bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Cost-effectiveness of Public Access Defibrillation in the United States
Authors: Nichol Graham , Hallstrom Alfred P. , Ornato Joseph P. , Riegel Barbara , Stiell Ian G. , Valenzuela Terry , Wells George A. , White Roger D. , Weisfeldt Myron L.
Published: June 2012

Background
—Approximately 360 000 Americans experience sudden cardiac arrest each year; current treatments are expensive and not very effective. Public access defibrillation (PAD) is a novel treatment for out-of-hospital sudden cardiac arrest that refers to use of automated external defibrillators by the lay public or by nonmedical personnel such as police. A clinical trial has been proposed to evaluate the effectiveness of public access defibrillation, but it is unclear whether such early defibrillation will offer sufficient value for money. Our objective was to estimate the potential cost-effectiveness of public access defibrillation by use of decision analysis.

Methods and Results
—A decision model compared the potential cost-effectiveness of standard emergency medical services (EMS) systems with that of EMS supplemented by PAD. We considered defibrillation by lay responders or police, using an analysis with a US health-care perspective. Input data were derived from published data or fiscal databases. Future costs and effects were discounted at 3%. Monte Carlo simulation was performed to estimate the variability in the costs and effects of each program. Sensitivity analyses assessed the robustness of the results to changes in input data. A standard EMS system had a median cost of $5900 per cardiac arrest patient (interquartile range, IQR, $3200 to $10 900) and yielded a median of 0.25 quality-adjusted life years (IQR, 0.20 to 0.30). PAD by lay responders had a median incremental cost of $44 000 per additional quality-adjusted life year (IQR, $29 000 to $68 900). PAD by police had a median incremental cost of $27 200 per additional quality-adjusted life year (IQR, $15 700 to $47 800). The results were sensitive to changes in the cost and relative survival benefit of PAD.

Conclusions
—Although more expensive than standard EMS for sudden cardiac arrest, PAD may be economically attractive. The effectiveness and cost-effectiveness of PAD should be assessed in a randomized, controlled trial.
Pathophysiologically Relevant Concentrations of Tumor Necrosis Factor-α Promote Progressive Left Ventricular Dysfunction and Remodeling in Rats
Authors: Bozkurt Biykem , Kribbs Scott B. , Clubb Fred J. , Michael Lloyd H. , Didenko Vladimir V. , Hornsby Peter J. , Seta Yukihiro , Oral Hakan , Spinale Francis G. , Mann Douglas L.
Published: June 2012

Background
—Although patients with heart failure express elevated circulating levels of tumor necrosis factor-α (TNF-α) in their peripheral circulation, the structural and functional effects of circulating levels of pathophysiologically relevant concentrations of TNF-α on the heart are not known.

Methods and Results
—Osmotic infusion pumps containing either diluent or TNF-α were implanted into the peritoneal cavity of rats. The rate of TNF-α infusion was titrated to obtain systemic levels of biologically active TNF-α comparable to those reported in patients with heart failure (≈80 to 100 U/mL), and the animals were examined serially for 15 days. Two-dimensional echocardiography was used to assess changes in left ventricular (LV) structure (remodeling) and LV function. Video edge detection was used to assess isolated cell mechanics, and standard histological techniques were used to assess changes in the volume composition of LV cardiac myocytes and the extracellular matrix. The reversibility of cytokine-induced effects was determined either by removal of the osmotic infusion pumps on day 15 or by treatment of the animals with a soluble TNF-α antagonist (TNFR:Fc). The results of this study show that a continuous infusion of TNF-α led to a time-dependent depression in LV function, cardiac myocyte shortening, and LV dilation that were at least partially reversible by removal of the osmotic infusion pumps or treatment of the animals with TNFR:Fc.

Conclusions
—These studies suggest that pathophysiologically relevant concentrations of TNF-α are sufficient to mimic certain aspects of the phenotype observed in experimental and clinical models of heart failure.
Locally Propagated Activation Immediately After Internal Defibrillation
Authors: Chattipakorn Nipon , KenKnight Bruce H. , Rogers Jack M. , Walker Robert G. , Walcott Gregory P. , Rollins Dennis L. , Smith William M. , Ideker Raymond E.
Published: June 2012

Background
—Electrical mapping studies indicate an interval of 40 to 100 ms between a defibrillation shock and the earliest activation that propagates globally over the ventricles (globally propagated activation, GPA). This study determined whether activation occurs during this interval but propagates only locally before being blocked (locally propagated activation, LPA).

Methods and Results
—In five anesthetized pigs, the heart was exposed and a 504-electrode sock with 4-mm interelectrode spacing was pulled over the ventricles. Ten biphasic shocks of a strength near the defibrillation threshold (DFT) were delivered via intracardiac catheter electrodes, and epicardial activation sequences were mapped before and after attempted defibrillation. Local activation was defined as dV/dt ≤−0.5 V/s. Postshock activation times and wave-front interaction patterns were determined with an animated display of dV/dt at each electrode in a computer representation of the ventricular epicardium. LPAs were observed after 40 of the 50 shocks. A total of 173 LPA regions were observed, each of which involved 2±2 (mean±SD) electrodes. LPAs were observed after both successful and failed shocks but occurred earlier (
P
<.0001) after failed (35±8 ms) than successful (41±16 ms) shocks, although the times at which the GPA appeared were not significantly different. On reaching the LPA region, the GPA front either propagated through it (n=135) or was blocked (n=38). The time from the onset of the LPA until the GPA front propagated to reach the LPA region was shorter (
P
<.01) when the GPA front was blocked (32±12 ms) than when it propagated through the LPA region (63±20 ms).

