bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Amiodarone on Clinical Status and Left Ventricular Function in Patients With Congestive Heart Failure
Authors: Massie Barry M. , Fisher Susan G. , Deedwania Prakash C. , Singh Bramah N. , Fletcher Ross D. , Singh Steven N.
Published: June 2012

Background
Although trials of amiodarone therapy in patients with congestive heart failure have produced discordant results with regard to effects on survival, most studies have reported a significant rise in left ventricular ejection fraction during long-term therapy. In the present study, we determined whether this increase in ejection fraction is associated with an improvement in the symptoms and/or physical findings of heart failure or a reduction in the number of hospitalizations for heart failure.

Methods and Results
In the Department of Veterans Affairs cooperative study of amiodarone in congestive heart failure, 674 patients with New York Heart Association class II through IV symptoms and ejection fractions of ≤40% were treated with amiodarone or placebo for a median of 45 months in a randomized, double-blind, placebo-controlled protocol. Clinical assessments and radionuclide ejection fraction were performed at baseline and after 6, 12, and 24 months. Compared with the placebo group, ejection fraction increased more in the amiodarone group at each time point (8.1±10.2% [mean±SD] versus 2.6±7.9% at 6 months, 8.0±10.9% versus 2.7±8.0% at 12 months, and 8.8±10.1% versus 1.9±9.4% after 24 months, all
P
<.001). However, this difference was not associated with greater clinical improvement, lesser diuretic requirements, or fewer hospitalizations for heart failure (11.1% for amiodarone and 13.6% for placebo group; overall relative risk in the amiodarone group, 0.81 [95% CI, 0.56 to 1.10],
P
=.18). Of note is the trend toward a reduction in the combined end point of hospitalizations and cardiac deaths (relative risk, 0.82 [CI, 0.65 to 1.03],
P
=.08), which was significant in patients with nonischemic etiology (relative risk, 0.56 [CI, 0.36 to 0.87],
P
=.01) and absent in the ischemic group (relative risk, 0.95).

Conclusions
Although amiodarone therapy resulted in a substantial increase in left ventricular ejection fraction in patients with congestive heart failure, this was not associated with clinical benefit in the population as a whole. The substantial reduction in the combined end point of cardiac death plus hospitalizations for heart failure in the nonischemic group suggests possible benefit in these patients.
Role of Nitric Oxide in the Local Regulation of Pulmonary Vascular Resistance in Humans
Authors: Cooper Christopher J. , Landzberg Michael J. , Anderson Todd J. , Charbonneau Francois , Creager Mark A. , Ganz Peter , Selwyn Andrew P.
Published: June 2012

Background
Endothelium-derived nitric oxide (NO) may be an important mediator of vascular resistance in the pulmonary circulation. We tested the hypotheses that in conscious adults the endothelium, through NO production, is important in maintaining basal pulmonary vascular resistance and that it can increase NO production further in response to receptor-mediated stimulation, leading to further vasodilation.

Methods and Results
Pulmonary arterial resistance vessel function was studied within the distribution of a segmental lower lobe pulmonary artery in eight conscious adults 37 to 76 years old who were undergoing cardiac catheterization. Segmental blood flow was determined with use of a Doppler-tip guide wire and quantitative angiography. Drugs were administered locally within the segmental artery through an infusion catheter.
N
G
-Monomethyl-
l
-arginine (L-NMMA) was used as a specific inhibitor of NO production, whereas acetylcholine (ACh) was used to test receptor-mediated vasodilation. To demonstrate that vasodilation to ACh was NO dependent, ACh response was tested alone, in the presence of L-NMMA, and in the presence of a control constrictor phenylephrine. Basal pulmonary vascular resistance was NO dependent because L-NMMA infusion resulted in a dose-dependent decrease in local flow velocity (
P
<.005), with flow decreasing 33% at the highest dose of L-NMMA. ACh infusion resulted in a dose-dependent increase in flow velocity (
P
=.001). The ACh response was at least in part NO dependent because it was diminished by the presence of L-NMMA (
P
<.05). The effect of L-NMMA on the ACh response was not due to nonspecific preconstriction because L-NMMA diminished the ACh response significantly more than did the endothelium-independent constrictor phenylephrine (
P
<.05) despite comparable preconstriction.

Conclusions
In healthy conscious adults, (1) normal basal pulmonary resistance is maintained in part by continuous local production of NO and (2) the local NO production is responsive to receptor-mediated stimulation, leading to further vasodilation, and can be tested with ACh.
Coupling Between Myosin ATPase Cycle and Creatine Kinase Cycle Facilitates Cardiac Actomyosin Sliding In Vitro
Authors: Sata Masataka , Sugiura Seiryo , Yamashita Hiroshi , Momomura Shin-ichi , Serizawa Takashi
Published: June 2012

Background
There is much evidence to support the favorable effects of the phosphocreatine shuttle on myocardial contraction and relaxation. However, experiments in which cardiac muscle fiber or myofibril was used have not elucidated its precise mechanism.

Methods and Results
Active movements of fluorescently labeled actin filaments on a cardiac myosin layer coimmobilized with creatine kinase (CK) onto a nitrocellulose-coated glass coverslip were studied under various concentrations of adenine nucleotides. At a constant phosphocreatine concentration (5 mmol/L, pH 7.1), the relation of sliding velocity to MgATP concentration followed Michaelis-Menten kinetics. The apparent
K
m
was significantly smaller in the presence of CK (0.041±0.001 mmol/L) than in the absence of CK (0.080±0.001 mmol/L), indicating that coattached CK facilitated the propelling of actin filaments by the myosin ATPase. This phenomenon was also seen under acidic conditions (pH 6.7) as well as in the presence of inorganic phosphate (10 mmol/L). At a constant MgATP concentration (1 mmol/L), the inhibitory effect of MgADP on the actin-myosin interaction was weaker in the presence of CK than in the absence of CK. Another ATP-regenerating system, pyruvate kinase and phospho(enol)pyruvate, while maintaining a low ratio of [MgADP] to [MgATP], did not reduce the
K
m
value (0.156±0.001 mmol/L), suggesting that the effect of coattached CK was not achieved only by prevention of MgADP accumulation.

