bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-term Economic and Health Benefits of Smoking Cessation
Authors: Lightwood James M. , Glantz Stanton A.
Published: June 2012

Background
Most analyses of the economic benefits of smoking cessation consider long-term effects, which are often not of interest to public and private policy makers. These analyses fail to account for the time course of the short-run cost savings from the rapid decline in risk of acute myocardial infarction (AMI) and stroke.

Methods and Results
We estimate the time course of the fall in risk of AMI and stroke after smoking cessation and simulate the impact of a 1% absolute reduction in smoking prevalence on the number of and short-term direct medical costs associated with the prevented AMIs and strokes. In the first year, there would be 924±679 (mean±SD) fewer hospitalizations for AMI and 538±508 for stroke, resulting in an immediate savings of $44±26 million. A 7-year program that reduced smoking prevalence by 1% per year would result in a total of 63 840±15 521 fewer hospitalizations for AMI and 34 261±9133 fewer for stroke, resulting in a total savings of $3.20±0.59 billion in costs, and would prevent ≈13 100 deaths resulting from AMI that occur before people reach the hospital. Creating a new nonsmoker reduces anticipated medical costs associated with AMI and stroke by $47 in the first year and by $853 during the next 7 years (discounting 2.5% per year).

Conclusions
Although primary prevention of smoking among teenagers is important, reducing adult smoking pays more immediate dividends, both in terms of health improvements and cost savings.
Do High Proinsulin and C-Peptide Levels Play a Role in Autonomic Nervous Dysfunction?
Authors: Töyry Jari P. , Niskanen Leo K. , Mäntysaari Matti J. , Länsimies Esko A. , Haffner Steven M. , Miettinen Heikki J.J. , Uusitupa Matti I.J.
Published: June 2012

Background
Immunoreactive insulin has been shown to predict the development of parasympathetic autonomic neuropathy. It is possible that constituents of immunoreactive insulin could explain this association. In this cross-sectional study, the relationship of specific insulin, C-peptide, and proinsulin with autonomic nervous dysfunction was evaluated in 57 NIDDM patients and 108 control subjects.

Methods and Results
The frequency-domain analysis of heart rate variability was determined by using spectral analysis from stationary regions of registrations while the subjects breathed spontaneously in a supine position. Total power was divided into three frequency bands: low (0 to 0.07 Hz), medium (MFP, 0.07 to 0.15 Hz), and high (HFP, 0.15 Hz to 0.50 multiplied by the frequency equal to the mean RR interval). In NIDDM patients, total power, the three frequency bands (
P
<.001 for each), and the MFP/HFP ratio (
P
=.016), which expresses sympathovagal balance, were reduced compared with control subjects. Fasting proinsulin (
r
s
=−.324,
P
=.014 for diabetics and
r
s
=−.286,
P
=.003 for control subjects), C-peptide (
r
s
=−.492,
P
<.001 for diabetics and
r
s
=−.304,
P
=.001 for control subjects), and total immunoreactive insulin (
r
s
=−.291,
P
=.028 for diabetics and
r
s
=−.228,
P
=.017 for control subjects) were inversely related to MFP/HFP. For proinsulin and C-peptide the results did not change after controlling for the effects of age, body mass index, and fasting glucose.

Conclusions
Both proinsulin and C-peptide levels were significantly associated with the sympathovagal balance of autonomic nervous function in NIDDM patients and control subjects, but this study cannot determine whether these compounds are directly involved in autonomic nervous dysfunction.
Expression and Localization of Platelet-Derived Growth Factor Ligand and Receptor Protein During Acute and Chronic Rejection of Rat Cardiac Allografts
Authors: Lemström Karl B. , Koskinen Petri K.
Published: June 2012

Background
The molecular mechanisms of cardiac allograft vasculopathy (CAV) remain largely unknown. Using rat cardiac allografts, we examined by immunohistochemistry the expression and localization of platelet-derived growth factor ligand (PDGF-AA and -BB) and receptor (Rα and Rβ) proteins during acute and chronic rejection.

Methods and Results
In acute rejection, a prominent induction of both PDGF ligand and receptor proteins occurred in the interstitial mononuclear inflammatory cells (
P
<.05), most of which were ED1-immunoreactive. PDGF-Rβ was also induced in the capillary endothelium (
P
<.01). In cardiac allografts with severe intimal thickening, PDGF-AA expression was localized to the media and intima, whereas PDGF-BB expression was less prominent and was detected mainly in interstitial ED1-immunoreactive inflammatory cells. Double staining revealed that intimal cells expressing PDGF-AA were α-smooth muscle actin–positive but also α-smooth muscle actin–negative myofibroblast-like cells and to a lesser extent, ED1-immunoreactive cells. Both PDGF-Rα and -Rβ expression occurred in intimal, arterial endothelial, and interstitial mononuclear inflammatory cells. High-dose cyclosporin A (CsA) treatment significantly reduced both PDGF-AA and PDGF-Rα expression in intimal cells. Furthermore, linear regression analysis revealed that PDGF-AA, PDGF-Rα, and PDGF-Rβ expression in intimal cells and PDGF-BB expression in interstitial mononuclear inflammatory cells correlated with intimal thickening.

Conclusions
Alloimmune injury induces the expression of PDGF ligands, especially of PDGF-AA, in the graft vasculature and sufficient immunosuppression with CsA suppresses the expression of PDGF and inhibits the development of CAV. PDGF may have a substantial role in the regulation of smooth muscle cell migration and proliferation in an autocrine or paracrine manner during the development of CAV.
Additional Hypotensive Effect of Endothelin-1 Receptor Antagonism in Hypertensive Dogs Under Angiotensin-Converting Enzyme Inhibition
Authors: Donckier Julian E. , Massart Pierre-Emmanuel , Hodeige Dominique , Van Mechelen Henri , Clozel Jean-Paul , Laloux Olivier , Ketelslegers Jean-Marie , Charlier André A. , Heyndrickx Guy R.
Published: June 2012

Background
Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI).