Conclusions
—LPAs exist after successful and failed shocks near the DFT. Thus, the time from the shock to the GPA is not totally electrically silent.
Association Between Body Iron Stores and the Risk of Acute Myocardial Infarction in Men
Authors: Tuomainen Tomi-Pekka , Punnonen Kari , Nyyssönen Kristiina , Salonen Jukka T.
Published: June 2012

Background
—Epidemiological evidence concerning the role of iron, a lipid peroxidation catalyst, in coronary heart disease (CHD) is inconsistent. We investigated the association of the concentration ratio of serum transferrin receptor to serum ferritin (TfR/ferritin), a state-of-the-art measurement of body iron stores, with the risk of acute myocardial infarction (AMI) in a prospective nested case-control study in men from eastern Finland.

Methods and Results
—Transferrin receptor assays were carried out for 99 men who had an AMI during an average 6.4 years of follow-up and 98 control men. Both the cases and the controls were nested from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) cohort of 1931 men who had no clinical CHD at the baseline study. The controls were matched for age, examination year, and residence. AMIs were registered prospectively. Soluble transferrin receptors were measured by immunoenzymometric assay and ferritin concentration by radioimmunoassay from frozen baseline serum samples. The mean TfR/ferritin ratio was 15.1 (SE, 2.0) among cases and 21.3 (SE, 2.2) among controls (
P
=.035 for difference). In logistic regression models adjusting for other strongest risk factors for AMI and indicators of inflammation and alcohol intake, men in the lowest and second lowest thirds of the TfR/ferritin ratio had a 2.9-fold (95% CI, 1.3 to 6.6,
P
=.011) and 2.0-fold (0.9 to 4.2,
P
=.081) risk of AMI compared with men in the highest third (
P
=.010 for trend).

Conclusions
—These data show an association between increased body iron stores and excess risk of AMI, confirming previous epidemiological findings.
Decompensation of Pressure-Overload Hypertrophy in Gαq-Overexpressing Mice
Authors: Sakata Yoshihito , Hoit Brian D. , Liggett Stephen B. , Walsh Richard A. , Dorn Gerald W.
Published: June 2012

Background
—Receptor-mediated activation of myocardial Gq signaling is postulated as a biochemical mechanism transducing pressure-overload hypertrophy. The specific effects of Gq activation on the functional and morphological adaptations to pressure overload are not known.

Methods and Results
—To determine the effects of intrinsic myocyte Gαq signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing Gαq specifically in the heart (Gαq-25) and nontransgenic siblings underwent microsurgical creation of transverse aortic coarctation and the morphometric, functional, and molecular characteristics of these pressure-overloaded hearts were compared at increasing times after surgery. Before aortic banding, isolated Gαq-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and −dl/dt) and Gαq-25 hearts showed a pattern of fetal gene expression similar to the known characteristics of nontransgenic pressure-overloaded mice. Three weeks after transverse aortic banding, Gαq-25 left ventricles hypertrophied to a similar extent (≈30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), Gαq-25 left ventricles developed eccentric hypertrophy and ejection performance deteriorated, ultimately resulting in left heart failure (decompensated hypertrophy). The signature hypertrophy-associated progress of fetal cardiac gene expression observed at baseline in Gαq-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded Gαq-25 mice.

Conclusions
—Intrinsic cardiac myocyte Gαq activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on Gαq overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore Gαq-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.
Effects of Total Replacement of Atrial Myosin Light Chain-2 With the Ventricular Isoform in Atrial Myocytes of Transgenic Mice
Authors: Pawloski-Dahm Corinn M. , Song Guojie , Kirkpatrick Darryl L. , Palermo Joe , Gulick James , Dorn Gerald W. , Robbins Jeffrey , Walsh Richard A.
Published: June 2012

Background
—In contrast to their well-known and critical role in excitation-contraction coupling of vascular smooth muscle, the effects of the myosin light chains on cardiomyocyte mechanics are poorly understood. Accordingly, we designed the present experiment to define the cardiac chamber–specific functional effects of the ventricular isoform of the regulatory myosin light chain (MLC2v).

Methods and Results
—Postnatal transgenic cardiac-specific overexpression of MLC2v was achieved by use of the α-myosin heavy chain promoter. Enzymatically disaggregated atrial and ventricular mouse myocytes were field-stimulated at multiple frequencies, and mechanical properties and calcium kinetics were studied by use of video edge detection and FURA 2-AM, respectively. MLC2v overexpression resulted in complete replacement of the atrial with the ventricular isoform of the regulatory myosin light chain at the steady-state mRNA and protein levels in the atria of transgenic mice. Mechanical properties of transgenic atrial myocytes were enhanced to the level of ventricular myocytes of control animals in association with modest decreases in the amplitude of the calcium transient.

Conclusions
—MLC2v modulates chamber-specific contractility by enhanced calcium sensitivity and/or improved cross-bridge cycling of the thin and thick filaments of the cardiomyocyte.
Analysis of the Effect of Flow Rate on the Doppler Continuity Equation for Stenotic Orifice Area Calculations
Authors: DeGroff Curt G. , Shandas Robin , Valdes-Cruz Lilliam
Published: June 2012

Background
—Flow-rate dependencies of the Doppler continuity equation are addressed in this study.

