but PSSS scores and other measures of social support were not. There was a significant interaction between depression and the PSSS (
P
=0.016). The relationship between depression and cardiac mortality decreased with increasing support. Furthermore, residual change score analysis revealed that among 1-year survivors who had been depressed at baseline, higher baseline social support was related to more improvement in depression symptoms than expected.

Conclusions
—Post-MI depression is a predictor of 1-year cardiac mortality, but social support is not directly related to survival. However, very high levels of support appear to buffer the impact of depression on mortality. Furthermore, high levels of support predict improvements in depression symptoms over the first post-MI year in depressed patients. High levels of support may protect patients from the negative prognostic consequences of depression because of improvements in depression symptoms.
Severe Aortic Stenosis With Low Transvalvular Gradient and Severe Left Ventricular Dysfunction
Authors: Connolly Heidi M. , Oh Jae K. , Schaff Hartzell V. , Roger Veronique L. , Osborn Sara L. , Hodge David O. , Tajik A. Jamil
Published: June 2012

Background
—The outcome of aortic valve replacement in patients with severe aortic stenosis, low transvalvular gradient, and severe left ventricular dysfunction is not well known.

Methods and Results
—Between 1985 and 1995, 52 patients with left ventricular ejection fraction (EF) ≤35% and aortic stenosis with transvalvular mean gradient <30 mm Hg underwent aortic valve replacement. The mean (±SD) preoperative characteristics included EF, 26±8%; aortic valve mean gradient, 23±4 mm Hg; aortic valve area, 0.7±0.2 cm
2
; and cardiac output, 3.7±1.2 L/min. Simultaneous coronary artery bypass graft surgery was performed in 32 patients (62%). Perioperative (30-day) mortality was 21% (11 of 52 patients). Ten additional patients died during follow-up. Advanced age (
P
=0.048) and small aortic prosthesis size (
P
=0.03) were significant predictors of hospital mortality by univariate analysis. By multivariate analysis, the only predictor of surgical mortality was smaller prosthesis size. The only predictor of postoperative survival was improvement in postoperative functional class (
P
=0.04). Postoperative functional improvement occurred in most patients. Postoperative EF was assessed in 93% of survivors; 74% demonstrated improvement. Positive change in EF was related to smaller preoperative aortic valve area and female sex.

Conclusions
—Despite severe left ventricular dysfunction, low transvalvular mean gradient, and increased operative mortality, aortic valve replacement was associated with improved functional status. Postoperative survival was related to younger patient age and larger aortic prosthesis size, and medium-term survival was related to improved postoperative functional class.
Fenfluramine and Phentermine and Cardiovascular Findings
Authors: Jollis James G. , Landolfo Carolyn K. , Kisslo Joseph , Constantine Ginger D. , Davis Kelly D. , Ryan Thomas
Published: June 2012

Background
—The combination of fenfluramine and phentermine was a widely used obesity treatment before the withdrawal of fenfluramine for an association with heart valve regurgitation. The prevalence and clinical significance of regurgitation among patients treated with these medications has yet to be fully established.

Methods and Results
—To evaluate the potential association between the duration of treatment and the prevalence of heart valve abnormalities, we examined 1163 patients who had taken fenfluramine-phentermine and 672 control patients who had not taken the drug combination within 5 years. Mild or greater aortic regurgitation was present in 8.8% of treated patients and 3.6% of control patients (
P
<0.001). Moderate or greater mitral regurgitation was present in 2.6% of treated patients and 1.5% of control patients (
P
=0.18). The adjusted odds ratio compared with controls of aortic regurgitation of mild or greater severity increased according to duration of treatment: 90 to 180 days, 1.5 (
P
=0.23); 181 to 360 days, 2.4 (
P
=0.002); 361 to 720 days, 4.6 (
P
<0.001); >720 days, 6.2 (
P
<0.001).

Conclusions
—This is the largest study to demonstrate a relation between the length of treatment with fenfluramine-phentermine and the prevalence of valvular abnormalities. These findings suggest that valvular abnormalities in patients who took fenfluramine-phentermine primarily involve those who had taken these medications for >6 months and predominantly results in mild aortic regurgitation. The valve regurgitation identified by this study was not accompanied by significant differences in cardiovascular symptoms nor physical findings other than a higher prevalence of heart murmurs.
Endothelin-1 Vasoconstriction During Swine Cardiopulmonary Resuscitation Improves Coronary Perfusion Pressures but Worsens Postresuscitation Outcome
Authors: Hilwig Ronald W. , Berg Robert A. , Kern Karl B. , Ewy Gordon A.
Published: June 2012

Background
—Vasoconstriction during cardiopulmonary resuscitation (CPR) improves coronary perfusion pressure (CPP) and thereby outcome. The combination of endothelin-1 (ET-1) plus epinephrine improved CPP during CPR compared with epinephrine alone in a canine cardiac arrest model. The effect of the combination on outcome variables, such as successful resuscitation and survival, has not been investigated.