Methods and Results
Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+0.23 mg/kg per hour to 3 mg/kg+7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (
P
=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173±26 to 130±25 mm Hg;
P
<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98±21 mm Hg (
P
<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (
P
<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (
P
<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan.

Conclusions
Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.
Role of Intracellular Ca
2+
in Activation of Protein Kinase C During Ischemic Preconditioning
Authors: Node Koichi , Kitakaze Masafumi , Sato Hiroshi , Minamino Tetsuo , Komamura Kazuo , Shinozaki Yoshiro , Mori Hidezo , Hori Masatsugu
Published: June 2012

Background
Activation of protein kinase C plays an important role in ischemic preconditioning. Given that protein kinase C is activated by an increase in the intracellular Ca
2+
concentration ([Ca
2+
]
i
) and that myocardial ischemia and reperfusion increase [Ca
2+
]
i
, the effect of transient exposures to Ca
2+
on infarct size and the effect of administration of EGTA during ischemic and α
1
-adrenoceptor–mediated preconditioning on the limitation of infarct size were investigated in the canine heart.

Methods and Results
In open-chest dogs, 5 minutes after the completion of either three 5-minute infusions of CaCl
2
or four 5-minute infusions of the α
1
-adrenoceptor agonist methoxamine into the coronary artery, the coronary arteries were occluded for 90 minutes; this occlusion was followed by a 6-hour reperfusion in both the Ca
2+
preconditioning and methoxamine groups. Infarct sizes in the Ca
2+
preconditioning (15.8±2.3%) and methoxamine (10.1±2.2%) groups were significantly (
P
<.01) smaller than in the control group (42.5±2.9%), and administration of either an inhibitor of protein kinase C (GF109203X) or an inhibitor of ecto-5′-nucleotidase (α,β-methyleneadenosine 5′-diphosphate) reduced the infarct size–limiting effect of Ca
2+
preconditioning. Administration of EGTA during ischemic or α
1
-adrenoceptor–mediated preconditioning inhibited both the infarct size–limiting effect and the activation of protein kinase C and ecto-5′-nucleotidase induced by these procedures.

Conclusions
[Ca
2+
]
i
during ischemic and α
1
-adrenoceptor–mediated preconditioning plays an important role in the infarct size–limiting effect of these procedures by activating protein kinase C and ecto-5′-nucleotidase in the canine heart.
Rat Arterial Wall Retains Myointimal Hyperplastic Potential Long After Arterial Injury
Authors: Sirois Martin G. , Simons Michael , Kuter David J. , Rosenberg Robert D. , Edelman Elazer R.
Published: June 2012

Background
Many novel molecular and pharmacological modalities have been proposed for the treatment of accelerated vascular diseases. Yet the fundamental question remains of whether the vessel wall can be treated once only or whether single-dose therapy simply delays the inevitable processes that lead to intimal hyperplasia. Since platelet adhesion and aggregation are critical events in vascular healing, we sought to determine whether the injured blood vessel would retain its myointimal potential after reversal of even prolonged periods of thrombocytopenia.

Methods and Results
A novel nonimmune method sustained thrombocytopenia and suppressed postinjury neointimal hyperplasia by 88%. Infusion of fresh platelets, even 14 days after initial denuding injury, restored the full neointimal hyperplastic potential. Platelet depletion presumably removed factors chemotactic for vascular smooth muscle cells but had no effect on the overexpression of the platelet-derived growth factor receptor-β (PDGFR-β) subunit after vascular injury. In native vessels, 26.5±2.5% of medial smooth muscle cells expressed PDGFR-β. In all animals, medial PDGFR-β expression doubled 2 weeks after endothelial denudation and was evident in up to 74.5±2.5% of the cells forming the neointima.

Conclusions
Thus, though the hyperplastic potential of the injured blood vessel can be delayed with removal of growth stimuli, it is not lost forever, and if the media is not made quiescent, neointimal hyperplasia is simply delayed rather than prevented. These results may have a profound effect on our understanding and treatment of accelerated proliferative vascular diseases.
Effects of Transvenous Electrode Polarity and Waveform Duration on the Relationship Between Defibrillation Threshold and Upper Limit of Vulnerability
Authors: Huang Jian , KenKnight Bruce H. , Walcott Gregory P. , Rollins Dennis L. , Smith William M. , Ideker Raymond E.
Published: June 2012

Background
The upper limit of vulnerability (ULV) hypothesis for defibrillation predicts that maneuvers that alter the ULV will cause a similar alteration in the defibrillation threshold (DFT). The purpose of this study was to test this prediction by evaluating the effects of electrode polarity and waveform duration on the relationship between the DFT and the ULV.

Methods and Results
Platinum spring electrodes were placed in the right ventricular (RV) apex and the superior vena cava in 12 pigs. Strength-duration curves were constructed for the DFT and ULV for each electrode polarity with monophasic waveforms (6 pigs) of different durations (2 to 14 ms) and biphasic truncated exponential waveforms (6 pigs) having phase 1 equal to 4 ms and phase 2 of different durations (0 to 10 ms). ULV data were gathered by scanning of the T wave. The ventricular pacing threshold (VPT) and ventricular fibrillation threshold (VFT) were also determined with these same waveforms. For the RV electrode as a cathode for monophasic and the first phase of biphasic stimuli, VPTs for the same waveform duration were significantly lower than for the configuration with the RV electrode as an anode. VFTs were not significantly different for the two electrode polarities with either monophasic or biphasic waveforms. The DFT changed in a fashion similar to the ULV with changes in electrode polarity and phase duration for both monophasic and biphasic waveforms. The ULV and DFT for each waveform duration for each polarity were strongly correlated (
r
=.83 to .99).

