bluuebunny/crossref_metadata_2025 huggingface dataset:
Ventricular Pacing With Premature Excitation for Treatment of Hypertensive-Cardiac Hypertrophy With Cavity-Obliteration
Authors: Kass David A. , Chen Chen-Huan , Talbot Maurice W. , Rochitte Carlos E. , Lima João A. C. , Berger Ronald D. , Calkins Hugh
Published: June 2012

Background
—Hypertensive left ventricular hypertrophy with supranormal systolic ejection and distal cavity obliteration (HHCO) can result in debilitating exertional fatigue and dyspnea. Dual-chamber pacing with ventricular preactivation generates discoordinate contraction, which can limit cavity obliteration and thereby increase potential ejection reserve. Accordingly, we hypothesized that pacing may improve exercise tolerance long-term in this syndrome.

Methods and Results
—Dual-chamber pacemakers were implanted in 9 patients with exertional dyspnea caused by HHCO. Intrinsic atrial rate was sensed, and ventricular preactivation was achieved by shortening the atrial-ventricular delay. Pacing was on or off for successive 3-month periods (randomized, double-blind, crossover design), followed by 6 additional pacing-on months. Metabolic exercise testing, quality-of-life assessment, and rest and dobutamine-stress echocardiographic/Doppler data were obtained. After 3 months of pacing-on, exercise duration rose from 324±133 to 588±238 s (mean±SD;
P
=0.001, with 7 of 9 patients improving ≥30%), and maximal oxygen consumption increased from 13.6±2.9 to 16.7±3.3 mL of O
2
· min
−1
· kg
−1
(
P
<0.02). Both parameters were little changed from baseline during the pacing-off period. Improved exercise capacity persisted at 1-year follow-up. Clinical symptoms and activities of daily living improved during the pacing-on period and stayed improved at 1 year, but they were little changed during the pacing-off period. Despite similar basal values, stroke volume (
P
<0.001) and cardiac output (
P
<0.02) increased with dobutamine stimulation 2 to 3 times more after 1 year of follow-up as compared with baseline.

Conclusions
—Long-term dual-chamber pacing can improve exercise capacity, cardiac reserve, clinical symptoms, and activities of daily living in patients with HHCO. This therapy may provide a novel alternative for patients in whom traditional pharmacological treatment proves inadequate.
Fully Discharging Phases
Authors: Yamanouchi Yoshio , Brewer James E. , Olson Kenneth F. , Mowrey Kent A. , Mazgalev Todor N. , Wilkoff Bruce L. , Tchou Patrick J.
Published: June 2012

Background
—Phase-2 voltage and maximum pulse width are dependent on phase-1 pulse characteristics in a single-capacitor biphasic waveform. The use of 2 separate output capacitors avoids these limitations and may allow waveforms with lower defibrillation thresholds. A previous report also suggested that the optimal tilt may be >70%. This study was designed to determine an optimal biphasic waveform by use of a combination of 2 separate and fully (95% tilt) discharging capacitors.

Methods and Results
—We performed 2 external defibrillation studies in a pig ventricular fibrillation model. In group 1, 9 waveforms from a combination of 3 phase-1 capacitor values (30, 60, and 120 μF) and 3 phase-2 capacitor values (0=monophasic, 1/3, and 1.0 times the phase-1 capacitor) were tested. Biphasic waveforms with phase-2 capacitors of 1/3 times that of phase 1 provided the highest defibrillation efficacy (stored energy and voltage) compared with corresponding monophasic and biphasic waveforms with the same capacitors in both phases except for waveforms with a 30-μF phase-1 capacitor. In group 2, 10 biphasic waveforms from a combination of 2 phase-1 capacitor values (30 and 60 μF) and 5 phase-2 capacitor values (10, 20, 30, 40, and 50 μF) were tested. In this range, phase-2 capacitor size was more critical for the 30-μF phase-1 than for the 60-μF phase-1 capacitor. The optimal combinations of fully discharging capacitors for defibrillation were 60/20 and 60/30 μF.

Conclusions
—Phase-2 capacitor size plays an important role in reducing defibrillation energy in biphasic waveforms when 2 separate and fully discharging capacitors are used.
Influence of Pre-PTCA Strategy and Initial PTCA Result in Patients With Multivessel Disease
Authors: Kip Kevin E. , Bourassa Martial G. , Jacobs Alice K. , Schwartz Leonard , Feit Frederick , Alderman Edwin L. , Weiner Bonnie H. , Weiss Melvin B. , Kellett Mirle A. , Sharaf Barry L. , Dimas Alexios P. , Jones Robert H. , Sopko George , Detre Katherine M.
Published: June 2012

Background
—In PTCA patients with multivessel coronary artery disease, incomplete revascularization (IR) is the result of both pre-PTCA strategy and initial lesion outcome. The unique contribution of these components on long-term patient outcome is uncertain.