Conclusions
Coupling between the ATPase cycle and the CK cycle may serve not only to maintain the ATP concentration within the myofibril but also to provide optimal conditions for cardiac actomyosin interaction. Consideration of this coupling will offer a clue to elucidating the systolic or diastolic dysfunction during myocardial ischemia or reperfusion.
ω-3 Lipid Infusion in a Heart Allotransplant Model
Authors: Grimminger F. , Grimm H. , Führer D. , Papavassilis C. , Lindemann G. , Blecher C. , Mayer K. , Tabesch F. , Krämer H.-J. , Stevens J. , Seeger W.
Published: June 2012

Background
ω-3 Fatty acids may have a major impact on immune responses involved in heart transplant rejection. We compared the effects of posttransplant intravenous supplementation with ω-3–rich versus ω-6–rich lipid emulsions on graft survival, plasma fatty acid profiles, and levels of arachidonic acid versus eicosapentaenoic acid–derived lipid mediators.

Methods and Results
Inbred PVG and Wistar-Kyoto rats were used as donors and recipients, respectively, in a model of heterotopic heart transplantation. Animals received 9 g/kg body wt per day of either fish oil–derived (n=8) or soybean oil–derived fat (n=7) in the form of a continuously infused lipid emulsion; controls were sham-infused with saline (n=8). Graft rejection was assessed by loss of activity of the transplant. The fish oil–derived preparation but not that originating from soybean oil caused an increase in total and free plasma fatty acids. Substantial quantities of eicosapentaenoic acid and docosahexaenoic acid appeared in the free fatty acid fraction, surpassing those of arachidonic acid. Ex vivo stimulation of neutrophils with the Ca
2+
ionophore A23187 demonstrated an increase in 5-series leukotriene (LT) generation in animals undergoing ω-3 lipid infusion (LTB
5
, ω-oxidation products of LTB
5
, LTA
5
secretion), with 5-series/4-series LT ratios ranging between 0.08 and 0.36. Ratios of TX B
3
/B
2
liberated from ex vivo stimulated platelets even approached 1:1 in ω-3 supplemented rats. Graft survival was 7.6±0.3 (mean±SEM) days in saline-infused, 10.4±0.7 in ω-6 lipid–infused, and 12.9±0.4 in ω-3 lipid–infused animals.

Conclusions
Posttransplant intravenous alimentation with fish oil–derived lipid emulsions prolongs heart transplant survival in excess to ω-6 lipids. Profound changes in fatty acid profiles and lipid mediator generation may underlie this finding.
Cost-effectiveness of Implantable Defibrillator as First-Choice Therapy Versus Electrophysiologically Guided, Tiered Strategy in Postinfarct Sudden Death Survivors
Authors: Wever Eric F.D. , Hauer Richard N.W. , Schrijvers Guus , van Capelle Frans J.L. , Tijssen Jan G.P. , Crijns Harry J.G.M. , Algra Ale , Ramanna Hemanth , Bakker Patricia F.A. , Robles de Medina Etienne O.
Published: June 2012

Background
Rising costs of health care, partly as a result of costly therapeutic innovations, are of concern to both the medical profession and healthcare authorities. The implantable cardioverter-defibrillator (ICD) is still not remunerated by Dutch healthcare insurers. The aim of this study was to evaluate the cost-effectiveness of early implantation of the ICD in postinfarct sudden death survivors.

Methods and Results
Sixty consecutive postinfarct survivors of cardiac arrest caused by ventricular tachycardia or fibrillation were randomly assigned either ICD as first choice (n=29) or a tiered therapy starting with antiarrhythmic drugs and guided by electrophysiological (EP) testing (n=31). Median follow-up was 729 days (range, 3 to 1675 days). Fifteen patients died, 4 in the early ICD group and 11 in the EP-guided strategy group (
P
=.07). For quantitative assessment, the cost-effectiveness ratio was calculated for both groups and expressed as median total costs per patient per day alive. Because effectiveness aspects other than mortality are not incorporated in this ratio, other factors related to quality of life were used as qualitative measures of cost-effectiveness. The cost-effectiveness ratios were $63 and $94 for the early ICD and EP-guided strategy groups, respectively, per patient per day alive. This amounts to a net cost-effectiveness of $11 315 per patient per year alive saved by early ICD implantation. Costs in the early ICD group were higher only during the first 3 months of follow-up, but as a result of the high proportion of therapy changes, including arrhythmia surgery and late ICD implantation, costs in the EP-guided strategy group became higher after that. Patients discharged with antiarrhythmic drugs as sole therapy had the lowest total costs. This subset, however, showed extremely high mortality, resulting in a poor cost-effectiveness ratio ($196 per day). Invasive therapies and hospitalization were the major contributors to costs. If quality-of-life measures are taken into account, the cost-effectiveness of early ICD implantation was even more favorable. Recurrent cardiac arrest and cardiac transplantation occurred in the EP-guided strategy group only, whereas exercise tolerance, total hospitalization duration, number of invasive procedures, and antiarrhythmic therapy changes were significantly in favor of early ICD implantation.