Conclusions
The almost identical changes in ULV and DFT with changes in electrode polarity and waveform duration provide new evidence to support the ULV hypothesis of defibrillation.
Lipid Lowering Versus Revascularization
Authors: Forrester James S. , Shah Prediman K.
Published: June 2012

Abstract
There is strong evidence that revascularization does not prevent myocardial infarction in patients with stable coronary artery disease (CAD). The anatomic basis for this counterintuitive conclusion seems to be that most myocardial infarctions occur at sites that did not previously exhibit an angiographically significant stenosis. These angiographic observations are further supported by thallium studies in stable CAD that demonstrate that the site of stress-induced ischemia is frequently not the site of subsequent myocardial infarction. Since both coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty are directed at more severe coronary stenoses, we are led to the remarkable conclusion that angiography does not identify, and consequently revascularization therapies do not treat, the lesions that lead to myocardial infarction. The pathology of coronary atherosclerosis provides the basis for understanding why revascularization does not prevent infarction: unstable lesions that cause infarction are not necessarily severely stenotic, and stenotic lesions are not necessarily unstable. In contrast to revascularization, lipid lowering reduces the rate of myocardial infarction by ≈30% over a period of 5 years. Thus, we might postulate that lipid lowering is the more effective therapy for both prevention of acute myocardial infarction and long-term survival. The health policy and economic implications of this viewpoint, should it emerge in the management of coronary heart disease, are clearly substantial. Consequently, the relative roles of lipid-lowering therapy and revascularization, both alone and together, must now be determined. It is an idea whose time—for testing—has come.
Predictive Value of Electrophoretically Detected Lipoprotein(a) for Coronary Heart Disease and Cerebrovascular Disease in a Community-Based Cohort of 9936 Men and Women
Authors: Nguyen Tu T. , Ellefson Ralph D. , Hodge David O. , Bailey Kent R. , Kottke Thomas E. , Abu-Lebdeh Haitham S.
Published: June 2012

Background
Elevated lipoprotein(a) [Lp(a)] levels have been associated with the presence of atherosclerotic disease. However, the results of prospective studies of Lp(a) and cardiovascular disease have been contradictory.

Methods and Results
From 1968 through 1982, lipoprotein analysis was performed in 11 335 Olmsted County residents. Quantitative cholesterol and triglycerides were obtained along with semiquantitative Lp(a) levels based on electrophoretic pattern. Lp(a) bands were scored from 0 (absent) to 3 (increased). A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a) determinations were followed up for 14 years for development of coronary artery disease (CAD) and cerebrovascular disease (CVD). During 131 330 person-years of follow-up, there were 1848 CAD events and 841 CVD events. Age, diabetes, hypertension, cholesterol, and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women. There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a) levels for men and women. For Lp(a) level 3, the hazard ratio was 1.9 (range, 1.3 to 2.9) in women and 1.6 (range, 1.0 to 2.5) in men. The adjusted hazard ratio for CVD showed an irregular association with Lp(a) levels in men and no association in women.

Conclusions
In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years, Lp(a) was a significant predictor of risk of future CAD. Lp(a) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women.
A Prospective Evaluation of Catheter Ablation of Ventricular Tachycardia as Adjuvant Therapy in Patients With Coronary Artery Disease and an Implantable Cardioverter-Defibrillator
Authors: Strickberger S. Adam , Man K. Ching , Daoud Emile G. , Goyal Rajiva , Brinkman Karin , Hasse Carol , Bogun Frank , Knight Bradley P. , Weiss Raul , Bahu Marwan , Morady Fred
Published: June 2012

Background
Implantable cardioverter-defibrillator (ICD) therapy is integral to current therapy for ventricular tachycardia. Patients with an ICD frequently require concomitant antiarrhythmic drug therapy. Despite this, some patients still receive frequent ICD therapies for ventricular tachycardia. Therefore, the purpose of this prospective study was to determine the utility of ablation of ventricular tachycardia in patients with an ICD who experience frequent ICD therapies.

Methods and Results
Twenty-one consecutive patients with frequent ICD therapies despite antiarrhythmic drug therapy were the subjects of this study. The mean age was 69±6 years, and 17 were men. The mean ejection fraction was 0.22±0.08, and all patients had coronary artery disease. During the 36±51 days (range, 4 days to 7 months) preceding the ablation procedures, the patients received 34±55 ICD therapies for the clinical ventricular tachycardia, or a mean of 25±88 ICD therapies per month. The patients underwent radiofrequency ablation of the presumed clinical ventricular tachycardia by inducing the tachycardia and mapping according to endocardial activation, continuous electrical activity, pace mapping, concealed entrainment, or mid-diastolic potentials. Ablation of the clinical arrhythmia was successful in 76% of patients during 1.4±0.6 (range, 1 to 3) ablation procedures and required 12.5±9.2 applications of energy. During 11.8±10.0 months of follow-up, the frequency of ICD therapies per month decreased from 60±80 before successful ablation to 0.1±0.3 ICD therapies per month after ablation (
P
=.01). A quality-of-life assessment demonstrated a significant improvement after successful (
P
=.02) but not unsuccessful ablation (
P
=.9).