Methods and Results
—Twenty-seven swine were randomly provided with 1 mg epinephrine (Epi group) or 1 mg epinephrine plus 0.1 mg ET-1 (ET-1 group) during a prolonged ventricular fibrillatory cardiac arrest. ET-1 resulted in substantially superior aortic relaxation pressure and CPP during CPR. These hemodynamic improvements tended to increase initial rates of restoration of spontaneous circulation (8 of 10 versus 8 of 17,
P
=0.12). However, continued intense vasoconstriction from ET-1 led to higher aortic diastolic pressure and very narrow pulse pressure after resuscitation. The mean pulse pressure 1 hour after resuscitation was 7±8 mm Hg with ET-1 versus 24±1 mm Hg with Epi,
P
<0.01. Most importantly, the postresuscitation mortality was dramatically higher in the ET-1 group (6 of 8 versus 0 of 8 in the Epi group,
P
<0.01).

Conclusions
—These data establish that administration of ET-1 during CPR can result in worse postresuscitation outcome. The intense vasoconstriction from ET-1 improved CPP during CPR but had detrimental effects in the postresuscitation period.
Intracoronary γ-Radiation Therapy After Angioplasty Inhibits Recurrence in Patients With In-Stent Restenosis
Authors: Waksman Ron , White R. Larry , Chan Rosanna C. , Bass Bill G. , Geirlach Lisa , Mintz Gary S. , Satler Lowell F. , Mehran Roxana , Serruys Patrick W. , Lansky Alexandra J. , Fitzgerald Peter , Bhargava Balram , Kent Kenneth M. , Pichard Augusto D. , Leon Martin B.
Published: June 2012

Background
—Treatment of in-stent restenosis presents a critical limitation of intracoronary stent implantation. Ionizing radiation has been shown to decrease neointimal formation within stents in animal models and in initial clinical trials. We studied the effects of intracoronary γ-radiation therapy versus placebo on the clinical and angiographic outcomes of patients with in-stent restenosis.

Methods and Results
—One hundred thirty patients with in-stent restenosis underwent successful coronary intervention and were then blindly randomized to receive either intracoronary γ-radiation with
192
Ir (15 Gy) or placebo. Four independent core laboratories blinded to the treatment protocol analyzed the angiographic and intravascular ultrasound end points of restenosis. Procedural success and in-hospital and 30-day complications were similar among the groups. At 6 months, patients assigned to radiation therapy required less target lesion revascularization and target vessel revascularization (9 [13.8%] and 17 [26.2%], respectively) compared with patients assigned to placebo (41 [63.1%,
P
=0.0001] and 44 [67.7%,
P
=0.0001], respectively). Binary angiographic restenosis was lower in the irradiated group (19% versus 58% for placebo,
P
=0.001). Freedom from major cardiac events was lower in the radiation group (29.2% versus 67.7% for placebo,
P
<0.001).

Conclusions
—Intracoronary γ-radiation used as adjunct therapy for patients with in-stent restenosis significantly reduces both angiographic and clinical restenosis.
Adenovirus-Based Phospholamban Antisense Expression as a Novel Approach to Improve Cardiac Contractile Dysfunction
Authors: Eizema Karin , Fechner Henry , Bezstarosti Karel , Schneider-Rasp Sonja , van der Laarse Arnoud , Wang Haili , Schultheiss Heinz-Peter , Poller Wolfgang C. , Lamers Jos M. J.
Published: June 2012

Background
—A decrease in sarcoplasmic reticulum Ca
2+
pump (SERCA2) activity is believed to play a role in the impairment of diastolic function of the failing heart. Because the expression ratio of phospholamban (PL) to SERCA2 may be a target to improve contractile dysfunction, a PL antisense RNA strategy was developed under the control of either a constitutive cytomegalovirus (CMV) or an inducible atrial natriuretic factor (ANF) promoter. The latter is upregulated in hypertrophied and failing heart, allowing “induction-by-disease” gene therapy.

Methods and Results
—Part of the PL cDNA was cloned in antisense and sense directions into adenovectors under the control of either a CMV (Ad5CMVPLas and Ad5CMVPLs, respectively) or ANF (Ad5ANFPLas and Ad5ANFPLs, respectively) promoter. Infection of cultured rat neonatal cardiomyocytes with Ad5CMVPLas reduced PL mRNA to 30±7% of baseline and PL protein to 24±3% within 48 and 72 hours, respectively. The effects were vector dose dependent. Ad5CMVPLas increased the Ca
2+
sensitivity of SERCA2 and reduced the time to 50% recovery of the Ca
2+
transient. A decrease of PL protein was also achieved by infection with Ad5ANFPLas, and the presence of the hypertrophic stimulus, endothelin-1, led to enhanced downregulation of PL. The adenovectors expressing PL sense RNA had no effect on any of the tested parameters.

Conclusions
—Vector-mediated PL antisense RNA expression may become a feasible approach to modulate myocyte Ca
2+
homeostasis in the failing heart. The inducible ANF promoter for the first time offers the perspective for induction-by-disease gene therapy, ie, selective expression of therapeutic genes in hypertrophied and failing cardiomyocytes.
Gadolinium Decreases Stretch-Induced Vulnerability to Atrial Fibrillation
Authors: Bode Frank , Katchman Alexander , Woosley Raymond L. , Franz Michael R.
Published: June 2012

Background
—Atrial fibrillation (AF) is frequently associated with atrial dilatation caused by pressure or volume overload. Stretch-activated channels (SACs) have been found in myocardial cells and may promote AF in dilated atria. To prove this hypothesis, we investigated the effect of the SAC blocker gadolinium (Gd
3+
) on AF propensity in the isolated rabbit heart during atrial stretch.