Methods and Results
—From the Bypass Angioplasty Revascularization Investigation (BARI), 2047 patients who underwent first-time PTCA were evaluated. Before enrollment, all significant lesions were assessed by the PTCA operator for clinical importance and intention to dilate. Complete revascularization (CR) was defined as successful dilatation of all clinically relevant lesions. Planned CR was indicated in 65% of all patients. More lesions were intended for PTCA in these patients compared with those with planned IR (2.8 versus 2.1). Successful dilatation of all intended lesions occurred in 45% of patients with planned CR versus 56% with planned IR (
P
<0.001). In multivariable analysis, planned IR (versus planned CR), initial lesions attempted (not all versus all intended lesions attempted), and initial lesion outcome (not all versus all attempted lesions successful) were unrelated to 5-year risk of cardiac death or death/myocardial infarction but were all independently related to risk of CABG.

Conclusions
—Overall, a pre-PTCA strategy of IR in BARI-like patients appears comparable to a strategy of CR except for a higher need for CABG. Whether the use of new devices may attenuate the elevated risk of CABG in patients with multivessel disease and planned IR remains to be determined.
Infarct Size Measured by Single Photon Emission Computed Tomographic Imaging With
99m
Tc-Sestamibi
Authors: Gibbons Raymond J. , Miller Todd D. , Christian Timothy F.
Published: June 2012

Background
—Use of mortality as an end point in randomized trials of reperfusion therapy requires increasingly large sample sizes to test advances compared with existing therapy, which is already highly effective. There has been a growing interest in infarct size measurements by
99m
Tc-sestamibi SPECT (single photon emission computed tomographic) imaging as a surrogate end point.

Methods and Results
—We reviewed the reports published in English regarding infarct size measurements by
99m
Tc-sestamibi. Four separate lines of published evidence support the validity of SPECT imaging with
99m
Tc-sestamibi for determination of infarct size. This end point has been used in a total of 7 randomized trials—1 single center and 6 multicenter. The end point compares favorably with left ventricular function and infarct size measurements with the use of other radiopharmaceuticals. The most important limitation of this approach is the absence thus far of a randomized trial that has shown a corresponding decrease in mortality in association with a therapy that reduces infarct size.

Conclusions
—SPECT imaging with
99m
Tc-sestamibi is the best available measurement tool for infarct size. It has already served as an end point in early pilot studies to evaluate potential efficacy and in dose-ranging studies. It has the potential to serve as a surrogate end point to uncover advantages of new therapies that may be equivalent to existing therapies with respect to early mortality.
Augmented Cardiac Cardiotrophin-1 in Experimental Congestive Heart Failure
Authors: Jougasaki Michihisa , Tachibana Issei , Luchner Andreas , Leskinen Hanna , Redfield Margaret M. , Burnett John C.
Published: June 2012

Background
—Cardiotrophin-1 (CT-1) is a potent hypertrophic factor discovered by coupling expression cloning in a mouse embryonic stem cell–based model of cardiogenesis.

Methods and Results
—The present study was designed to investigate the potential activation of atrial and ventricular CT-1 expression in pacing-induced experimental congestive heart failure (CHF) and its relationship to left ventricular hypertrophy by the method of Northern blot analysis and immunohistochemistry. We used a canine model of pacing-induced experimental CHF based on hemodynamic and neurohumoral characteristics that closely mimic human dilated cardiomyopathy. Northern blot analysis demonstrated that CT-1 gene expression was present in normal atrium and ventricle and was increased in CHF hearts. There was a positive correlation between ventricular CT-1 mRNA and left ventricular mass index. Immunohistochemistry revealed positive immunostaining in the atrial and ventricular cardiomyocytes from both normal and CHF hearts. CT-1 immunoreactivity was more intense in the atrium and ventricle from CHF hearts than in normal hearts.

Conclusions
—The present study demonstrates that both atrium and ventricle synthesize CT-1 and that cardiac production of CT-1 is augmented in a canine model of experimental CHF. This study also demonstrates that ventricular CT-1 mRNA correlates with left ventricular hypertrophy, suggesting that CT-1 plays an important role in the structural remodeling that characterizes CHF.
Heat Shock Protein 47 Is Expressed in Fibrous Regions of Human Atheroma and Is Regulated by Growth Factors and Oxidized Low-Density Lipoprotein
Authors: Rocnik Edward , Chow Lawrence H. , Pickering J. Geoffrey
Published: June 2012

Background
—Heat shock protein 47 (Hsp47) is a stress protein that may act as a chaperone for procollagen. Its involvement in atherosclerosis is unknown.