Conclusions
Radiofrequency ablation of ventricular tachycardia as adjuvant therapy in patients with coronary artery disease and an ICD has a reasonable success rate, significantly reduces ICD therapies, and appears to be associated with an improved quality of life.
Selective Modulation of Inducible Nitric Oxide Synthase Isozyme in Myocardial Infarction
Authors: Wildhirt Stephen M. , Suzuki Hiroshi , Horstman Damian , Weismüller Susanne , Dudek Ryszard R. , Akiyama Kazuhide , Reichart Bruno
Published: June 2012

Background
Inducible nitric oxide synthase (iNOS) is activated in cardiac disorders. We investigated the contribution of increased iNOS activity to the development of left ventricular dysfunction after myocardial infarction by selective inhibition of the isozyme.

Methods and Results
Male New Zealand rabbits were subjected to myocardial infarction. Animals were treated with either saline,
S
-methylisothiourea sulfate (SMT) (a selective iNOS inhibitor), or
N
ω
-nitro-
l
-arginine (L-NNA) (a nonselective NOS inhibitor). Inducible and constitutive NOS (cNOS) activity, plasma NO
x
, cGMP, hemodynamics, and myocardial blood flow were measured before and 5, 24, and 72 hours after coronary occlusion. Infarction 72 hours after occlusion resulted in increased myocardial iNOS activity, increased cardiac NO
x
production, and elevated cGMP levels. cNOS remained unchanged. Infarction increased left ventricular end-diastolic pressure (LVEDP) and decreased maximum +dP/dt and −dP/dt. L-NNA inhibited iNOS and cNOS activities and plasma NO
x
levels. L-NNA further increased LVEDP and reduced myocardial blood flow. Administration of SMT 72 hours after infarction significantly inhibited iNOS and cardiac NO
x
production but had no effects on cNOS. SMT improved left ventricular maximum +dP/dt and −dP/dt and decreased LVEDP. Myocardial blood flow in the remote myocardium increased.

Conclusions
These findings suggest that induction of iNOS activity 72 hours after infarction exerts negative inotropic effects and contributes to the development of myocardial dysfunction; selective modulation of increased iNOS activity by SMT improves cardiac performance, enhances myocardial blood flow, and may be beneficial in the treatment of acute myocardial infarction.
Angiotensin-Converting Enzyme Inhibition Abolishes Medial Smooth Muscle PDGF-AB Biosynthesis and Attenuates Cell Proliferation in Injured Carotid Arteries
Authors: Wong James , Rauhöft Claudia , Dilley Rodney J. , Agrotis Alex , Jennings Garry L. , Bobik Alex
Published: June 2012

Background
ACE inhibitors can attenuate the development of intimal fibrocellular lesions after balloon catheter vessel injury, but the mechanisms responsible are unknown.

Methods and Results
To evaluate how basic fibroblast growth factor (FGF-2) and the platelet-derived growth factor (PDGF) isoforms are affected by ACE inhibition in injured rat carotid arteries in relation to smooth muscle cell (SMC) proliferation, we examined the effects of oral perindopril on FGF-2 and PDGF isoform levels in carotid arteries 2 days after balloon catheter injury. [
3
H]Thymidine incorporation into medial and intimal SMCs was also assessed. Uninjured vessels contained two forms of FGF-2, with molecular weights of 18 and 22 kD, and PDGF-AA. Two days after injury, FGF-2 and PDGF-AA levels were markedly reduced, but high levels of PDGF-AB became apparent when the SMCs were proliferating. Perindopril completely abolished the biosynthesis of PDGF-AB but had little effect on residual FGF-2. This was accompanied by a 25% reduction in medial SMC proliferation. Neointimal cell proliferation 10 days after injury was unaffected by perindopril, although neointima size was reduced by 30%. Commencing perindopril treatment 4 days after the injury confirmed that early events associated with effects on medial SMCs were the major contributors to the attenuated neointimal lesions.

Conclusions
The ability of ACE inhibitors such as perindopril to attenuate neointima formation and growth in balloon catheter–injured rat carotid arteries is dependent on early events in the media, the inhibition of SMC PDGF-AB biosynthesis and attenuation of proliferation. Neointima formation in similarly injured vessels containing SMCs that are either unresponsive to PDGF-AB or exhibit an ACE-independent profile of growth factor biosynthesis responses may account for the ineffectiveness of ACE inhibition in some species.
Human Platelet Ca
2+
Mobilization, Glycoprotein IIb/IIIa Activation, and Experimental Coronary Thrombosis In Vivo in Dogs Are All Inhibited by the Inotropic Agent Amrinone
Authors: Sill J. C. , Bertha B. , Berger I. , Uhl C. , Nugent M. , Folts J.
Published: June 2012

Background
Inotropic drugs are often used to treat acute, severe heart failure resulting from acute myocardial infarction and other unstable coronary artery syndromes. However, catecholamine inotropic agents may potentiate coronary thrombosis via a platelet α
2
-adrenergic mechanism, thus exacerbating the original problem. The present studies were designed to determine whether the nonadrenergic inotropic and vasodilator drug amrinone, which elevates platelet cAMP levels, would both inhibit human platelet Ca
2+
mobilization and adhesion molecule expression ex vivo and protect against experimental coronary thrombosis in vivo in dogs.