Methods and Results
—In 16 isolated Langendorff-perfused rabbit hearts, the interatrial septum was perforated to equalize biatrial pressures. Caval and pulmonary veins were occluded. Intra-atrial pressure (IAP) was increased in steps of 2 to 3 cm H
2
O by increasing the pulmonary outflow fluid column. Vulnerability to AF was evaluated by 15-second burst pacing at each IAP level. At baseline, IAP needed to be raised to 8.8±0.2 cm H
2
O (mean±SEM) to induce AF. A dose-dependent decrease in AF vulnerability was observed after Gd
3+
12.5, 25, and 50 μmol/L was added. AF threshold increased to 19.0±0.5 cm H
2
O with Gd
3+
50 μmol/L (
P
<0.001 versus baseline). Spontaneous runs of AF occurred in 5 hearts on a rise of IAP to 13.8±3.3 cm H
2
O at baseline but never during Gd
3+
. Atrial effective refractory period shortened progressively from 78±3 ms at 0.5 cm H
2
O to 52±3 ms at 20 cm H
2
O (
P
<0.05). Gd
3+
50 μmol/L had no significant effect on effective refractory period.

Conclusions
—Acute atrial stretch significantly enhances the vulnerability to AF. Gd
3+
reduces the stretch-induced vulnerability to AF in a dose-dependent manner. Block of SAC might represent a novel antiarrhythmic approach to AF under conditions of elevated atrial pressure or volume.
Investigation Into the Sources of Superoxide in Human Blood Vessels
Authors: Berry Colin , Hamilton Carlene A. , Brosnan M. Julia , Magill Fergus G. , Berg Geoffrey A. , McMurray John J. V. , Dominiczak Anna F.
Published: June 2012

Background
—Increased vascular superoxide anion (·O
2
−
) production contributes to endothelial dysfunction and hypertension in animal models of cardiovascular disease. Observations in experimental animals suggest that angiotensin II (Ang II) increases ·O
2
−
production by activation of vascular NAD(P)H oxidase. We studied the sources of ·O
2
−
production in human blood vessels and investigated whether, and by what mechanism, Ang II might alter vascular ·O
2
−
production.

Methods and Results
—Internal mammary arteries (IMAs) and saphenous veins (SVs) were collected at the time of cardiac surgery. Vessels were incubated in Krebs buffer at 37°C. ·O
2
−
was measured by lucigenin chemiluminescence. Basal ·O
2
−
concentrations were greater in IMAs than SVs. Inhibitors of NAD(P)H oxidase (10 μmol/L to 200 μmol/L diphenyleneiodonium) and xanthine oxidase (1 mmol/L allopurinol) caused reductions in ·O
2
−
concentrations in both IMAs and SVs. Western blotting of superoxide dismutase proteins demonstrated similar expression in IMAs and SVs. Vessels were also incubated in the presence or absence of Ang II (1 pmol/L to 1 μmol/L). Ang II increased ·O
2
−
production in IMAs at 4 hours of incubation (control, 978±117 pmol · min
−1
· mg
−1
; 1 μmol/L of Ang II, 1690±213 pmol · min
−1
· mg
−1
; n=27,
P
=0.0001, 95% CI 336, 925) but not in SVs. This effect was completely inhibited by coincubation of IMAs with DPI (100 μmol/L), a nonspecific Ang II antagonist ([sar
1
, thre
8
]–Ang II, 1 μmol/L) and a specific Ang II type 1 (AT
1
) receptor antagonist (losartan, 1 μmol/L).

Conclusions
— ·O
2
−
production is greater in human IMAs than in SVs. NAD(P)H oxidase and xanthine oxidase are sources of ·O
2
−
production in these vessels. The vasoactive peptide Ang II increases ·O
2
−
production in human arteries by an AT
1
receptor–dependent mechanism.
Mechanisms Responsible for Endothelial Dysfunction Associated With Acute Estrogen Deprivation in Normotensive Women
Authors: Virdis Agostino , Ghiadoni Lorenzo , Pinto Stefania , Lombardo Maurizio , Petraglia Felice , Gennazzani Andrea , Buralli Simona , Taddei Stefano , Salvetti Antonio
Published: June 2012

Background
—The goal of this study was to evaluate whether endothelial dysfunction associated with acute estrogen deprivation is caused by an alteration in the
l
-arginine–nitric oxide (NO) pathway and oxidative stress.