Methods and Results
—By use of computational fluid dynamic (CFD) software with turbulence modeling, three-dimensional axisymmetric models of round stenotic orifices were created. Flow simulations were run for various orifice area sizes (0.785, 1.13, 1.76, and 3.14 cm

2

) and flow rates (0.37 to 25.0 L/min). Reynolds numbers ranged from 100 to 8000. Once adequate convergence was obtained with each simulation, the location of the vena contracta was determined. For each run, maximum and average velocities across the cross section of the vena contracta were tabulated and vena contracta cross-sectional area (effective orifice area) determined. The difference between the maximum velocity and the average velocity at the vena contracta was smallest at high-flow states, with more of a difference at low-flow states. At lower-flow states, the velocity vector profile at the vena contracta was parabolic, whereas at high-flow states, the profile became more flattened. Also, the effective orifice area (vena contracta cross-sectional area) varied with flow rate. At moderate-flow states, the effective orifice area reached a minimum and expanded at low- and high-flow states, remaining relatively constant at high-flow states.

Conclusions
—We have shown that significant differences exist between the maximum velocity and the average velocity at the vena contracta at low flow rates. A likely explanation for this is that viscous effects cause lower velocities at the edges of the vena contracta at low flow rates, resulting in a parabolic profile. At higher-flow states, inertial forces overcome viscous drag, causing a flatter profile. Effective orifice area itself varies with flow rate as well, with the smallest areas seen at moderate-flow states. These flow-dependent factors lead to flow rate–dependent errors in the Doppler continuity equation. Our results have strong relevance to clinical measurements of stenotic valve areas by use of the Doppler continuity equation under varying cardiac output conditions.
Distribution of Atrial and Nodal Cells Within the Rabbit Sinoatrial Node
Authors: Verheijck E. Etienne , Wessels Andy , van Ginneken Antoni C. G. , Bourier Jan , Markman Marry W. M. , Vermeulen Jacqueline L. M. , de Bakker Jacques M. T. , Lamers Wouter H. , Opthof Tobias , Bouman Lennart N.
Published: June 2012

Background
—In the sinoatrial node (SAN) the course of the action potential gradually changes from the primary pacemaker region toward the atrium. It is not known whether this gradient results from different intrinsic characteristics of the nodal cells, from an increasing electrotonic interaction with the atrium, or from both. Therefore we have characterized the immunohistochemical, morphological, and electrophysiological correlates of this functional gradient.

Methods and Results
—The distribution of rabbit nodal myocytes in the SAN has been studied by immunohistochemistry. After cell isolation, the electrophysiological characteristics of different nodal cell types were measured. (1) The staining pattern of a neurofilament protein coincides with the electrophysiologically mapped pacemaker region in the SAN. (2) Enzymatic digestion of the SAN reveals three morphologically different nodal cell types and one atrial type. Of each nodal cell type, neurofilament-positive as well as neurofilament-negative myocytes are found. Atrial cells are all neurofilament-negative. (3) In contrast to previous findings, we observed atrial cells in the very center of the SAN. The relative number of atrial cells gradually increases from the central pacemaker area toward the atrium. (4) Differences in electrophysiological characteristics between individual nodal cells are not associated with differences in cell type.

Conclusions
—(1) The expression of neurofilaments can be used to delineate the nodal area in the intact SAN but is not sufficiently sensitive for characterizing all individual isolated nodal cells. (2) A fundamentally different organization of the SAN is presented: The gradual increase in density of atrial cells from the dominant area toward the crista terminalis in the SAN causes a gradual increase of atrial electrotonic influence that may be an important cause of the gradual transition of the nodal to the atrial type of action potential.
Thrombolysis for Acute Myocardial Infarction
Authors: White Harvey D. , Van de Werf Frans J. J.
Published: June 2012

Abstract
—Thrombolytic therapy has been a major advance in the management of acute myocardial infarction. Unfortunately, it continues to be underused or is administered later than is optimal. Thrombolytic therapy works by lysing infarct artery thrombi and achieving reperfusion, thereby reducing infarct size, preserving left ventricular function, and improving survival. The most effective thrombolytic regimens achieve angiographic epicardial infarct-artery patency in only ≈50% of patients within 90 minutes. Bleeding requiring transfusion occurs in ≈5% of patients and stroke in ≈1.8% with these regimens, which include adjunctive aspirin and intravenous heparin. There are several ways in which reperfusion rates and thus patient outcomes might be improved, such as different dosing regimens of established agents; combinations of different agents; improved adjunctive therapy such as direct antithrombin agents, low-molecular-weight heparin, or glycoprotein IIb/IIIa receptor antagonists; or the development of novel thrombolytic agents with enhanced fibrin specificity, resistance to native inhibitors, or prolonged half-lives allowing bolus administration. All of these strategies are being tested in clinical trials. The best approach currently is to administer thrombolytic therapy as soon as possible to all patients without contraindications who present within 12 hours of symptom onset and have ST-segment elevation on the ECG or new-onset left bundle-branch block, unless an alternative reperfusion strategy is planned.
Economic Assessment of Low-Molecular-Weight Heparin (Enoxaparin) Versus Unfractionated Heparin in Acute Coronary Syndrome Patients
Authors: Mark Daniel B. , Cowper Patricia A. , Berkowitz Scott D. , Davidson-Ray Linda , DeLong Elizabeth R. , Turpie Alexander G. G. , Califf Robert M. , Weatherley Beth , Cohen Marc
Published: June 2012

Background
—In the ESSENCE trial, subcutaneous low-molecular-weight heparin (enoxaparin) reduced the 30-day incidence of death, myocardial infarction, and recurrent angina relative to intravenous unfractionated heparin in 3171 patients with acute coronary syndrome (unstable angina or non–Q-wave myocardial infarction). No increase in major bleeding was seen.