Methods and Results
—Hsp47 expression in human coronary arteries was assessed by immunostaining. Strong focal expression was evident in atherosclerotic, but not normal, arteries and was prevalent in the collagenous regions. Double immunostaining revealed that all cells expressing type I procollagen also expressed Hsp47. Moreover, parallel regulation of proα1(I)collagen and Hsp47 mRNA expression occurred with cultured human smooth muscle cells stimulated with transforming growth factor-β1 or fibroblast growth factor-2. However, a proportion of Hsp47-expressing cells in plaque did not express type I procollagen, and this pattern could be reproduced in culture. Heat shock and oxidized LDL stimulated the expression of Hsp47 mRNA by smooth muscle cells, without a concomitant rise in proα1(I)collagen expression.

Conclusions
—These findings identify Hsp47 as a novel constituent of human coronary atheroma. Its localization to the fibrous cap, regulation by growth factors in parallel with type I procollagen, and selective upregulation by stress raise the possibility that Hsp47 is a determinant of plaque stability.
Ambient Pollution and Heart Rate Variability
Authors: Gold Diane R. , Litonjua Augusto , Schwartz Joel , Lovett Eric , Larson Andrew , Nearing Bruce , Allen George , Verrier Monique , Cherry Rebecca , Verrier Richard
Published: June 2012

Background
—We investigated associations between ambient pollution levels and cardiovascular function in a repeated measures study including 163 observations on twenty-one 53- to 87-year-old active Boston residents observed up to 12 times from June to September 1997. Particles with aerodynamic diameter ≤2.5 μm (PM
2.5
) were measured continuously using a tapered element oscillating microbalance.

Methods and Results
—The protocol involved 25 minutes per week of continuous Holter ECG monitoring, including 5 minutes of rest, 5 minutes of standing, 5 minutes of exercise outdoors, 5 minutes of recovery, and 20 cycles of slow breathing. Heart rate variability (HRV) was assessed through time domain variables: the standard deviation of normal RR intervals (SDNN) and the square root of the mean of the squared differences between adjacent normal RR intervals (r-MSSD). Mean 4-hour PM
2.5
levels ranged from 3 to 49 μg/m
3
; 1-hour ozone levels ranged from 1 to 77 ppb. In multivariate analyses, significantly less HRV (SDNN and r-MSSD) was associated with elevated PM
2.5
. During slow breathing, a reduction in r-MSSD of 6.1 ms was associated with an interquartile (14.3 μg/m
3
) increase in PM
2.5
during the hour of and the 3 hours previous to the Holter session (
P
=0.006). During slow breathing, a multiple pollution model was associated with a reduction in r-MSSD of 5.4 ms (
P
=0.02) and 5.5 ms (
P
=0.03) for interquartile changes in PM
2.5
and ozone, respectively, resulting in a combined effect equivalent to a 33% reduction in the mean r-MSSD.

Conclusions
—Particle and ozone exposure may decrease vagal tone, resulting in reduced HRV.
Hypoxia-Induced Pulmonary Blood Redistribution in Subjects With a History of High-Altitude Pulmonary Edema
Authors: Hanaoka Masayuki , Tanaka Masao , Ge Ri-Li , Droma Yunden , Ito Atsuko , Miyahara Takashige , Koizumi Tomonobu , Fujimoto Keisaku , Fujii Tadashige , Kobayashi Toshio , Kubo Keishi
Published: June 2012

Background
—Pulmonary hypertension has been suggested to play an important role in development of high-altitude pulmonary edema (HAPE), and individual susceptibility has been suggested to be associated with enhanced pulmonary vascular response to hypoxia. We hypothesized that much greater pulmonary vasoconstriction would be induced by acute alveolar hypoxia in HAPE-susceptible (HAPE-s) subjects and that changes in pulmonary blood flow distribution could be demonstrated by radionuclide study.

Methods and Results
—We performed ventilation-perfusion scintigraphy in 8 HAPE-s subjects and 5 control subjects while each was in the supine position and acquired functional images of pulmonary blood flow and ventilation under separate normoxic and hypoxic (arterial oxygen saturation, 70%) conditions. We also measured acceleration time/right ventricular ejection time (AcT/RVET) with Doppler echocardiography under each condition in both groups. Moreover, we assayed human leukocyte antigen (HLA) alleles serologically in the HAPE-s group. Pulmonary blood flow was significantly shifted from the basal lung region to the apical lung region under hypoxia in HAPE-s subjects, although no significant change in regional ventilation was observed. With Doppler echocardiography, HAPE-s subjects showed increased pulmonary arterial pressure during hypoxia compared with control subjects. The magnitude of cephalad redistribution of lung blood flow was significantly higher in the HLA-DR6–positive than in HLA-DR6–negative HAPE-s subjects.