Methods and Results
—In 26 healthy women (age, 45.7±5.4 years) and 18 fertile women with leiomyoma (age, 44.5±5.1 years), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, or 15 μg · 100 mL
−1
· min
−1
) or sodium nitroprusside (1, 2, or 4 μg · 100 mL
−1
· min
−1
), an endothelium-dependent or -independent vasodilator, respectively. The NO pathway was evaluated by repeating acetylcholine during
l
-arginine (200 μg · 100 mL
−1
· min
−1
; 13 control subjects and 9 patients) or
N
G
-monomethyl-
l
-arginine (L-NMMA; 100 μg · 100 mL
−1
· min
−1
; 13 control subjects and 9 patients); production of cyclooxygenase-derived vasoconstrictors was assessed by repeating acetylcholine during indomethacin (50 μg · 100 mL
−1
· min
−1
; 13 control subjects and 9 patients) or vitamin C (8 mg · 100 mL
−1
· min
−1
; 13 control subjects and 9 patients). Patients repeated the study within 1 month after ovariectomy and again after 3 months of estrogen replacement therapy (ERT; 17 β-estradiol TTS, 50 μg/d). Basally, vasodilation to acetylcholine was potentiated and inhibited by
l
-arginine and L-NMMA, respectively (
P
<0.05), but was unaffected by indomethacin or vitamin C. After ovariectomy, the modulating effect of
l
-arginine and L-NMMA disappeared, whereas indomethacin and vitamin C potentiated the response to acetylcholine (
P
<0.05). ERT restored
l
-arginine and L-NMMA effects on vasodilation to acetylcholine but prevented the potentiation caused by indomethacin or vitamin C. Response to sodium nitroprusside was unaffected by either ovariectomy or ERT.

Conclusions
—Endothelial dysfunction secondary to acute endogenous estrogen deprivation is caused by reduced NO availability. Cyclooxygenase-dependent production of oxidative stress could be responsible for this alteration.
Vascular Extracellular Superoxide Dismutase Activity in Patients With Coronary Artery Disease
Authors: Landmesser Ulf , Merten Roland , Spiekermann Stephan , Büttner Karsten , Drexler Helmut , Hornig Burkhard
Published: June 2012

Background
—Increased inactivation of nitric oxide by oxygen free radicals contributes to endothelial dysfunction in patients with coronary artery disease (CAD). We therefore determined the activity of extracellular superoxide dismutase (EC-SOD), the major antioxidant enzyme system of the vessel wall, and its relation to flow-dependent, endothelium-mediated dilation (FDD) in patients with CAD.

Methods and Results
—SOD isoenzyme activity was determined in coronary arteries from 10 patients with CAD and 10 control subjects. In addition, endothelium-bound EC-SOD activity (eEC-SOD), released by heparin bolus injection, and FDD of the radial artery were measured in 35 patients with CAD and 15 control subjects. FDD, determined by high-resolution ultrasound, was assessed at baseline, after intra-arterial infusion of vitamin C,
N
-monomethyl-
l
-arginine, and combination of both. EC-SOD activity in coronary arteries (control subjects: 126±14; CAD: 63±11 U/mg protein;
P
<0.01) and eEC-SOD activity in vivo (control subjects: 14.5±1.1; CAD: 3.8±1.1 U · mL
−1
· min
−1
;
P
<0.01) were reduced in patients with CAD. Activity of eEC-SOD was positively correlated with FDD (
r
=0.47;
P
<0.01) and negatively with the effect of the antioxidant vitamin C on FDD (
r
=−0.59;
P
<0.01). In young individuals with hypercholesterolemia, however, eEC-SOD activity was increased (21.0±1.2 U · mL
−1
· min
−1
; n=10;
P
<0.05).

Conclusions
—In patients with CAD, vascular EC-SOD activity is substantially reduced. The close relation between endothelium-bound EC-SOD activity and FDD suggests that reduced EC-SOD activity contributes to endothelial dysfunction in patients with CAD. In young hypercholesterolemic individuals, however, endothelium-bound EC-SOD activity is increased and may, in part, counteract impairment of endothelial function as the result of increased formation of oxygen free radicals.
Effect of 40-kHz Ultrasound on Acute Thrombotic Ischemia in a Rabbit Femoral Artery Thrombosis Model
Authors: Suchkova V. N. , Baggs R. B. , Francis C. W.
Published: June 2012

Background
—We have shown previously that 40-kHz ultrasound (US) at low intensity accelerates fibrinolysis in vitro with little heating and good tissue penetration. These studies have now been extended to examine the effects of 40-kHz US on thrombolysis and tissue perfusion in a rabbit model.

Methods and Results
—Treatment was administered with either US alone at 0.75 W/cm
2
, streptokinase alone, or the combination of US and streptokinase. US or streptokinase resulted in minimal thrombolysis, but reperfusion was nearly complete with the combination after 120 minutes. US also reversed the ischemia in nonperfused muscle in the absence of arterial flow. Tissue perfusion decreased after thrombosis from 13.7±0.2 to 6.6±0.8 U and then declined further to 4.5±0.4 U after 240 minutes. US improved perfusion to 10.6±0.5 and 12.1±0.5 U after 30 and 60 minutes, respectively. This effect was reversible and declined to pretreatment values after US was discontinued. Similarly, tissue pH declined from normal to 7.05±0.02 after thrombosis, but US improved pH to 7.34±0.03 after 60 minutes. US-induced improvement in tissue perfusion and pH also occurred after femoral artery ligation, indicating that thrombolysis did not cause these effects.