Conclusions
In terms of cost-effectiveness, early ICD implantation is superior to the EP-guided therapeutic strategy in postinfarct sudden death survivors.
1,3 Butadiene, a Vapor Phase Component of Environmental Tobacco Smoke, Accelerates Arteriosclerotic Plaque Development
Authors: Penn Arthur , Snyder Carroll A.
Published: June 2012

Background
Our recent results support predictions from epidemiology studies that thousands of excess heart disease–related deaths result yearly in the United States from involuntary exposure to environmental tobacco smoke (ETS). Limited exposures of cockerels to ETS significantly accelerate arteriosclerosis. Despite little direct in vivo support, tar fraction rather than vapor phase compounds are considered largely responsible for the plaque-promoting effects of cigarette smoke. Here, we evaluate the effects of two ETS components on plaque development: the vapor phase component, 1,3 butadiene, and the tar component, the tobacco-specific
N
-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). At relatively high doses, injected NNK is carcinogenic in rodents. Epidemiology studies have identified increased mortality from arteriosclerotic heart disease among black men working in the butadiene rubber industry. Neither butadiene nor NNK has been tested experimentally for a possible role in plaque development.

Methods and Results
Cockerels inhaled butadiene (20 ppm; 16 weeks) or were injected biweekly with NNK (10 mg/kg, 16 weeks). Control cockerels were exposed to filtered air or were injected with the NNK solvent dimethylsulfoxide. Plaque incidence, prevalence, location, and size were determined double-blind. NNK had no significant effect on any of these measurements. In contrast, butadiene elicited a statistically significant increase in plaque size comparable to that seen after steady-state exposure to ETS from 5 cigarettes.

Conclusions
(1) This study represents the first time that a single cigarette smoke component has been demonstrated to accelerate arteriosclerosis, at a dose that is environmentally relevant. (2) The plaque-promoting components of ETS may reside in the vapor phase. (3) The cockerel model should be valuable in understanding the mechanism underlying the reported increases in heart disease deaths among black workers in the butadiene rubber industry.
Dose-Dependent Effect of Endothelin-1 on Blood Flow to Normal and Collateral-Dependent Myocardium
Authors: Traverse Jay H. , Judd Dianne , Bache Robert J.
Published: June 2012

Background
Plasma levels of endothelin-1 (ET-1) increase during ischemia and could potentially contribute to impairment of myocardial blood flow (MBF). Because collateral vessels demonstrate enhanced responsiveness to certain vasoconstrictors, blood flow to collateral-dependent myocardium could be particularly sensitive to increases in ET-1 levels.

Methods and Results
Studies were performed in 13 dogs in which collateral vessel development was produced by fluoroscopic embolization of the midleft anterior descending coronary artery with a hollow plug 4 to 6 weeks before the study. MBF was measured with radioactive microspheres at baseline and during 30-minute infusions of ET-1 (1, 10, and 100 ng/min) into the left main coronary artery. Because ET-1 stimulates endothelial prostacyclin release, aortic and coronary sinus levels of ET-1 and 6-keto–prostaglandin F
1α
were measured at the end of each infusion. ET-1 increased MBF from 0.82 mL·min
−1
·g
−1
at baseline to 0.92 mL·min
−1
·g
−1
at 10 ng/min (
P
<.05), which corresponded to a coronary plasma concentration of 73±16 pg/mL. Blood flow in the collateral zone was less (0.74 mL·min
−1
·g
−1
) than in the normal zone (
P
<.05) and did not increase at an ET-1 dose of 10 ng/min. MBF in the normal and collateral zones significantly decreased when ET-1 was increased to 100 ng/min, corresponding to a coronary sinus concentration of 175±45 pg/mL (
P
<.05). ET-1 produced dose-related increases in aortic and coronary sinus 6-keto–prostaglandin F
1α
and the transcoronary difference (
P
<.05). To assess the importance of prostacyclin in opposing the vasoconstriction produced by ET-1, additional studies were performed after cyclooxygenase blockade with indomethacin. After indomethacin administration, ET-1 (10 ng/min) caused a 120±23% increase in collateral vascular resistance (
P
<.05) and abolished the vasodilation that this dose produced in the normal zone.

Conclusions
Blood flow to normal myocardium is increased at moderate plasma elevations of ET-1, whereas collateral blood flow is unchanged. Only at significantly elevated plasma concentrations of ET-1 is blood flow to normal and collateral-dependent myocardium impaired. Coronary endothelial production of prostacyclin in response to increasing concentrations of ET-1 represents an important means of blunting the vasoconstrictor properties of ET-1 in the canine coronary circulation. Coronary collateral vessels demonstrate a much greater dependence on prostacyclin production in blunting the vasoconstrictor properties of ET-1.
Optical Mapping in a New Guinea Pig Model of Ventricular Tachycardia Reveals Mechanisms for Multiple Wavelengths in a Single Reentrant Circuit
Authors: Girouard Steven D. , Pastore Joseph M. , Laurita Kenneth R. , Gregory Kenton W. , Rosenbaum David S.
Published: June 2012

Background
Although the relationship between cardiac wavelength (λ) and path length importantly determines the stability of reentrant arrhythmias, the physiological determinants of λ are poorly understood. To investigate the cellular mechanisms that control λ during reentry, we developed an experimental system for continuously monitoring λ within a reentrant circuit with the use of voltage-sensitive dyes and a new guinea pig model of ventricular tachycardia (VT).