Methods and Results
—Of the 936 ESSENCE patients randomized in the United States, 655 had hospital billing data collected. For the remainder, hospital costs were imputed with a multivariable linear regression model (
R
2
=.86). Physician fees were estimated from the Medicare Fee Schedule. During the initial hospitalization, major resource use was reduced for enoxaparin patients, with the largest effect seen with coronary angioplasty (15% versus 20% for heparin,
P
=.04). At 30 days, these effects persisted, with the largest reductions seen in diagnostic catheterization (57% versus 63% for heparin,
P
=.04) and coronary angioplasty (18% versus 22%,
P
=.08). All resource use trends seen in the US cohort were also evident in the overall ESSENCE study population. In the United States, the mean cost of a course of enoxaparin therapy was $155, whereas that for heparin was $80. The total medical costs (hospital, physician, drug) for the initial hospitalization were $11 857 for enoxaparin and $12 620 for heparin, a cost advantage for the enoxaparin arm of $763 (
P
=.18). At the end of 30 days, the cumulative cost savings associated with enoxaparin was $1172 (
P
=.04). In 200 bootstrap samples of the 30-day data, 94% of the samples showed a cost advantage for enoxaparin.

Conclusions
—In patients with acute coronary syndrome, low-molecular-weight heparin (enoxaparin) both improves important clinical outcomes and saves money relative to therapy with standard unfractionated heparin.
Mitral Regurgitation
Authors: Conway Michael A. , Bottomley Paul A. , Ouwerkerk Ronald , Radda George K. , Rajagopalan Bheeshma
Published: June 2012

Background
—A number of phosphorus (
31
P) magnetic resonance spectroscopy (MRS) studies link alterations of high-energy phosphate metabolism in valvular disease and cardiomyopathy to the clinical severity of heart failure. However, correlations between MRS and indexes of ventricular dysfunction are inconclusive to date. We examined whether changes in
31
P MRS are associated with the impaired contractility, which predisposes to chronic congestive heart failure in patients with mitral regurgitation.

Methods and Results
—Thirteen normal control subjects and 22 patients with echocardiographically characterized chronic mitral regurgitation were studied by
31
P MRS. The apical phosphocreatine-to-ATP ratio (PCr/ATP) was lower in severe disease (
P
<.02) and those on therapy (n=13, 1.29±0.29,
P
<.01) in contrast to control subjects (n=13, 1.61±0.3). Compared to those with mild mitral regurgitation, patients with more severe incompetence had lower mean myocardial PCr/ATP ratios (mild, n=6, 1.73 [0.17],
P
<.05 and
P
<.01; moderate, n=5, 1.49 [0.18],
P
<.05; and severe, n=11, 1.29 [0.32],
P
<.01). PCr/ATP in those referred for mitral valve replacement was lower (n=8, 1.17±0.23) although not significantly decreased compared with the ratio among subjects on medical therapy alone (n=5, 1.48±0.29). PCr/ATP correlated with the end-systolic diameter (
r
2
=.7,
P
<.001), end-diastolic diameter (
r
2
=.32,
P
<.05), left ventricular wall thickness (
r
2
=.38,
P
<.01), left atrial dimension (
r
2
=.36,
P
<.05), and derived measurements such as the percent fractional shortening (
r
2
=.5,
P
<.01), and left ventricular mass/body surface area (
r
2
=.5,
P
<.001) but not with wall stress.

Conclusions
—These results demonstrate that abnormalities of PCr/ATP in mitral regurgitation are related to disease severity as measured by dimensional indexes of left ventricular dilatation. They suggest that impaired high-energy phosphate metabolism is a marker of hypertrophy and heart failure.
Antibiotic Prophylaxis for Permanent Pacemaker Implantation
Authors: Da Costa Antoine , Kirkorian Gilbert , Cucherat Michel , Delahaye François , Chevalier Philippe , Cerisier Alexis , Isaaz Karl , Touboul Paul
Published: June 2012

Background
—Infection remains a serious complication after permanent pacemaker implantation. Antibiotic prophylaxis is frequently prescribed at the time of insertion to reduce its incidence, although results of well-designed, controlled studies are lacking.

Methods and Results
—We performed a meta-analysis of all available randomized trials to evaluate the effectiveness of antibiotic prophylaxis to reduce infection rates after permanent pacemaker implantation. Reports of trials were identified through a Medline, Embase, Current Contents, and an extensive bibliography search. Trials that met the following criteria were included: (1) prospective, randomized, controlled, open or blind trials; (2) patients assigned to a systemic antibiotic group or a control group; (3) end point events related to any infection after pacemaker implantation: wound infection, septicemia, pocket abscess, purulent secretion, right infective endocarditis, inflammatory signs, a positive culture, septic pulmonary embolism, or repeat operation for an infective complication. Seven trials met the inclusion criteria. They included 2023 patients with established permanent pacemaker implantation (new implants or replacements). The incidence of end point events in control groups ranged from 0% to 12%. The meta-analysis suggested a consistent protective effect of antibiotic pretreatment (
P
=.0046; common odds ratio: 0.256, 95% confidence interval: 0.10 to 0.656).