Conclusions
—40-kHz US at low intensity markedly accelerates fibrinolysis and also improves tissue perfusion and reverses acidosis, effects that would be beneficial in treatment of acute thrombosis.
Angiopoietin-1 Inhibits Irradiation- and Mannitol-Induced Apoptosis in Endothelial Cells
Authors: Kwak Hee Jin , Lee Song Jae , Lee Yeun-Hee , Ryu Chul Hee , Koh Keum Nim , Choi Ha Young , Koh Gou Young
Published: June 2012

Background and Purpose
—Angiopoietin-1 (Ang1) is a vasculogenic factor that signals through the endothelial cell–specific Tie2 receptor tyrosine kinase. We recently reported that Ang1 prevented apoptosis induced by serum deprivation in endothelial cells. In this study, we examined whether Ang1 prevents apoptosis in endothelial cells treated with irradiation or clinical concentrations of mannitol.

Methods and Results
—Ang1 prevented irradiation- and mannitol-induced apoptosis in human umbilical vein endothelial cells in a dose-dependent manner. Pretreatment with soluble Tie2 receptor, but not Tie1 receptor, blocked the antiapoptotic effect of Ang1. Two phosphatidylinositol 3′-kinase (PI3-kinase)–specific inhibitors, wortmannin and LY294002, blocked the Ang1-induced antiapoptotic effect. The antiapoptotic potency of Ang1 was similar to or greater than that of vascular endothelial growth factor, basic fibroblast growth factor, and endothelin-1. Ang1 also prevented apoptosis in cultured endothelial cells from porcine pulmonary and coronary arteries and in endothelial cells of explanted rat aorta.

Conclusions
—Ang1 promotes the survival of endothelial cells in irradiation- and mannitol-induced apoptosis through Tie2 receptor binding and PI3-kinase activation. Pretreatment with Ang1 could be beneficial in maintaining normal endothelial cell integrity during intracoronary irradiation or systemic mannitol therapy.
Effect of Intracoronary Recombinant Human Vascular Endothelial Growth Factor on Myocardial Perfusion
Authors: Hendel Robert C. , Henry Timothy D. , Rocha-Singh Krishna , Isner Jeffrey M. , Kereiakes Dean J. , Giordano Frank J. , Simons Michael , Bonow Robert O.
Published: June 2012

Background
—Animal models of therapeutic angiogenesis have stimulated development of clinical application in patients with limited options for coronary revascularization. The impact of recombinant human vascular endothelial growth factor (rhVEGF) on myocardial perfusion in humans has not been reported.

Methods and Results
—Fourteen patients underwent exercise (n=11), dobutamine (n=2), or dipyridamole (n=1) myocardial perfusion single photon emission CT (SPECT) before as well as 30 and 60 days after rhVEGF administration. After uniform processing and display, 2 observers blinded to the timing of the study and dose of rhVEGF reviewed the SPECT images. By a visual, semiquantitative 20-segment scoring method, summed stress scores (SSS) and summed rest scores (SRS) were generated. Although the SSS did not change from baseline to 30 days (21.6 versus 21.5;
P
=NS), the SRS improved after rhVEGF (13.2 versus 10.4;
P
<0.05). Stress and rest perfusion improved in >2 segments infrequently in patients treated with low-dose rhVEGF. However, 5 of 6 patients had improvement in >2 segments at rest and stress with the higher rhVEGF doses. Furthermore, although neither the SSS nor the SRS changed in patients treated with the low doses, the SRS decreased in the high-dose rhVEGF patients at 60 days (14.7 versus 10.7;
P
<0.05). Quantitative analysis was consistent with the visual findings but failed to demonstrate statistical significance.

Conclusions
—Although not designed to demonstrate rhVEGF efficacy, these phase 1 data support the concept that rhVEGF improves myocardial perfusion at rest and provide evidence of a dose-dependent effect.
Association of Serology With the Endovascular Presence of
Chlamydia pneumoniae
and Cytomegalovirus in Coronary Artery and Vein Graft Disease
Authors: Bartels Claus , Maass Matthias , Bein Gregor , Brill Nicole , Bechtel J. F. Matthias , Leyh Rainer , Sievers Hans-Hinrich
Published: June 2012

Background
—Chemotherapeutic treatment for patients with symptomatic coronary artery disease to reduce cardiovascular events may be initiated in response to elevated antibody titers against
Chlamydia pneumoniae
or cytomegalovirus. How antibody titers are associated with the endovascular presence of these microorganisms is still unclear.