Methods and Results
Action potentials were recorded simultaneously from 128 ventricular sites in Langendorff-perfused hearts (n=15) in which propagation was confined to a two-dimensional rim of epicardium by an endocardial cryoablating procedure. The reentrant path was precisely controlled by creating an epicardial obstacle (2×10 mm) with an argon laser. To control for fiber orientation and rate-dependent membrane properties, λ during reentry was compared with λ during plane wave propagation transverse and longitudinal to cardiac fibers at a stimulus cycle length (CL) comparable to the VT CL. Reentrant VT (CL=97.0±6.2 ms) was reproducibly induced by programmed stimulation in 93% of preparations. λ varied considerably within the reentrant circuit (range, 10.6 to 22.5 mm), because of heterogeneities of conduction rather than action potential duration. λ was significantly shorter during reentrant propagation (ie, with pivoting) parallel to fibers (10.6±4.2 mm) compared with plane wave propagation (ie, without pivoting) parallel to fibers (32.8±6.5 mm,
P
<.02), indicating that wave-front pivoting was primarily responsible for shortening of λ during reentry. The mechanism of λ shortening was conduction slowing from increased current load experienced by the pivoting wave front.

Conclusions
We provide direct experimental evidence that multiple wavelengths are present even within a relatively simple reentrant circuit. Abrupt changes in loading during wave-front pivoting, rather than membrane ionic properties or fiber structure, were a major determinant of λ and, therefore, may play an important role in the stability of reentry.
Pure β-ParticleEmitting Stents Inhibit Neointima Formation in Rabbits
Authors: Hehrlein Christoph , Stintz Marc , Kinscherf Ralf , Schlösser Klaus , Huttel Ehrhard , Friedrich Ludwig , Fehsenfeld Peter , Kübler Wolfgang
Published: June 2012

Background
Considerable experimental evidence exists that neointimal hyperplasia after angioplasty is inhibited by γ-irradiation of the treated arteries. A β-particle radiation is absorbed in tissue within a shorter distance away from the source than γ-radiation and may be more suitable for localized vessel irradiation. This study outlines a method to implant a β-particle–emitting radioisotope (
32
P; half-life, 14.3 days) into metallic stents. The effects of these stents on the inhibition of neointimal hyperplasia was compared with conventional stents in a rabbit model.

Methods and Results
32
P was produced by irradiation of red amorphous phophorus (
31
P) with neutrons and was implanted into Palmaz-Schatz stents (7.5 mm in length) after being kept apart from
31
P in a mass separator. The radioisotope was tightly fixed to the stents, and the ion implantation process did not alter the surface texture. Stent activity levels of 4 and 13 μCi were chosen for the study. Four and 12 weeks after placement of conventional stents and
32
P-implanted stents in rabbit iliac arteries, vascular injury and neointima formation were studied by histomorphometry. Immunostaining for smooth muscle cell (SMC) α-actin was performed to determine SMC cellularity in the neointima. SMCs were quantified by computer-assisted counting of α-actin immunoreactive cells. Endothelialization of the stents was evaluated by immunostaining for endothelial cell von Willebrand factor. No difference in vessel wall injury was found after placement of conventional and
32
P-implanted stents. Neointima formation was potently inhibited by
32
P-implanted stents only at an activity level of 13 μCi after 4 and 12 weeks. Neointimal SMC cellularity was reduced in
32
P-implanted stents compared with conventional stents. Radioactive stents were endothelialized after 4 weeks, but endothelialization was less dense than in conventional stents.

Conclusions
Neointima formation in rabbits is markedly suppressed by a β-particle–emitting stent incorporating the radioisotope
32
P. In this model, a dose-response relation with this type of radioactive stent was observed, indicating that a threshold radiation dose must be delivered to inhibit neointima formation after stent placement over the long term.
Enhanced Coronary Vasoconstriction to Endothelin-BReceptor Activation in Experimental Congestive Heart Failure
Authors: Cannan Charles R. , Burnett John C. , Lerman Amir
Published: June 2012

Background
Endothelin (ET), a coronary vasoconstrictor, mediates its activity through the specific receptors ET-A and ET-B, which may demonstrate different activity under pathophysiological conditions. Thoracic inferior vena cava constriction (TIVCC) is an experimental model of congestive heart failure that is characterized by a decrease in cardiac output and an increase in circulating ET concentrations. The present study was designed to test the hypothesis that experimental heart failure altered coronary vascular responsiveness to ET-A– and ET-B–receptor stimulation in vivo.

Methods and Results
ET-1 was infused at a rate of 2 ng/kg per minute into the left circumflex coronary artery in normal dogs (n=5) and in dogs subjected to TIVCC (TIVCC dogs, n=6). Similarly, sarafotoxin, an ET-B–receptor agonist, was infused at the same dosage in normal (n=5) and TIVCC (n=6) dogs. Intracoronary infusion of ET-1 significantly decreased coronary blood flow and increased coronary vascular resistance in normal dogs; this effect was significantly attenuated in TIVCC compared with normal dogs. The percent changes in coronary blood flow and coronary vascular resistance in the TIVCC compared with the normal dogs was −11±8% versus −48±7% (
P
<.01) and 29±10% versus 105±23% (
P
<.01), respectively. There was no significant effect on coronary blood flow, coronary vascular resistance, or coronary artery diameter in normal dogs that received an intracoronary infusion of sarafotoxin. In contrast, the administration of intracoronary sarafotoxin in TIVCC compared with normal dogs resulted in significant percent changes in coronary blood flow and coronary vascular resistance (−31±4% versus −7±3% [
P
<.001] and 53±12% versus 12±8% [
P
<.02], respectively).