Methods and Results
Human platelets in suspension were preincubated with amrinone 2.5 to 15 μg/mL; stimulated with the agonists thrombin 0.1 U/mL, ADP 10
−6
mol/L, or arginine vasopressin 10
−7
mol/L; and studied for Ca
2+
mobilization, glycoprotein IIb/IIIa activation, and P-selectin expression by fluorescent flow cytometry methods. Experimental coronary thrombosis in vivo was studied in an open-chest dog model with critical coronary artery stenosis and deep vessel wall injury. Results showed that at the cellular level, amrinone inhibited agonist-induced Ca
2+
mobilization and had modest inhibitory effects on adhesion molecule expression. In vivo in dogs, intravenous amrinone 2 mg/kg plus infusion at 20 μg·kg
−1
·min
−1
completely abolished coronary thrombosis.

Conclusions
The fact that amrinone inhibited human platelet activation at the cellular level and protected against experimental coronary thrombosis in vivo in dogs suggests a potentially advantageous antithrombotic action for this inotropic and vasodilator drug.
Effect of Intravascular Irradiation on Cell Proliferation, Apoptosis, and Vascular Remodeling After Balloon Overstretch Injury of Porcine Coronary Arteries
Authors: Waksman Ron , Rodriguez José C. , Robinson Keith A. , Cipolla Gustavo D. , Crocker Ian R. , Scott Neal A. , King Spencer B. , Wilcox Josiah N.
Published: June 2012

Background
Ionizing radiation has been shown to reduce vascular lesion formation after balloon overstretch injury of pig coronary arteries. The present series of experiments examines the mechanism by which this occurs.

Methods and Results
Balloon injury was performed on porcine coronary arteries, followed immediately by ionizing radiation using either a source train of
90
Sr/Y or
192
Ir seeds designed to deliver 14 or 28 Gy at a depth of 2 mm from the source. The animals were killed 3, 7, or 14 days after injury. Bromodeoxyuridine was administered 24 hours before euthanasia to label proliferating cells. Cell proliferation was significantly reduced on day 3 in the adventitia and media of the irradiated vessels compared with controls. Two weeks after injury, there were fewer α-actin–positive myofibroblasts in the adventitia of the irradiated vessels than in nonirradiated controls, and morphometric analysis indicated that the vessel perimeter of the irradiated vessels was significantly larger than in controls. Together, these results suggest a positive effect of intravascular irradiation on vascular remodeling. Apoptosis was estimated by terminal transferase dUTP-biotin nick-end labeling (TUNEL) 3 and 7 days after injury. TUNEL-labeled cells were found primarily in the adventitia at the medial tear, but no differences were detected between irradiated and control vessels.

Conclusions
These studies suggest that intracoronary radiation primarily inhibits the first wave of cell proliferation in the vessel wall and demonstrates a favorable effect on late remodeling by preventing adventitial fibrosis at the injury site.
Quantifying Aortic Regurgitation by Using the Color Doppler–Imaged Vena Contracta
Authors: Ishii Masahiro , Jones Michael , Shiota Takahiro , Yamada Izumi , Heinrich Russell S. , Holcomb Scott R. , Yoganathan Ajit P. , Sahn David J.
Published: June 2012

Background
The aim of the present study was to evaluate the accuracy of determining aortic effective regurgitant orifice area (EROA) and aortic regurgitant volume by using the color Doppler–imaged vena contracta (CDVC).

Methods and Results
Twenty-nine hemodynamically different states were obtained pharmacologically in eight sheep with surgically induced aortic regurgitation. Instantaneous regurgitant flow rates (RFRs) were obtained with aortic and pulmonary electromagnetic flowmeters (EFMs), and aortic EROAs were determined from EFM RFRs divided by continuous wave Doppler velocities. Color Doppler–derived EROAs were estimated by measuring the maximal diameters of the CDVC. Peak and mean RFRs and regurgitant volumes per beat were calculated from vena contracta area continuous wave diastolic Doppler velocity curves. Peak EFM-derived RFRs varied from 1.8 to 13.6 (6.3±3.2) L/min (range [mean±SD]), mean RFRs varied from 0.7 to 4.9 (2.7±1.3) L/min, regurgitant volumes per beat varied from 7.0 to 48.0 (26.9±12.2) mL/beat, and the regurgitant fractions varied from 23% to 78% (55±16%). EROAs determined by using CDVC measurements correlated well with reference EROAs obtained by using the EFM method (
r
=.91, SEE=0.07 cm
2
). Excellent correlations and agreements between peak and mean RFR and regurgitant volumes per beat as determined by Doppler echocardiography and EFM were also demonstrated (
r
=.95 to .96).

Conclusions
Our study indicates that the CDVC method can be used to quantify both aortic EROAs and regurgitant flow rates.
Safety of Atrial Defibrillation Shocks Synchronized to Narrow and Wide QRS Complexes During Atrial Pacing Protocols Simulating Atrial Fibrillation in Dogs
Authors: Keelan Edward T. , Krum David , Hare John , Mughal Kashef , Li Huagui , Akhtar Masood , Jazayeri Mohammad R.
Published: June 2012

Background
The potential ventricular proarrhythmic effect of atrial defibrillation shocks (ADS) remains a concern with automatic internal atrial defibrillation. Optimal R-wave synchronization alone may not be sufficient to prevent the induction of ventricular fibrillation (VF).

Methods and Results
The proarrhythmic effect of ADS synchronized to normally conducted QRS complexes (NQRS) and to supraventricular complexes with left or right bundle-branch block (L/RBBB) was investigated in a canine atrial pacing study. Short-long-short, single premature, and burst pacing protocols from the high right atrium were performed at baseline, during isoproterenol infusion, and after intravenous procainamide. The ADS were delivered between decapolar catheters in the coronary sinus and lateral right atrium. They were initially delivered 20 milliseconds (ms) after the end of the last conducted QRS complex and then scanned decrementally through that complex until VF was induced. For NQRS complexes, VF occurred only when the ADS were delivered at or before the onset of the QRS complex and never during the complex itself. In the presence of LBBB or RBBB, VF was induced by ADS delivered at the onset of or within the first 45 ms of the QRS complex in 16 animals. The longest RR (VV) intervals preceding ADS-induced VF were 345 ms at baseline and 380 ms after procainamide.