Methods and Results
—Antibody titers against
C pneumoniae
(microimmunofluorescence) and cytomegalovirus (ELISA) in patients undergoing primary (coronary desobliterates, n=80) or repeated CABG (occluded vein grafts, n=45) were correlated with the endovascular presence of the 2 microorganisms.
C pneumoniae
was detected by means of a nested polymerase chain reaction (PCR) and by culturing. Both conventional PCR and quantitative PCR were applied for detection of cytomegalovirus.
C pneumoniae
(PCR/culture) was detected in 19/9% (15/80 and 7/80) of coronary desobliterates and in 18/11% (8/45 and 5/45) of occluded vein grafts. There was no statistical evidence that IgG values differed between patients with or without
C pneumoniae
detection who were undergoing primary CABG. In contrast, repeated-CABG patients with a positive PCR (
P
=0.0027) or
C pneumoniae
culture (
P
=0.0018) had distinctly elevated IgG titers compared with patients in whom
C pneumoniae
was not detected. Cytomegalovirus could not be detected in the examined specimens.

Conclusions
—Cytomegalovirus infection does not seem to be associated with advanced coronary artery lesions.
C pneumoniae
antibody titers are not associated with the endovascular presence of
C pneumoniae
in patients with coronary artery disease. The observed strong association between elevated IgG titers and the detection of
C pneumoniae
in occluded vein grafts warrants further investigation.
Destabilizing Effects of Mental Stress on Ventricular Arrhythmias in Patients With Implantable Cardioverter-Defibrillators
Authors: Lampert Rachel , Jain Diwaker , Burg Matthew M. , Batsford William P. , McPherson Craig A.
Published: June 2012

Background
—The incidence of sudden cardiac death increases in populations who experience disasters such as earthquakes. The physiological link between psychological stress and sudden death is unknown; one mechanism may be the direct effects of sympathetic arousal on arrhythmias. To determine whether mental stress alters the induction, rate, or termination of ventricular arrhythmias, we performed noninvasive programmed stimulation (NIPS) in patients with defibrillators and ventricular tachycardia (VT), which is known to be inducible and terminated by antitachycardia pacing, at rest and during varying states of mental arousal.

Methods and Results
—Eighteen patients underwent NIPS in the resting-awake state (nonsedated). Ten underwent repeat testing during mental stress (mental arithmetic and anger recall). Induced VT was faster in 5 patients (
P
=0.03). VT became more difficult to terminate in 5 patients during mental stress; 4 required a shock (
P
=0.03). There was no change in ease of induction with mental stress. There was no evidence of ischemia on ECG or continuous ejection fraction monitoring. Eight patients received a shock in the resting-awake state and did not perform mental stress. Four underwent repeat NIPS after sedation; 3 then had induced VT terminated with antitachycardia pacing. All patients with an increase in norepinephrine of >50% had alterations in VT that required shock for termination (
P
<0.01).

Conclusions
—Mental stress alters VT cycle length and termination without evidence of ischemia. This suggests that mental stress may lead to sudden death through the facilitation of lethal ventricular arrhythmias.
Dilated Cardiomyopathy Associated With Simian AIDS in Nonhuman Primates
Authors: Shannon Richard P. , Simon Meredith A. , Mathier Michael A. , Geng Yong-Jian , Mankad Sunil , Lackner Andrew A.
Published: June 2012

Background
—Cardiomyopathy is being recognized with increasing frequency in patients with AIDS, yet the relationship between HIV infection and cardiac contractile dysfunction remains obscure. The purpose of the present study was to determine if infection with simian immunodeficiency virus (SIV) in nonhuman primates is associated with cardiac dysfunction and myocardial injury.

Methods and Results
—Left ventricular size and function were determined by 2D echocardiography in 16 rhesus macaques before and at weekly intervals following infection with cloned pathogenic SIV
mac
239 or the highly attenuated SIV
mac
239 nef deletion mutant. A second group of 15 rhesus macaques chronically infected with pathogenic (n=6) or nonpathogenic (n=9) virus were studied at >2 years following infection. Cardiac tissues from 24 rhesus macaques chronically infected (>2 years) with pathogenic SIV were reviewed for evidence of cardiac pathology. Acute infection (<6 weeks) with either pathogenic or nonpathogenic SIV caused neither contractile dysfunction nor cardiac pathology. However, LV ejection fraction was significantly (
P
<0.05) depressed (43±7%) in rhesus macaques chronically infected with pathogenic SIV compared with rhesus macaques chronically infected with nonpathogenic SIV (61±3%). Furthermore, two thirds of rhesus macaques that succumbed to simian AIDS had myocardial pathology including lymphocytic myocarditis (n=9) and coronary arteriopathy (n=6), with complete vessel occlusion (n=4) and associated myocardial infarction and necrosis.

Conclusions
—This unique model is valuable in understanding the pathogenesis of cardiac injury associated with retroviral infection in a relevant nonhuman primate model of AIDS.
Estrogen-Induced Vasoprotection Is Estrogen Receptor Dependent
Authors: Bakir Stephen , Mori Tatsuhiko , Durand Joan , Chen Yiu-Fai , Thompson J. Anthony , Oparil Suzanne
Published: June 2012

Background
—Previous studies have shown that estrogen (E2) is vasoprotective in multiple animal models of vascular injury, including mice with homologous disruptions of either the α or β isoforms of the estrogen receptor (ER) gene, calling into question the ER dependency of the vasoprotective effect. This study used ICI 182,780, a nonselective ER antagonist, to test the hypothesis that the vasoprotective effect of E2 in the rat carotid injury model is ER mediated.