Conclusions
—Results of the present meta-analysis suggest that systemic antibiotic prophylaxis significantly reduces the incidence of potentially serious infective complications after permanent pacemaker implantation. They support the use of prophylactic antibiotics at the time of pacemaker insertion to prevent short-term pocket infection, skin erosion or septicemia.
Influence of Phase Duration of Biphasic Waveforms on Defibrillation Energy Requirements With a 70-μF Capacitance
Authors: Schauerte Patrick , Schöndube Friedrich A. , Grossmann Marius , Dörge Hilmar , Stein Frank , Dohmen Bernd , Moumen Abdel , Erena Konstantin , Messmer Bruno J. , Hanrath Peter , Stellbrink Christoph
Published: June 2012

Background
—Phase duration of biphasic shocks may be an important determinant of defibrillation success. The purpose of this study was to investigate the effect of changing phase duration of biphasic pulses delivered by 70-μF capacitors on defibrillation energy requirements. This may be clinically relevant for the optimization of implantable cardioverter-defibrillator design and programming.

Methods and Results
—Defibrillation thresholds (DFTs) were determined for 13 waveforms in 13 pigs by application of a 70-μF capacitance and a transvenous/submuscular lead system. In part I, phase-1 duration varied, preserving a phase-1/phase-2 duration ratio of 60%/40%. The phase-1 durations were 1, 2, 3, 4, 5, and 6 ms. The DFT was lowest (22.9±7 J) for phase 1=3 ms compared with phase 1=1 ms (36.4±7.5 J), 2 ms (25±6.5 J), 4 ms (25±7.6 J), 5 ms (30.7±7.3 J), or 6 ms (32.9±8.1 J) (
P
<.001). In part II, phase-1 duration was 3 ms but phase-2 duration varied: 0.7, 1.3, 2, 2.7, 3.3, 4, and 6 ms. Significant DFT minima were found at phase 2=2 ms (22.5±4.2 J) and phase 2=4 ms (22.5±4.2 J) compared with phase 2=0.7 ms (31.7±9.3 J), phase 2=3.3 ms (26.7±6.1 J), or phase 2=6 ms (28.3±6.8 J) (
P
<.05).

Conclusions
—The strength-duration curve of biphasic defibrillation shocks demonstrates a single optimum for phase-1 duration. In contrast, two optima with minimal energy requirements were found for phase-2 duration. Optimization of both phases of low-capacitance biphasic shocks may reduce energy requirements for defibrillation.
Atrial Mapping and Radiofrequency Catheter Ablation in Patients With Idiopathic Atrial Fibrillation
Authors: Gaita Fiorenzo , Riccardi Riccardo , Calò Leonardo , Scaglione Marco , Garberoglio Lucia , Antolini Renzo , Kirchner Michele , Lamberti Filippo , Richiardi Elena
Published: June 2012

Background
—Knowledge of the electrophysiological substrates and the cure of atrial fibrillation (AF) is still unsatisfactory. The goal of this study was to evaluate the electrophysiological features of idiopathic AF and their relationship to the results of radiofrequency (RF) catheter ablation of AF and the safety and effectiveness of this procedure.

Methods and Results
—Sixteen patients with idiopathic AF underwent atrial mapping during AF and then RF ablation in the right atrium. The atrial activation was simultaneously recorded in four regions in the right atrium: high lateral wall (HL), low lateral wall (LL), high septum (HS), and low septum (LS) and in the left atrium through the coronary sinus (CS). In these regions, we evaluated the atrial fibrillation intervals (FF) and the morphological features of AF recordings by Wells’ classification. No complications occurred during RF ablation. Of the 16 patients, 9 (56%) without AF recurrences during the follow-up (11±4 months) were considered successfully ablated. These patients showed a significantly shorter mean FF interval in the HS and the LS (122±32 and 126±28 ms, respectively) than in the HL and LL (159±24 and 156±28 ms, respectively). Moreover, the septum had more irregular electrical activity with greater beat-to-beat changes in FF and a higher prevalence of type III AF than the lateral region. The CS had similar behavior to the septum. Conversely, patients with unsuccessful ablation had an irregular atrial activity in the lateral wall, septum, and CS with no significant differences between the different sites.

Conclusions
—Right atrial endocardial catheter ablation of AF is a safe procedure and may be effective in some patients with idiopathic AF. The atrial mapping during AF showed a more disorganized right atrial activation in the septum than in the lateral wall in patients with successful ablation.
Preserved Relative Dispersion but Blunted Stimulation of Mean Flow, Absolute Dispersion, and Blood Volume by Insulin in Skeletal Muscle of Patients With Essential Hypertension
Authors: Laine Hanna , Knuuti M. Juhani , Ruotsalainen Ulla , Utriainen Tapio , Oikonen Vesa , Raitakari Maria , Luotolahti Matti , Kirvelä Olli , Vicini Paolo , Cobelli Claudio , Nuutila Pirjo , Yki-Järvinen Hannele
Published: June 2012

Background
—We examined the integrity of the effects of insulin on mean muscle blood flow, flow heterogeneity, and blood volume in essential hypertension.