Conclusions
In this study, ADS synchronized to NQRS complexes appeared to be safe regardless of the preceding RR interval. In the presence of LBBB or RBBB, RR intervals preceding the ADS of >345 ms at baseline and >380 ms in the presence of procainamide would have been required to avoid VF. Alternatively, ADS delivered 50 ms after the onset of the RV electrogram appeared to be safe in all circumstances regardless of the preceding RR interval.
Phentolamine Prevents Adaptation to Ischemia During Coronary Angioplasty
Authors: Tomai Fabrizio , Crea Filippo , Gaspardone Achille , Versaci Francesco , Ghini Anna S. , De Paulis Ruggero , Chiariello Luigi , Gioffrè Pier A.
Published: June 2012

Background
Experimental studies indicate that α-adrenergic receptors are involved in ischemic preconditioning. Their role in humans is unknown.

Methods and Results
Eighteen patients undergoing angioplasty for an isolated stenosis of the left anterior descending coronary artery were randomized to receive intravenous infusion of phentolamine or placebo during the procedure. Intracoronary ECG and cardiac pain were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire. In both phentolamine- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (
P
<.01), but it did not show any further increase during the second inflation. In phentolamine-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (13±9 versus 12±8 mm,
P
=NS, and 51±34 versus 54±32 mm,
P
=NS, respectively), whereas in placebo-treated patients, they were significantly less (6±4 versus 13±7 mm,
P
<.01, and 26±20 versus 49±22 mm,
P
<.05, respectively).

Conclusions
The adaptation to ischemia observed in humans after two sequential coronary balloon inflations is abolished by phentolamine and is independent of collateral recruitment. Thus, it occurs due to ischemic preconditioning and is, at least in part, mediated by α-adrenergic receptors.
Adventitial Gene Transfer of Recombinant Endothelial Nitric Oxide Synthase to Rabbit Carotid Arteries Alters Vascular Reactivity
Authors: Kullo Iftikhar J. , Mozes Geza , Schwartz Robert S. , Gloviczki Peter , Crotty Thomas B. , Barber Dustan A. , Katusic Zvonimir S. , O’Brien Timothy
Published: June 2012

Background
Adventitial gene transfer may serve as a tool to study vascular biology and may have therapeutic potential. We investigated the hypothesis that adenovirus-mediated transfer of the gene for endothelial nitric oxide synthase (eNOS) to the adventitia would alter vascular reactivity.

Methods and Results
Rabbit carotid arteries were surgically isolated and adenoviral vectors encoding eNOS (AdeNOS) or β-galactosidase instilled into the periarterial sheath at a concentration of 1×10
10
pfu/mL. Arteries were harvested 4 days later for immunostaining, NOS enzymatic assay, measurement of cGMP, and vasomotor studies. Transgene expression in the adventitia was confirmed by histochemistry for β-galactosidase and immunostaining for eNOS with a monoclonal antibody. Calcium-dependent NOS enzymatic activity and cGMP levels were significantly greater in the AdeNOS-transduced arteries. Maximal contractions to phenylephrine (10
−5
mol/L) were diminished in the AdeNOS-transduced arteries (4.6±0.2 versus 5.6±0.2 g;
P
<.05), but in the presence of the eNOS inhibitor
N
G
-monomethyl-
l
-arginine (3×10
−4
mol/L) there was no difference between the two groups (7.1±0.2 versus 7.5±0.3 g;
P
=NS). Relaxations to calcium ionophore obtained during submaximal contractions to phenylephrine were significantly enhanced in the AdeNOS-transduced arteries (−log EC
50
, 7.77±0.08 versus 7.45±0.07;
P
<.02).

Conclusions
We conclude that eNOS gene transfer to the adventitia alters vascular reactivity, as demonstrated by diminished contractile responses to phenylephrine and enhanced relaxations to calcium ionophore. This may represent a therapeutic strategy for vascular diseases characterized by decreased bioavailability of NO.
Advanced Glycation End Product (AGE)–Mediated Induction of Tissue Factor in Cultured Endothelial Cells Is Dependent on RAGE
Authors: Bierhaus Angelika , Illmer Thomas , Kasper Michael , Luther Thomas , Quehenberger Peter , Tritschler Hans , Wahl Peter , Ziegler Reinhard , Müller Martin , Nawroth Peter P.
Published: June 2012

Background
Binding of advanced glycation end products (AGEs) to the cellular surface receptor (RAGE) induces translocation of the transcription factor NF-κB into the nucleus and NF-κB–mediated gene expression. This study examines the role of RAGE in the AGE albumin–mediated induction of endothelial tissue factor, known to be partly controlled by NF-κB.

Methods and Results
Endothelial cells (ECs) were incubated in the presence of an 18-mer phosphorothioate oligodeoxynucleotide antisense to the 5′-coding sequence of the RAGE gene (antisense RAGE; 0.1 μmol/L). Sense oligonucleotides (sense RAGE, 0.1 μmol/L) of the same region served as control. The cellular uptake of oligonucleotides was controlled by immunofluorescence microscopy. RAGE transcription was suppressed by antisense RAGE, as demonstrated by RT-PCR reactions. AGE albumin–mediated activation of cultured ECs was studied after 48 hours of preincubation of ECs with antisense or sense RAGE. Electrophoretic mobility shift assays and Western blot analysis demonstrated that the AGE albumin–induced translocation of NF-κB from the cytoplasm into the nucleus was suppressed in the presence of antisense RAGE but not by sense RAGE. In parallel, AGE albumin–mediated tissue factor transcription, activity, and antigen were significantly reduced in ECs exposed to antisense RAGE, whereas sense RAGE (and nonspecific oligonucleotides) did not influence tissue factor expression.