Conclusions
The present study demonstrates an attenuated coronary vasoconstrictor response to ET-1 with an enhanced vasoconstrictor response to sarafotoxin and suggests an alteration in coronary ET receptor sensitivity in experimental heart failure.
ATP-Dependent Potassium Channel in Rat Cardiomyocytes Is Blocked by Lidocaine
Authors: Olschewski A. , Bräu M.E. , Olschewski H. , Hempelmann G. , Vogel W.
Published: June 2012

Background
During myocardial ischemia, lidocaine has favorable antiarrhythmic properties. Malignant arrhythmias result from heterogeneity between ischemic and nonischemic regions in extracellular potassium concentration and action potential duration. These effects have been attributed to the activation of ATP-dependent potassium (K
ATP
) channels. In this study, we investigated the action of lidocaine on the K
ATP
channels to test the possible link between the antiarrhythmic properties of lidocaine and its action on the K
ATP
channel.

Methods and Results
The patch-clamp technique was employed on enzymatic dissociated cardiomyocytes of adult rats. Lidocaine was applied to the outer side of excised membrane patches by means of a multibarrel perfusion system. Lidocaine reversibly blocked the mean current of the K
ATP
channels in a concentration-dependent manner (IC
50
=43±4.7 μmol/L, E=0 mV, n=6), while the amplitude of the single-channel current remained unchanged. The half-maximum blocking concentration corresponds to the therapeutic range for the antiarrhythmic application of a lidocaine bolus in humans.

Conclusions
The open probability but not the conductance of the K
ATP
channel in the membrane of rat cardiomyocytes is blocked by lidocaine. This action may explain, in part, the favorable antiarrhythmic properties of lidocaine during acute myocardial ischemia.
Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors in the Failing Human Heart
Authors: Torre-Amione Guillermo , Kapadia Samir , Lee Joseph , Durand Jean-Bernard , Bies Roger D. , Young James B. , Mann Douglas L.
Published: June 2012

Background
Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that produces negative inotropic effects in the heart. Recently, elevated levels of TNF-α have been reported in patients with advanced congestive heart failure. Although TNF-α is thought to exert its deleterious effects by binding to two cell surface receptors, TNFR1 and TNFR2, the level of expression and regulation of TNF receptors in the heart in cardiac disease states is not known.

Methods and Results
We examined mRNA and protein levels for TNFR1, TNFR2, and TNF-α in explanted hearts from organ donors as well as in patients with end-stage dilated cardiomyopathy (DCM) and ischemic heart disease (IHD). Northern blot analysis revealed that mRNA for TNFR1 and TNFR2 was present in nonfailing, DCM, and IHD hearts. TNFR1 and TNFR2 receptor protein levels, as measured by ELISA, were decreased 60% in DCM and IHD patients compared with nonfailing hearts (
P
<.005). To determine a potential mechanism for the decrease in TNF receptor expression, we measured levels of circulating soluble TNF receptors (sTNFRs) in DCM and IHD patients. This analysis showed that there was a significant one-and-a-half to threefold increase in sTNFRs in DCM (
P
<.03) and IHD patients (
P
<.001). Another important finding was that TNF-α mRNA and TNF-α protein were present in the explanted hearts from DCM and IHD patients but not in nonfailing hearts.

Conclusions
In summary, the results of this study constitute the initial demonstration that TNF receptor proteins are dynamically regulated in patients with advanced congestive heart failure. Moreover, the observation that failing hearts express elevated levels of TNF-α suggests that overexpression of this cytokine may be one of several different maladaptive mechanisms responsible for the progressive cardiac decompensation that occurs in advanced heart failure.
Limitations of Angiography in the Assessment of Plaque Distribution in Coronary Artery Disease
Authors: Mintz Gary S. , Popma Jeffrey J. , Pichard Augusto D. , Kent Kenneth M. , Satler Lowell F. , Chien Chuang Ya , DeFalco Robert A. , Leon Martin B.
Published: June 2012

Background
Plaque distribution (eccentricity) may be a determinant of the success of transcatheter therapy, and certain devices may be better suited to treating severely eccentric lesions than others. However, no study has compared methods for assessing plaque distribution or systematically studied the validity of the angiographic assessment of plaque distribution.

Methods and Results
We studied 1446 native vessel target lesions in 1349 patients by intravascular ultrasound and coronary angiography. Angiographic and intravascular ultrasound criteria for lesion eccentricity were compared. Angiography showed that 795 of 1446 (55.0%) of target lesions were eccentric. When intravascular ultrasound was used, only 219 lesions (15.1%) had an arc of normal arterial wall within the lesion (equivalent to the pathological definition of lesion eccentricity). When an eccentricity index of ≥3.0 was used, intravascular ultrasound classified 659 lesions (45.6%) as eccentric. The concordance rates of classification were only 47.7% (versus lesions containing an arc of normal arterial wall) and 53.8% (versus lesions with an ultrasound eccentricity index of ≥3.0). More eccentric lesions had larger lumen cross-sectional areas, smaller plaque plus media and external elastic membrane cross-sectional areas, and smaller arcs of calcium, suggesting that they may represent less advanced atherosclerotic disease.

Conclusions
There was significant discordance between angiography and ultrasound in assessing plaque distribution. Angiography appeared to detect lesion eccentricity more often than intravascular ultrasound. Furthermore, markedly eccentric lesions, in which there is an arc of normal vessel wall, were uncommon.
Platelet-Derived Growth Factor–A mRNA Expression in Fetal, Normal Adult, and Atherosclerotic Human Aortas
Authors: Murry Charles E. , Bartosek Trudy , Giachelli Cecilia M. , Alpers Charles E. , Schwartz Stephen M.
Published: June 2012

Background
To understand which growth factors are important for growth of atherosclerotic plaques, it is necessary to know the factor’s relative abundance and how its gene is regulated in relation to cell proliferation. We tested whether platelet-derived growth factor–A (PDGF-A) mRNA levels correlated with cell proliferation in developing aorta, normal adult aorta, and atherosclerotic plaques.