Methods and Results
—Intact female Sprague-Dawley rats were divided into 4 groups and treated with the nonselective ER antagonist ICI 182,780 (ICI; 0.5, 1.5, or 5 mg · kg
−1
· d
−1
, subcutaneously [S.C.]) or vehicle, beginning before balloon injury of the right common carotid artery and continuing for 14 days afterward. Four groups of ovariectomized rats (OVX) were treated with 17β estradiol (E2) (20 μg · kg
−1
· d
−1
, S.C.) alone or combined with ICI 5 mg · kg
−1
· d
−1
, S.C.; with ICI 5 mg · kg
−1
· d
−1
alone; or with vehicle according to a similar protocol. Two weeks after injury, rats were killed, and the carotid arteries were evaluated for neointima formation using morphometric analysis. ICI 182,780 blunted the E2-related protective effect and increased neointima formation in injured carotid arteries of intact female rats in a dose-dependent fashion. ICI had no effect on neointima formation in OVX, but addition of ICI to E2 in OVX blocked the inhibitory effect of exogenous E2 on neointima formation.

Conclusions
—These results indicate that the vasoprotective effect of E2 in the balloon-injured rat carotid artery model is mediated by ER.
Acute and Chronic Angiotensin-1 Receptor Antagonism Reverses Endothelial Dysfunction in Atherosclerosis
Authors: Prasad Abhiram , Tupas-Habib Theresa , Schenke William H. , Mincemoyer Rita , Panza Julio A. , Waclawin Myron A. , Ellahham Samer , Quyyumi Arshed A.
Published: June 2012

Background
—The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The present study was performed to determine whether angiotensin-1 (AT
1
) receptor inhibition improves endothelial dysfunction.

Methods and Results
—In the femoral circulation of 19 patients with atherosclerosis and of 9 control subjects, we studied microvascular responses to reactive hyperemia, angiotensin II, acetylcholine, and sodium nitroprusside before and after the administration of intra-arterial losartan (10 mg). Femoral artery flow velocity was measured with a Doppler flow wire, and the femoral vascular resistance index (FVRI) was calculated as mean arterial pressure divided by flow velocity. Losartan induced a minor (5.9±2%,
P
=0.02) reduction in FVRI and inhibited angiotensin II–mediated vasoconstriction in both patient groups (
P
<0.01). After the administration of losartan, acetylcholine-mediated vasodilation was augmented in patients (44±5% to 58±4% reduction in FVRI with infusion at a rate of 150 μg/min,
P
<0.001) but not control subjects. Vasodilation during reactive hyperemia was also greater after AT
1
receptor inhibition (
P
=0.03) in patients, but the response to sodium nitroprusside remained unchanged. In a separate group of 31 patients with atherosclerosis, we investigated the effect of 8 weeks of oral losartan therapy on brachial artery flow-mediated vasodilation with the use of high-resolution ultrasound. Oral losartan therapy improved flow-mediated brachial artery dilation (1.4±0.9% to 3.2±0.8%,
P
=0.03) but had no effect on the nitroglycerin response. Serum nitrogen oxide levels increased from 21.6±1.7 to 26.7±2.4 μmol/L (
P
=0.008).

Conclusions
—The results of the present study indicate that inhibition of the AT
1
receptor in patients with atherosclerosis reverses endothelial dysfunction by improving NO availability and therefore may have long-term therapeutic benefits.
Relation of Phasic Coronary Flow Velocity Characteristics With TIMI Perfusion Grade and Myocardial Recovery After Primary Percutaneous Transluminal Coronary Angioplasty and Rescue Stenting
Authors: Akasaka Takashi , Yoshida Kiyoshi , Kawamoto Takahiro , Kaji Shuichiro , Ueda Yoshiaki , Yamamuro Atsushi , Takagi Tsutomu , Hozumi Takeshi
Published: June 2012

Background
—A residual stenosis and/or microvascular damage have been proposed as mechanisms of TIMI 2 flow for acute myocardial infarction. Coronary flow dynamics were assessed in patients with TIMI 2 flow to predict whether additional intervention would improve TIMI grade.

Methods and Results
—In 35 patients who had a successfully recanalized anterior acute myocardial infarction using angioplasty or rescue stenting, coronary flow patterns were compared with corresponding TIMI grade and regional left ventricular wall motion (LVWM) 1 month after the intervention. After angioplasty, the time-averaged peak velocity (APV) was lower in patients with TIMI 2 flow (n=22) than in those with TIMI 3 flow (n=13; 7.9±3.9 versus 20.6±5.1 cm/s;
P
<0.001). Two different flow patterns were recorded in patients with TIMI 2 flow (versus TIMI 3,
P
<0.001); patients with type 1 TIMI 2 flow (n=15) had a reduced diastolic APV (8.3±4.8 versus 24.2±7.4 cm/s), prolonged diastolic deceleration time (1176±455 versus 728±205 ms), and a small diastolic/systolic APV ratio (1.3±0.6 versus 2.1±0.7); patients with type 2 TIMI 2 flow (n=7) had systolic flow reversal (systolic APV, −7.9±4.6 versus 11.7±4.5 cm/s), a rapid diastolic deceleration time (221±84 versus 728±205 ms), and a negative diastolic/systolic APV ratio (−2.1±1.4 versus 2.1±0.7). A significantly lower mean chord LVWM (−3.0±0.2 versus −1.9±0.8;
P
<0.001) and a greater number of chords <−2SD (50±2 versus 28±18;
P
<0.001) were present in patients with type 2 versus type 1 TIMI 2 flow. Stenting increased TIMI 2 flow to TIMI 3 flow more in patients with type 1 than type 2 flow (67% versus 0%;
P
=0.003). Patients with TIMI 2 flow after stenting continued to demonstrate a type 2 pattern, and they had poor LVWM recovery.