Conclusions
Activation of ECs and induction of tissue factor by AGE albumin in ECs is dependent on RAGE.
Myocardial Uptake and Redistribution of
99m
Tc-N-NOET in Dogs With Either Sustained Coronary Low Flow or Transient Coronary Occlusion
Authors: Vanzetto Gérald , Calnon Dennis A. , Ruiz Mirta , Watson Denny D. , Pasqualini Roberto , Beller George A. , Glover David K.
Published: June 2012

Background
99m
Tc-N-NOET (NOET) is a new myocardial perfusion imaging agent that redistributes over time. We sought to better define the redistribution kinetics of NOET using open-chest canine models of sustained low coronary flow (protocol 1) and transient coronary occlusion followed by reflow (protocol 2).

Methods and Results
In protocol 1 (n=10), NOET and
201
Tl were injected during low flow in the left anterior descending coronary artery (LAD) that was sustained for 2 hours. Protocol 2 dogs (n=6) were injected with NOET during 20 minutes of LAD occlusion followed by 2 hours of reflow. In both protocols, serial NOET planar images were acquired, and myocardial flow and 2-hour tracer activities were determined by gamma-well counting. Defect resolution was observed on images in both protocols. Initial defect count ratios, reflecting flow disparity at injection (0.66±0.03 and 0.57±0.04, respectively), increased over 2 hours (0.73±0.02 and 0.75±0.04, respectively;
P
<.001 versus initial). Quantitative imaging showed that NOET redistribution resulted from greater clearance from normal areas versus low-flow or transiently occluded areas. In protocol 1, 2-hour NOET and
201
Tl stenotic-to-normal tissue activity ratios were similar (0.76±0.06 versus 0.73±0.04,
P
=NS) and higher than injection flow ratios (0.52±0.06 and 0.56±0.07, respectively,
P
<.001), consistent with tracer redistribution. In protocol 2, NOET redistributed to an even greater extent (injection flow ratio, 0.27±0.04; 2-hour tissue activity ratio, 0.84±0.03,
P
<.001).

Conclusions
NOET is the first
99m
Tc-labeled myocardial imaging agent with kinetics similar to
201
Tl in experimental models, permitting redistribution imaging. NOET appears to be a promising agent for assessing patients with coronary artery disease.
Effects of Dobutamine Stress on Myocardial Blood Flow,
99m
Tc Sestamibi Uptake, and Systolic Wall Thickening in the Presence of Coronary Artery Stenoses
Authors: Calnon Dennis A. , Glover David K. , Beller George A. , Vanzetto Gérald , Smith William H. , Watson Denny D. , Ruiz Mirta
Published: June 2012

Background
Although dobutamine stress is used with both
99m
Tc sestamibi (sestamibi) myocardial perfusion imaging and echocardiography for detecting coronary artery stenoses, the impact of stenosis severity on test end points (myocardial sestamibi uptake and systolic thickening, respectively) has not been clearly defined.

Methods and Results
In 15 open-chest dogs, dobutamine (2.5 to 30 μg · kg
−1
· min
−1
) was infused after placement of an LAD stenosis that reduced (n=8) or abolished (n=7) flow reserve. In dogs with reduced flow reserve, the stenotic-to-normal sestamibi activity ratio (0.86±0.03) significantly underestimated the ≈2-to-1 dobutamine-induced flow disparity at the time of sestamibi injection (flow ratio, 0.53±0.04;
P
<.001). Stenotic-zone thickening increased at low but not at higher doses of dobutamine (2.9±0.4 versus 4.2±0.4 mm in normal zone at peak dobutamine;
P
=.055) but did not fall below baseline (2.7±0.3 mm). Similarly, in dogs with absent flow reserve, the sestamibi activity ratio (0.78±0.02) underestimated the ≈2.5-to-1 dobutamine-induced flow disparity (flow ratio, 0.41±0.05;
P
<.001), and failure to increase systolic thickening was observed in the stenotic zone (2.7±0.4 versus 4.6±0.3 mm in the normal zone at peak stress,
P
<.01). In both groups of dogs, myocardial sestamibi uptake and image defect magnitudes were less than expected for the dobutamine-induced hyperemia, suggesting that dobutamine adversely affects myocardial sestamibi binding. Finally, a significant reduction in stenotic-zone thickening was seen during postdobutamine recovery, consistent with myocardial stunning.

Conclusions
In the presence of stenoses that reduced or abolished regional flow reserve, (1) myocardial sestamibi uptake significantly underestimated the dobutamine-induced flow heterogeneity, (2) a “failure to increase systolic thickening” rather than a reduction in thickening was observed during dobutamine stress, and (3) myocardial stunning was observed during postdobutamine recovery.
Platelet-Derived Growth Factor–Stimulated Superoxide Anion Production Modulates Activation of Transcription Factor NF-κB and Expression of Monocyte Chemoattractant Protein 1 in Human Aortic Smooth Muscle Cells
Authors: Marumo Takeshi , Schini-Kerth Valérie B. , Fisslthaler Beate , Busse Rudi
Published: June 2012

Background
Platelet-derived growth factor (PDGF) and superoxide anion (O
2
·−
) have been implicated in vascular diseases. We investigated whether PDGF stimulates the production of O
2
·−
in human aortic smooth muscle cells (HSMCs) and whether O
2
·−
leads in this way to the activation of nuclear factor–κB (NF-κB) and induction of monocyte chemoattractant protein 1 (MCP-1) in PDGF-stimulated HSMCs.