Methods and Results
We developed a competitive reverse transcription–polymerase chain reaction (RT-PCR) assay to measure human PDGF-A mRNA levels in small tissue samples. A mutated PDGF-A synthetic RNA was used as an internal standard to compete with endogenous PDGF-A mRNA for amplification. The assay is highly sensitive and much more precise than routine RT-PCR. Correction for heteroduplex pairing between the endogenous and mutant PCR products correlates precisely with synthetic RNA standards and quantitative Northern blotting. Immunostaining with the proliferation marker (proliferating cell nuclear antigen) showed the following rank order of proliferation: fetal aorta>>atherosclerotic plaque>normal aortic media. PDGF-A mRNA levels, however, did not correlate with proliferation. Normal adult aorta contained the most PDGF-A mRNA (34.0±7.6 amol/μg total RNA). Fetal aortas were intermediate (10.2±1.6 amol/μg total RNA); advanced atherosclerotic plaques contained the least PDGF-A mRNA (0.3±0.1 amol/μg total RNA). PDGF-A protein was readily detectable in normal media by immunostaining. Advanced plaques generally had less cell-associated PDGF-A protein, although A-chain was also detected in plaque matrix.

Conclusions
PDGF-A mRNA and protein do not correlate with proliferation among these three groups. The significance of high levels of PDGF-A mRNA in the “quiescent” aortic media is unknown, but it clearly does not promote cell replication.
Heart Rate Variability Assessment Early After Acute Myocardial Infarction
Authors: Singh Narendra , Mironov Dmitry , Armstrong Paul W. , Ross Allan M. , Langer Anatoly
Published: June 2012

Background
Diminished heart rate variability is associated with less favorable prognosis after myocardial infarction. However, the prognostic value of early (first 48 hours) measurement and the influence of thrombolytic strategies, myocardial infarction location, left ventricular function, ST-segment shift, and infarct-related artery patency on heart rate variability have not been examined comprehensively.

Methods and Results
Heart rate variability and ST-segment analysis of 48-hour Holter tapes were performed with the use of a commercial system in 204 patients who were part of an ST-monitoring substudy of the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-I) trial. Both time-domain measures (SD of the average normal RR interval for all 5-minute segments of a 24-hour ECG recording [SDANN] and percent difference between adjacent normal RR intervals >50 ms computed over the entire 24-hour ECG recording [pNN50]) and frequency-domain measures (low frequency [LF], high frequency [HF], and LF/HF ratio) were assessed on days 1 and 2 after acute myocardial infarction. Coronary angiography performed within the first 24 hours was also available in 75% of the patients. All heart rate variability measures decreased between day 1 and day 2 (
P
=.001) except the LF/HF ratio. There was no difference in heart rate variability among groups assigned to one of four different thrombolytic treatment strategies (streptokinase/subcutaneous heparin, streptokinase/intravenous heparin, accelerated tissue plasminogen activator, and combination streptokinase/tissue plasminogen activator). Heart rate variability measures were lower in anterior versus nonanterior infarcts (SDANN, 53±21 versus 63±24 ms;
P
<.005) and increased with TIMI grade 3 flow (LF, 5.3±1.0 versus 4.8±1.2 ms
2
;
P
<.01) and better ejection fraction (
r
=.2,
P
<.03). An inverse correlation between the duration of ST shift and frequency domain measures was observed (LF,
r
=−.2,
P
<.009; HF,
r
=−2,
P
<.03). Lower LF/HF ratio by 24 hours after myocardial infarction was seen in those who ultimately died at 30 days (1.0±0.2 versus 1.3±0.2,
P
<.001) or at 1 year (1.17±0.14 versus 1.26±0.19,
P
=.05).

Conclusions
Changes in heart rate variability occurred early after thrombolysis and may be of prognostic value. Heart rate variability measures were improved in patients with better ejection fraction and greater angiographic patency. This suggests a possible mechanism for the enhanced survival observed with TIMI grade 3 flow in the GUSTO angiographic substudy. These data indicate that early heart rate variability assessment after myocardial infarction may be useful in noninvasive risk stratification.
Thrombin Activity and Early Outcome in Unstable Angina Pectoris
Authors: Ardissino Diego , Merlini Piera Angelica , Gamba Gabriella , Barberis Paolo , Demicheli Gloria , Testa Sophie , Colombi Elisabetta , Poli Arnaldo , Fetiveau Raffaela , Montemartini Carlo
Published: June 2012

Background
The blood coagulation system is frequently activated in the acute phase of unstable angina, but it is unknown whether the augmented function of the hemostatic mechanism may serve as a marker of increased risk for an early unfavorable outcome.

Methods and Results
Plasma concentrations and 24-hour urinary excretion of fibrinopeptide A were prospectively determined in 150 patients with unstable angina. All patients underwent 24-hour Holter monitoring, during which time urine was collected; at the end of this period, a blood sample was taken and coronary arteriography was performed. The patients were followed up for the occurrence of cardiac events (death and myocardial infarction) until they underwent coronary revascularization or until they were discharged from the hospital. Fibrinopeptide A plasma levels and 24-hour urinary excretion were found to be abnormally elevated in 50% and 45% of the study population, respectively. During hospitalization, 11 patients developed myocardial infarction and 2 patients died. Kaplan-Meier analysis demonstrated a significantly higher probability of developing cardiac events in patients with abnormal rather than normal plasma levels of fibrinopeptide A (
P
<.01), whereas no difference in outcome was observed between patients with normal and those with abnormal 24-hour urinary excretion. Cox regression analysis showed that the only variables independently related to an early unfavorable outcome were the presence of persistent ischemia during 24-hour Holter monitoring (
P
<.0001), the presence of intracoronary thrombosis at angiography (
P
=.016), and abnormal fibrinopeptide A plasma levels (
P
=.038).