Methods and Results
—Positron emission tomography, combined with [
15
O]H
2
O and [
15
O]CO as tracers for direct measurement of blood flow and volume in skeletal muscle, and a new bayesian iterative reconstruction algorithm allowing pixel-by-pixel quantitation of blood flow and flow dispersion, were used. Measurements were performed basally after an overnight fast and under normoglycemic hyperinsulinemic conditions in 11 newly diagnosed, untreated mildly hypertensive men (age, 35±1 years; body mass index, 25.2±0.4 kg/m
2
, blood pressure 141±4/96±2 mm Hg, mean±SE) and 11 matched normotensive men. Insulin-stimulated whole body glucose uptake was significantly decreased in the hypertensive men (41±4 μmol/kg per minute) compared with the normotensive (59±4 μmol/kg per minute,
P
<0.005) men. Mean blood flow in skeletal muscle was significantly lower in the hypertensive than the normal subjects basally (1.7±0.2 versus 2.7±0.4 mL/0.1 kg per minute,
P
<0.05) and during hyperinsulinemia (2.3±0.2 versus 4.2±0.8,
P
<0.05). The flow response to insulin (0.6±0.2 versus 1.9±0.5 mL/0.1 kg per minute, hypertensive versus normal subjects,
P
<0.05) was also significantly blunted. Muscle blood volume was significantly lower in the hypertensive than in the normal subjects, both basally (3.0±0.2 versus 3.5±0.2 mL/0.1 kg,
P
<0.05) and during hyperinsulinemia (3.1±0.2 versus 4.0±0.2 mL/0.1 kg muscle,
P
<0.02). The increase in muscle blood volume by insulin was significant in the normal (
P
<0.05) but not the hypertensive subjects. Regional pixel-by-pixel analysis within femoral muscles revealed significant spatial heterogeneity of blood flow. Insulin increased absolute dispersion of blood flow significantly more in the normal subjects than in the hypertensive subjects (
P
<0.05).

Conclusions
—True flow heterogeneity, as judged from the coefficients of variation (relative dispersion), was comparable between the groups basally and during hyperinsulinemia. We conclude that mean flow, its absolute dispersion, and blood volume exhibit insulin resistance in patients with essential hypertension.
Diabetes and Dyslipidemia
Authors: Hoang Khanh , Chen Y.-D. Ida , Reaven Gerald , Zhang Lunan , Ross Heather , Billingham Margaret , Valantine Hannah
Published: June 2012

Background
—Clinical observations suggest that transplant coronary artery disease (TxCAD) is immunologically mediated but may be accelerated by metabolic derangements. We developed a rat model of heterotopic heart transplantation in the presence of diabetes and dyslipidemia to further study their role in TxCAD development.

Methods and Results
—Major histocompatibility complex–mismatched strains of inbred rats underwent heterotopic heart transplantation (ACI-to-Lewis allografts). Diabetes (DM) was induced by streptozotocin injection (80 mg/kg) after transplantation; dyslipidemia was worsened by feeding of a 60% high-fructose diet (+F). Allograft transplants were divided into four groups: (1) +DM/+F; (2) +DM/−F; (3) −DM/+F; and (4) −DM/−F. Isograft transplants (Lewis to Lewis, +DM/±F) were controls. All animals received daily cyclosporine (5 mg/kg). Grafts surviving >30 days were evaluated for TxCAD on histological sections and graded 0 to 5 for intimal thickness. All streptozotocin-treated animals were diabetic within 2 weeks, with fourfold increases in plasma glucose concentrations versus nondiabetics. Severe TxCAD was observed in diabetic allografts only. The mean grade of TxCAD in diabetic allografts was 3.2±0.5 versus 1.1±0.4 in diabetic isografts (
P
<0.03) and zero TxCAD in nondiabetic allografts (
P
≤0.0001). Fructose feeding resulted in a 1.5-fold higher triglyceride and a 1.3-fold higher cholesterol level versus the regular diet (−F) but showed no independent contribution to the development of TxCAD.

Conclusions
—These findings suggest that metabolic derangements associated with diabetes play an important role in TxCAD development in heterotopic ACI-to-Lewis rat heart transplantation. In this model of TxCAD in major histocompatibility complex–mismatched, diabetic, and dyslipidemic rats, immunologic and metabolic mechanisms that contribute to TxCAD can be further delineated and approaches to its prevention assessed.
Impaired Modulation of Sympathetic Excitability by Nitric Oxide After Long-term Administration of Organic Nitrates in Pigs
Authors: Zanzinger Johannes , Czachurski Jürgen , Seller Horst
Published: June 2012

Background
—Endogenous nitric oxide (NO) reduces sympathetic vasoconstriction by attenuating neuronal excitability in the brain stem and inhibition of postganglionic neurotransmission. We studied whether this modulation of sympathetic circulatory control by NO may be altered during chronic administration of NO donor drugs in pigs.

Methods and Results
—Nitrate tolerance was induced by oral administration of isosorbide dinitrate (ISDN, 4 mg/kg per day for 4 weeks) in eight pigs. Four of them were chronically instrumented for the measurement of mean arterial blood pressure and cardiac output in the conscious state. ISDN treatment caused hemodynamic tolerance to NO donors and significantly increased the hypotensive responses to pharmacologic ganglionic blockade in conscious pigs. In general anesthesia, ISDN-treated animals and age-matched controls (n=5) had similar baseline renal sympathetic nerve activity and in both groups neither inhibition of NO synthases (NOS) nor administration of NO donors to the brain stem by intracerebroventricular (ICV) infusions caused significant changes in baseline renal sympathetic nerve activity. However, whereas sympathoexcitatory responses to glutamate (0.5 mL, 0.1 mol/L, ICV) or electrical stimulation of somatic nerve afferents were significantly potentiated by central NOS inhibition and attenuated by NO donors in controls, these treatments no longer had significant effects in ISDN-treated pigs. Furthermore, reflex sympathetic activation in response to intravenous NO donor treatment was more pronounced in nitrate tolerant animals, which suggests loss of central sympathoinhibitory effects of NO. Subsequent histology on brain stem slices with NADPH-diaphorase as NOS marker revealed significant reduction of NOS density in ISDN-treated pigs.