Methods and Results
PDGF-AB concentration- and time-dependently stimulated O
2
·−
generation from HSMCs. The stimulatory effect of PDGF-AB was mimicked by PDGF-BB but not by PDGF-AA. The generation of O
2
·−
by PDGF-AB was attenuated by the NAD(P)H oxidase inhibitor iodonium diphenyl, the specific protein kinase C (PKC) inhibitor Ro 31-8220, and the phosphatidylinositol 3-kinase inhibitor wortmannin. Allopurinol and nifedipine had no effect on PDGF-AB–induced O
2
·−
release, whereas indomethacin potentiated this response. Gel mobility shift assay revealed that PDGF-AB increased the binding activity of NF-κB, which contained predominantly the p50/p65 heterodimer in nuclear extracts from HSMCs. Superoxide dismutase as well as iodonium diphenyl, Ro 31-8220, and wortmannin attenuated PDGF-AB–induced activation of NF-κB and expression of MCP-1 mRNA. In contrast, superoxide dismutase did not inhibit the interleukin-1β–induced NF-κB activation.

Conclusions
The results demonstrate that PDGF stimulates O
2
·−
generation in HSMCs via PKC-dependent and wortmannin-sensitive pathways involving flavoenzyme(s). This PDGF-induced O
2
·−
production may be involved in vascular lesion formation by mediating, at least in part, NF-κB activation and MCP-1 induction.
Right and Left Myocardial Antioxidant Responses During Heart Failure Subsequent to Myocardial Infarction
Authors: Hill Michael F. , Singal Pawan K.
Published: June 2012

Background
Heart failure subsequent to myocardial infarction (MI) is accompanied by depressed antioxidants and increased oxidative stress in the myocardium. Antioxidant enzyme activities and oxidative stress were examined in the viable left (LV) and right (RV) ventricles in relation to their hemodynamic function.

Methods and Results
The left coronary artery in rats was ligated. At 1 week after MI, LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), and RV end-diastolic pressure (RVEDP) remained near control values, whereas RV systolic pressure (RVSP) was significantly elevated. In the 4, 8, and 16 week post-MI animals, LVSP was significantly reduced, with values of 112.0±1.57, 99.9±0.52, and 89.2±1.4 mm Hg, whereas LVEDP was significantly elevated, with values of 8.2±0.52, 17.4±1.7, and 31.4±1.5 mm Hg, respectively. RVEDP was higher at 8 and 16 weeks, and RVSP was significantly reduced at 16 weeks. At 1 week after MI, myocardial catalase activity in the LV was maintained near control levels, whereas in the RV, it was 134% compared with its control value. At 4, 8, and 16 weeks, catalase activity in the LV was 71%, 48%, and 28% of respective controls. Catalase activity in the RV was significantly reduced only at 16 weeks. A similar trend was seen with respect to glutathione peroxidase activity. Reduced/oxidized glutathione ratio was significantly depressed in the LV at 1, 4, 8, and 16 weeks, whereas in the RV, this ratio was significantly reduced only at 8 and 16 weeks. Myocardial lipid peroxidation in the LV at 4, 8, and 16 weeks was elevated by ≈40%, 51%, and 100%, respectively, whereas in the RV, an increase of ≈50% was seen only at 16 weeks.

Conclusions
These data show that heart failure subsequent to MI is associated with an antioxidant deficit as well as increased oxidative stress, first in the LV, followed by the RV. Furthermore, these changes correlated with the hemodynamic function in each of the ventricles, suggesting their role in the pathogenesis of ventricular dysfunction.
Negative Inotropic Effect of Basic Fibroblast Growth Factor on Adult Rat Cardiac Myocyte
Authors: Ishibashi Yuji , Urabe Yoshitoshi , Tsutsui Hiroyuki , Kinugawa Shintaro , Sugimachi Masaru , Takahashi Masaru , Yamamoto Shimako , Tagawa Hirofumi , Sunagawa Kenji , Takeshita Akira
Published: June 2012

Background
Basic fibroblast growth factor (bFGF) is highly expressed in the myocardium in some cardiac disorders, such as ischemia-reperfusion and cardiac allograft rejection. However, whether bFGF has any effects on myocardial contraction is unknown.

Methods and Results
We examined the effects of bFGF on myocardial contractility using isolated adult rat cardiac myocyte preparations. bFGF exerted a direct negative inotropic effect that was concentration and time dependent. The pretreatment of myocytes with a neutralizing anti-bFGF antibody (100 ng/mL) abolished the negative inotropic effects of bFGF (100 ng/mL). Platelet-derived growth factor (12.5 ng/mL) and transforming growth factor-β (1 ng/mL) did not exert such effects, which indicated that bFGF-induced negative inotropism was considered to be specific for this growth factor. bFGF decreased the peak intracellular Ca
2+
transient by 46% during systole. The enhanced production of nitric oxide was unlikely to be responsible for the bFGF-induced negative inotropic effect.

Conclusions
bFGF, primarily a potent growth promoter, produced acute negative inotropic effects in the adult cardiac myocyte that could have resulted from alterations in intracellular Ca
2+
homeostasis. The negative inotropic effect of bFGF may contribute to myocardial dysfunction associated with ischemia-reperfusion injury and heart transplant rejection.