Conclusions
Patients with unstable angina pectoris and abnormal fibrinopeptide A plasma levels are at increased risk for an early unfavorable outcome.
Atrial Contractile Dysfunction After Short-term Atrial Fibrillation Is Reduced by Verapamil but Increased by BAY K8644
Authors: Leistad Elisabeth , Aksnes Gunnar , Verburg Esther , Christensen Geir
Published: June 2012

Background
Reduced atrial contractility occurs after cessation of atrial fibrillation. Its mechanism is unknown, and no pharmacological treatment exists. It has been hypothesized that this atrial contractile dysfunction results from intracellular calcium overload due to rapid depolarizations during fibrillation. Accordingly, we examined the effects of drugs that reduce or increase transsarcolemmal calcium influx on postfibrillation atrial dysfunction. Furthermore, we examined whether the dysfunction could be attributed to atrial ischemia.

Methods and Results
Atrial contractility after atrial fibrillation was examined in open-chest pigs paced with a constant ventricular rate after complete AV block. Atrial contractility was computed as systolic shortening of left atrial diameter divided by atrial preload. Three groups of six pigs each were subjected to two 5-minute periods of atrial fibrillation separated by 1 hour of AV pacing. Verapamil or the calcium channel agonist BAY K8644 was administered intravenously before the second fibrillation period. The degree and duration of postfibrillation atrial contractile dysfunction were reduced with verapamil but increased with BAY K8644. In a control group, parallel changes occurred after the first and second fibrillation periods. Atrial tissue content of creatine phosphate declined slightly during fibrillation, whereas the tissue content of ATP and lactate remained unchanged.

Conclusions
Atrial contractile dysfunction after short-term atrial fibrillation is reduced by the calcium antagonist verapamil, which suggests that transsarcolemmal calcium influx contributed to this dysfunction. The calcium agonist BAY K8644 increased postfibrillation atrial contractile dysfunction. Atrial ischemia was not observed during fibrillation.
Modulation of Oxidant Stress In Vivo in Chronic Cigarette Smokers
Authors: Reilly Murdeach , Delanty Norman , Lawson John A. , FitzGerald Garret A.
Published: June 2012

Background
Free radical–induced oxidative damage is thought to be involved in the pathogenesis of diseases associated with cigarette smoking. We examined the production of 8-
epi-
prostaglandin (PG) F
2
α
, a stable product of lipid peroxidation in vivo, and its modulation by aspirin and antioxidant vitamins in chronic cigarette smokers.

Methods and Results
We performed the following studies: (1) a cross-sectional comparison of smokers and control subjects, (2) an examination of the dose-response relationship, (3) an exploration of the effect of smoking cessation (3 weeks) and nicotine patch supplementation, (4) the effect of aspirin consumption, and (5) the effects of 5 days’ dosing with vitamin E (100 and 800 U), vitamin C (2 g), and their combination. 8-
epi
-PGF
2
α
excretion (in pmol/mmol, mean±SEM) was 176.5±30.6 in heavy smokers, 92.7±4.8 (
P
<.05) in moderate smokers, and 54.1±2.7 (
P
<.005) in nonsmokers. Urinary levels fell from 145.5±24.9 to 114.6±27.1 (week 2,
P
<.05) and 112.6±24.9 (week 3,
P
<.05) on cessation of smoking. Aspirin treatment failed to suppress urinary levels of 8-
epi-
PGF
2
α
despite a significant reduction in urinary 11-dehydro-TxB
2
production and suppression of 8-
epi-
PGF
2
α
and TxB
2
in serum. Vitamin C (pre, 194.6±40.9; post, 137.2±34.1;
P
<.05) and a combination of vitamin C and E (pre, 171.0±39.8; post, 133.5±29.6;
P
<.05) suppressed urinary 8-
epi-
PGF
2
α
, whereas vitamin E alone had no effect.

Conclusions
Urinary 8-
epi-
PGF
2
α
may represent a noninvasive, quantitative index of oxidant stress in vivo. Elevated levels of 8-
epi-
PGF
2
α
in smokers may be modulated by quitting cigarettes and switching to nicotine patches or by antioxidant vitamin therapy.
Sympathetic Stimulation Overrides Flow-Mediated Endothelium-Dependent Epicardial Coronary Vasodilation in Transplant Patients
Authors: Aptecar Eduardo , Dupouy Patrick , Benvenuti Christophe , Mazzucotelli Jean-Philippe , Teiger Emmanuel , Geschwind Herbert , Castaigne Alain , Loisance Daniel , Dubois-Rande Jean-Luc
Published: June 2012

Background
Abnormal coronary vasomotor responses have been described in transplant patients. The aim of this study was to evaluate the graft epicardial vasomotor responses to different stimuli that increase coronary blood flow.