Conclusions
—The differentiation between 2 types of TIMI 2 flow can predict the improvement of TIMI grade and LVWM recovery after additional stenting.
Assessment of Myocardial Reperfusion by Intravenous Myocardial Contrast Echocardiography and Coronary Flow Reserve After Primary Percutaneous Transluminal Coronary Angiography in Patients With Acute Myocardial Infarction
Authors: Lepper Wolfgang , Hoffmann Rainer , Kamp Otto , Franke Andreas , de Cock Carel C. , Kühl Harald P. , Sieswerda Gertjan T. , Dahl Jürgen vom , Janssens Uwe , Voci Paolo , Visser Cees A. , Hanrath Peter
Published: June 2012

Background
—This study investigated whether the extent of perfusion defect determined by intravenous myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction (AMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) relates to coronary flow reserve (CRF) for assessment of myocardial reperfusion and is predictive for left ventricular recovery.

Methods and Results
—Twenty-five patients with first AMI underwent intravenous MCE with
NC100100
with intermittent harmonic imaging before PTCA and after 24 hours. MCE before PTCA defined the risk region and MCE at 24 hours the “no-reflow” region. The no-reflow region divided by the risk region determined the ratio to the risk region. CFR was assessed immediately after PTCA and 24 hours later. Left ventricular wall motion score indexes were calculated before PTCA and after 4 weeks. CFR at 24 hours defined a recovery (CFR ≥1.6; n=17) and a nonrecovery group (CFR <1.6; n=8). Baseline CFR did not differ between groups. MCE ratio to the risk region was smaller in the recovery group compared with the nonrecovery group (34±49% vs 81±46%,
P
=0.009). A ratio to the risk region of ≤50% defined an MCE reperfusion group. It was associated with improvement of CFR from 1.67±0.47 at baseline to 2.15±0.53 at 24 hours (
P
<0.001) and of regional wall motion score index from 2.6±0.5 to 1.9±0.5 at 4 weeks (
P
<0.001).

Conclusions
—Intravenous MCE can be used to define perfusion defects after AMI. Assessment of microcirculation by MCE corresponds to evaluation by CFR. Serial intravenous MCE has the potential to identify patients likely to have improved left ventricular function after AMI.
AT
1
Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor
Authors: Dechend Ralf , Homuth Volker , Wallukat Gerd , Kreuzer Jörg , Park Jeun Koon , Theuer Jürgen , Juepner Axel , Gulba Dietrich C. , Mackman Nigel , Haller Hermann , Luft Friedrich C.
Published: June 2012

Background
—We recently described autoantibodies (angiotensin-1 receptor autoantibodies, AT
1
-AA) directed at the AT
1
receptor in the serum of preeclamptic patients, whose placentas are commonly infarcted and express tissue factor (TF). Mechanisms of how AT
1
-AA might contribute to preeclampsia are unknown. We tested the hypothesis that AT
1
-AA cause vascular smooth muscle cells (VSMC) to express TF.

Methods and Results
—IgG from preeclamptic patients containing AT
1
-AA was purified with anti-human IgG columns. AT
1
-AA were separated from the IgG by ammonium sulfate precipitation. We transfected Chinese hamster ovary cells overexpressing the AT
1
receptor with TF promoter constructs coupled to a luciferase reporter gene. VSMC were obtained from human coronary arteries. Extracellular signal-related kinase activation was detected by an in-gel kinase assay. AP-1 activation was determined by electromobility shift assay. TF was measured by ELISA and detected by immunohistochemistry. Placentas from preeclamptic women stained strongly for TF, whereas control placentas showed far less staining. We proved AT
1
-AA specificity by coimmunoprecipitating the AT
1
receptor with AT
1
-AA but not with nonspecific IgG. Angiotensin (Ang) II and AT
1
-AA both activated extracellular signal-related kinase, AP-1, and the TF promoter transfected VSMC and Chinese hamster ovary cells, but only when the AP-1 binding site was present. We then demonstrated TF expression in VSMC exposed to either Ang II or AT
1
-AA. All these effects were blocked by losartan. Nonspecific IgG or IgG from nonpreeclamptic pregnant women had a negligible effect.

Conclusions
—We conclude that AT
1
-AA and Ang II both stimulate the AT
1
receptor and initiate a signaling cascade resulting in TF expression. These results show an action of AT
1
-AA on human cells that could contribute to the pathogenesis of preeclampsia.