Conclusions
—Long-term administration of organic nitrates reduces the number of NO-producing neurons in the brain stem and causes loss of inhibitory effects of NO on sympathetic excitability. This component of tolerance to organic nitrates may be important in patients confronted frequently with sympathetic activation caused by mental and/or physical stressors.
Dual-Tracer Assessment of Coupling Between Cardiac Sympathetic Neuronal Function and Downregulation of β-Receptors During Development of Hypertensive Heart Failure of Rats
Authors: Nozawa Takashi , Igawa Akihiko , Yoshida Naohiro , Maeda Masatoshi , Inoue Minoru , Yamamura Yoshitaka , Asanoi Hidetsugu , Inoue Hiroshi
Published: June 2012

Background
—Heart failure is associated with activation of the sympathetic nervous system and downregulation of β-receptors. However, the coupling between cardiac sympathetic neuronal function and the β-receptor during the development of hypertensive heart failure is not clear.

Methods and Results
—We determined cardiac neuronal function and β-receptors with a dual-tracer method of [
131
I]metaiodobenzylguanidine (MIBG) and
125
I-cyanopindolol (ICYP) in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The rats were fed an 8% NaCl diet after the age of 6 weeks. Blood pressure was raised to >200 mm Hg at 12 weeks in DS rats and remained elevated until 18 weeks, but only slightly in DR rats. Left ventricular (LV) function of DS rats was preserved at 12 weeks but deteriorated at 18 weeks. Despite a 56% reduction of cardiac norepinephrine (NE) content at 12 weeks in DS rats, neither MIBG nor ICYP uptake in DS rats was different from that of DR rats. At 18 weeks, both MIBG and ICYP uptakes decreased, by 52% and 39%, respectively, in association with 71% reduction of cardiac NE, in DS rats. MIBG uptake of the LV was homogeneous at 6 weeks but was lower in the LV endocardial regions at 18 weeks in DS rats.

Conclusions
—The present results indicate that cardiac sympathetic neuronal function is relatively preserved at the compensated, hypertrophic stage of DS rats but deteriorates in association with β-receptor downregulation at the failing stage. The cardiac neuronal dysfunction occurs heterogeneously. A combination of scintigraphic portrayal of β-receptors with MIBG should provide valuable information regarding sympathetic nerve signaling in living hearts.
Low Recurrence of Angina Pectoris After Coronary Artery Bypass Graft Surgery With Bilateral Internal Thoracic and Right Gastroepiploic Arteries
Authors: Bergsma T. Margot , Grandjean Jan G. , Voors Adriaan A. , Boonstra Piet W. , den Heyer Peter , Ebels Tjark
Published: June 2012

Background
—In the past 10 years, there has been a trend to use more arterial grafts instead of vein grafts for coronary artery bypass graft surgery. Although there are many reports on the short- and mid-term follow-up of patients who underwent arterial revascularization with 1 or 2 arteries, little has been reported on the follow-up of patients with 3-vessel disease who received 3 arteries.

Methods and Results
—We reviewed a group of 256 patients with 3-vessel disease who received the right gastroepiploic artery together with both internal thoracic arteries (ITAs). Vein grafts were not used in these patients. The patients were monitored for up to 7 years (mean, 51±15 months). Seven-year actuarial survival was 91.1%. The cumulative probability of event-free survival for myocardial infarction, reintervention, and angina pectoris at 7 years was 97.3%, 95.4%, and 85.4%, respectively.

Conclusions
—We conclude that concomitant use of the gastroepiploic artery with both ITAs results in low mortality and a low incidence of myocardial infarction and reintervention at follow-up. Most interestingly, we found 85.4% freedom from angina pectoris after 7 years, which is considerably lower than the results of studies in which vein grafts, single ITA grafts, or double ITA grafts are used. These results strongly support the use of both ITAs and the right gastroepiploic artery for bypass grafting in patients with 3-vessel disease.
A Recessive Variant of the Romano-Ward Long-QT Syndrome?
Authors: Priori Silvia G. , Schwartz Peter J. , Napolitano Carlo , Bianchi Laura , Dennis Adrienne , Fusco Maurizio De , Brown Arthur M. , Casari Giorgio
Published: June 2012

Background
—The congenital long-QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged ventricular repolarization and life-threatening arrhythmias. Mutations of the
KVLQT1
gene, a cardiac potassium channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a dominant trait, and the Jervell and Lange-Nielsen syndrome, inherited as an autosomal recessive trait.

Methods and Results
—A consanguineous family with the clinical phenotype of LQTS was screened for mutations in the
KVLQT1
gene. Complementary RNAs for injection into
Xenopus
oocytes were prepared, and currents were recorded with the double microelectrode technique. A homozygous missense mutation, leading to an alanine-to-threonine substitution at the beginning of the pore domain of the KVLQT1 channel, was found in the proband, a 9-year-old boy with normal hearing, a prolonged QT interval, and syncopal episodes during physical exercise. The parents of the proband were heterozygous for the mutation and had a normal QT interval. The functional evaluation of the mutant channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster activation rate consistent with a mild mutation likely to require homozygosity to manifest the phenotype.