Methods and Results
Twelve heart transplant recipients with angiographically normal epicardial coronary arteries were compared 2.7±1.2 months after surgery with 6 control subjects. Coronary flow velocity was measured with a guidewire Doppler. Coronary diameter changes of the proximal and midportion of the left anterior descending coronary artery were assessed by quantitative coronary angiography during rapid atrial pacing, cold pressor test, supine exercise, and subselective infusion of papaverine and after intracoronary injection of linsidomine (SIN-1). Catecholamine plasmatic levels were determined at the different stages of the protocol. In 6 other transplant patients, a cold pressor test was performed before and after intracoronary infusion of phentolamine (10 μg·kg
−1
·min
−1
). Coronary flow velocity increased significantly in both groups during each phase of the protocol. In control subjects, dilation was observed in response to atrial pacing (8.7±7.6%;
P
<.05), CPT (8.8±2.3%;
P
<.01), exercise (14.5±9.4%;
P
<.001), and papaverine infusion (14.2±6.1%;
P
<.001) and after injection of SIN-1 (26.8±11.9%;
P
<.001). In transplant patients, similar dilation was observed during atrial pacing (8.2±8.3%;
P
<.05) and papaverine infusion (14.6±7.8%;
P
<.001) and after SIN-1 (25.8±10.8%;
P
<.001). CPT and exercise caused slight constriction (−3.5±4.5% and −2.7±10.5%, respectively; both
P
<.001 versus control subjects). Norepinephrine plasmatic levels increased in both groups during CPT and exercise. Slight constriction during the cold pressor test (−4.5±9.6%) changed to dilation (6.8±7.0%) after α-blockade with phentolamine (
P
<.001).

Conclusions
These results show that flow-mediated, endothelium-dependent vasodilation is preserved early after transplantation. Sympathetic stimulation, which overrides the endothelium-dependent mechanism, can be related to hypersensitivity to catecholamines due to denervation.
Modulation of Atrioventricular Nodal Function by Metabolic and Allosteric Regulators of Endogenous Adenosine in Guinea Pig Heart
Authors: Dennis Donn M. , Raatikainen M.J. Pekka , Martens Jeffrey R. , Belardinelli Luiz
Published: June 2012

Background
There has been increasing interest in the development of agents that utilize endogenous adenosine to exert their actions. We tested the hypothesis that substances that either potentiate the activity (allosteric enhancers) or increase the interstitial concentration (inhibitors of metabolism) of endogenous adenosine may cause event (tachycardia)-specific depression of AV nodal conduction.

Methods and Results
The frequency-dependent effects of iodotubercidin (ITU, an inhibitor of adenosine kinase),
erythro
-9-(2-hydroxy-3-nonyl)adenine (EHNA, an inhibitor of adenosine deaminase), draflazine (a nucleoside transport blocker), and PD81,723 (an allosteric enhancer of the A
1
adenosine receptor binding) on the stimulus-to–His bundle (SH) interval, a measure of AV nodal conduction, were determined in guinea pig hearts and compared with those of adenosine and diltiazem. All drugs depressed AV nodal conduction in a frequency-dependent manner. The ratios of SH interval prolongations at fast to slow pacing rates for draflazine, ITU+EHNA, PD81,723, adenosine, and diltiazem were 17.5±3.4, 11.1±5.0, 3.5±0.9, 10.1±2.8, and 8.3±3.5, respectively. Coincident with the prolongation of the SH interval at rapid pacing rates, draflazine and ITU+EHNA increased the epicardial fluid adenosine concentrations by 2.2- and 2.6-fold, respectively. In contrast, epicardial transudate levels of adenosine do not change in the presence of PD81,723. The AV nodal effects of draflazine, ITU, EHNA, and PD81,723 were reversed by the A
1
adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase, implicating endogenous adenosine acting at the A
1
adenosine receptor.

Conclusions
Adenosine-regulating agents that act in an event- and site-specific manner represent a novel drug design strategy that may potentially be valuable for the long-term treatment of supraventricular arrhythmias and control of ventricular rate during atrial fibrillation or flutter.
Assessment of Myocardial Viability in Patients With Chronic Coronary Artery Disease
Authors: Perrone-Filardi Pasquale , Pace Leonardo , Prastaro Mariella , Squame Fiorenzo , Betocchi Sandro , Soricelli Andrea , Piscione Federico , Indolfi Ciro , Crisci Teresa , Salvatore Marco , Chiariello Massimo
Published: June 2012

Background
To date, late redistribution after resting
201
Tl injection has not been evaluated. In addition, the concordance between resting
201
Tl imaging and dobutamine echocardiography in identifying viable myocardium has not been assessed.

Methods and Results
Forty patients with coronary artery disease underwent rest–4-hour–24-hour
201
Tl tomography and dobutamine echocardiography (5 to 10 μg·kg
−1
·min
−1
). Late redistribution occurred in 46 (21%) of 219 persistent defects at 4 hours. Systolic function and contractile reserve were similar among persistent defects at 4 hours with and without late redistribution. Contractile reserve was more frequent in segments with normal
201
Tl uptake (59%), completely reversible defects (53%), or mild to moderate defects at 4 hours (56%) compared with severe defects (14%;
P
<.02 versus all). Of 105 hypokinetic segments, 99 (94%) were viable by
201
Tl, and 88 (84%) showed contractile reserve. In contrast, of 155 akinetic segments, 119 (77%) were viable by
201
Tl, but only 34 (22%) had contractile reserve. Concordance between
201
Tl and dobutamine was 82% in hypokinetic segments but 43% in akinetic segments. In 109 revascularized segments, positive accuracy for functional recovery was 72% for
201
Tl and 92% for dobutamine, whereas negative accuracy was 100% and 65%, respectively. Sensitivity was 100% for
201
Tl and 79% for dobutamine.

Conclusions
Late redistribution occurs in one fifth of persistent defects at 4 hours, and it does not correlate to systolic function or contractile reserve. Dobutamine and
201
Tl yield concordant information in the majority of hypokinetic segments, whereas concordance is low in akinetic segments. Dobutamine demonstrates higher positive accuracy and sensitivity in predicting recovery of dysfunctional myocardium, whereas
201
Tl shows higher negative predictive accuracy but reduced positive accuracy.