Conclusions
—These findings provide the first evidence for a recessive form of the Romano-Ward long-QT syndrome and indicate that homozygous mutations on
KVLQT1
do not invariably produce the Jervell and Lange-Nielsen syndrome. The implications of this observation prompt a reconsideration of the penetrance of different mutations responsible for LQTS and suggest that mild mutations in LQTS genes may be present among the general population and may predispose to drug-induced ventricular arrhythmias.
New Method for Nonfluoroscopic Endocardial Mapping in Humans
Authors: Smeets Joep L. R. M. , Ben-Haim Shlomo A. , Rodriguez Luz-Maria , Timmermans Carl , Wellens Hein J. J.
Published: June 2012

Background
—Accurate mapping of the site of origin and activation sequence of a cardiac arrhythmia is essential for a successful catheter ablation procedure. To achieve this, precise and reproducible catheter manipulation is mandatory. The aim of this study was (1) to assess the accuracy of a new nonfluoroscopic mapping system in humans and (2) to report the first result of endocardial activation mapping with this system during sinus rhythm and several types of supraventricular and ventricular tachycardias.

Methods and Results
—Fifteen patients were studied. Accuracy measurements were performed in 5 of them (patients 5, 6, 7, 8, and 14). The distances between two subsequent catheter positions in the inferior caval vein as determined by the nonfluoroscopic mapping system were compared with measurements made with calipers by four independent investigators using identification marks on the catheter shaft. The difference between these two methods was 0.95±0.8 mm. In 15 patients, activation of the right atrium and/or the right or left ventricle was recorded during sinus rhythm. Three-dimensional activation maps were constructed in patients with atrial and ventricular tachycardias and Wolff-Parkinson-White syndrome.

Conclusions
—With this new nonfluoroscopic mapping technique, accurate positioning of the catheter tip is possible. A three-dimensional activation map can be reconstructed during sinus rhythm and during supraventricular and ventricular tachycardias of different compartments of the heart.
Profound Underestimation of Glucose Uptake by [
18
F]2-Deoxy-2-fluoroglucose in Reperfused Rat Heart Muscle
Authors: Doenst Torsten , Taegtmeyer Heinrich
Published: June 2012

Background
—[
18
F]2-deoxy-2-fluoroglucose (FDG) is widely used as a tracer for glucose uptake in ischemic heart muscle. We tested the effects of low-flow ischemia and reperfusion on the ratio of tracer/tracee (lumped constant, LC).

Methods and Results
—Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing only glucose 5 mmol/L (group 1) or glucose 5 mmol/L plus oleate 0.4 mmol/L (group 2, fed; group 3, fasted). Dynamic glucose uptake was measured simultaneously with [2-
3
H]glucose and with FDG. After 20 minutes, coronary flow was reduced by 75% for 30 minutes before it was returned to control conditions for the final 20 minutes. Hexokinase activity in the cytosolic and mitochondrial fractions and tissue metabolites were determined. Rates of glucose uptake were highest when glucose was the only substrate. Glucose uptake, FDG uptake, and the LC increased during ischemia only in group 3. There was no change of these parameters during ischemia in groups 1 and 2. FDG uptake decreased significantly with reperfusion in groups 2 and 3, and there was a striking fall in the LC (from >1.0 to <0.2,
P
<.001). The fall in the LC was associated with a significant increase in intracellular free glucose. Neither ischemia nor reperfusion affected the kinetic properties of hexokinase.

Conclusions
—FDG profoundly underestimates glucose uptake during reperfusion in the presence of fatty acids. In the fasted state, however, FDG overestimates glucose uptake during ischemia. The results indicate limitations in the use of FDG to quantify myocardial glucose uptake in human heart.
Vein Graft Stenosis and the Heparin Responsiveness of Human Vascular Smooth Muscle Cells
Authors: Refson Jonathan S. , Schachter Michael , Patel Mahendra K. , Hughes Alun D. , Munro Euan , Chan Philip , Wolfe John H. N. , Sever Peter S.
Published: June 2012

Background
—Vascular smooth muscle cell (VMSC) proliferation is an essential component of myointimal hyperplasia, which is implicated in the failure of 30% to 50% of vascular interventions, such as coronary angioplasty and peripheral vein grafting. We have shown that cells derived from stenotic lesions in infrainguinal vein grafts were significantly more resistant than controls to growth inhibition by heparin.

Methods and Results
—In a prospective study, we correlated antiproliferative responses to heparin in vitro with graft patency after 1 year. Sixty-two patients with infrainguinal vein grafts were entered into a graft surveillance program for ≥1 year. At operation, saphenous vein segments were explanted for VSMC culture. Cell proliferation in response to fetal calf serum was later determined in the presence and absence of heparin. In 35 cell cultures, including 13 from the above-mentioned patients, [
3
H]heparin binding was also estimated. VSMCs from patients with patent grafts were significantly more sensitive to growth inhibition by heparin than cells from patients with stenoses (median, 54% versus 20.9%,
P
<0.001), and [
3
H]heparin binding was strongly correlated with inhibition of proliferation (
r
=0.81).

Conclusions
—Responsiveness to heparin in cultured VSMCs is a strong predictor of outcome for infrainguinal vein grafts, and reduced sensitivity to heparin is correlated with decreased heparin binding. Relative resistance to the antiproliferative action of heparin may be a marker for aberrant regulation of VSMC growth.