Conclusions
—These findings suggest that acute hypoxia induces much greater cephalad redistribution of pulmonary blood flow that results from exaggerated vasoconstriction in the basal lung in HAPE-s subjects. Furthermore, pulmonary vascular hyperreactivity to hypoxia may be associated with HLA-DR6.
Monoclonal Anti-CD18 Antibody Prevents Transcellular Biosynthesis of Cysteinyl Leukotrienes In Vitro and In Vivo and Protects Against Leukotriene-Dependent Increase in Coronary Vascular Resistance and Myocardial Stiffness
Authors: Sala Angelo , Rossoni Giuseppe , Berti Ferruccio , Buccellati Carola , Bonazzi Albino , Maclouf Jacques , Folco Giancarlo
Published: June 2012

Background
—Cysteinyl leukotrienes (cys-LT) can constrict small and large vessels and increase vascular permeability. Formation of cys-LT arising from polymorphonuclear leukocytes (PMNL) and endothelial cell cooperation (transcellular synthesis) led to the hypothesis that PMNL–endothelial cell adhesion may represent a key step toward the formation of vasoactive cys-LT.

Methods and Results
—We studied the effect of pretreatment with a monoclonal antibody directed against the CD18 subunit of PMNL β
2
-integrin on the synthesis of cys-LT in a PMNL-perfused isolated rabbit heart in vitro and in a model of permanent ligature of the left descending coronary artery in the rabbit in vivo. Challenge of PMNL-perfused rabbit hearts with formyl-met-leu-phe (0.3 μmol/L) caused synthesis of cys-LT and increase in coronary perfusion pressure that were prevented by the anti-CD18 antibody. Similar results were obtained with the use of A-23187 (0.5 μmol/L) as a challenge. Persistence of PMNL-associated myeloperoxidase activity in the perfusion buffer was observed in the presence of the anti-CD18 antibody, indicating decreased PMNL infiltration. Coronary artery ligature in vivo increased urinary excretion of leukotriene E
4
, supporting the activation of the 5-lipoxygenase pathway during experimental acute myocardial infarction. Pretreatment with the anti-CD18 antibody (1 mg/kg) prevented the increase in leukotriene E
4
excretion.

Conclusions
—These data support the importance of adhesion in promoting cys-LT formation, originating from PMNL–endothelial cell cooperation, and contributing to myocardial stiffness and increased coronary resistance.
Oxidized Lipoproteins Degrade the Endothelial Surface Layer
Authors: Vink Hans , Constantinescu Alina A. , Spaan Jos A. E.
Published: June 2012

Background
—Flowing erythrocytes and platelets are separated from the luminal endothelial cell (EC) surface by a 0.5-μm-wide space named the endothelial surface layer. We hypothesized that the disruption of the endothelial surface layer by oxidized low-density lipoproteins (Ox-LDL) contributes to atherogenic increases in vascular wall adhesiveness.

Methods and Results
—The hamster cremaster muscle preparation was used for intravital microscopic observation of the distance between erythrocytes and the capillary EC surface. Moderate Ox-LDL was prepared by exposing native LDL to CuSO
4
for 6 hours. The dimension of the EC surface layer averaged 0.6±0.1 μm during control situations, but a bolus intravenous injection of Ox-LDL (0.4 mg/100 g of body weight) transiently diminished the EC surface layer by 60% within 25 minutes, which correlated with a transient increase in the number of platelet-EC adhesions. Combined administration of superoxide dismutase and catalase completely blocked the effect of Ox-LDL on the dimension of the EC surface layer and inhibited platelet-EC adhesion.

Conclusions
—Oxygen-derived free radicals mediate the disruption of the EC surface layer and increase vascular wall adhesiveness by Ox-LDL.
Relationship Between Serum Amino-Terminal Propeptide of Type III Procollagen and Changes of Left Ventricular Function After Acute Myocardial Infarction
Authors: Poulsen Steen H. , Høst Nis B. , Jensen Svend E. , Egstrup Kenneth
Published: June 2012

Background
—The amino-terminal propeptide of type III procollagen (PIIINP) is a marker of type III collagen synthesis, which has previously been shown to correlate with infarct size in nonthrombolyzed myocardial infarction (MI) and to provide prognostic information after MI.

Methods and Results
—The relationship between PIIINP and changes of left ventricular (LV) function was studied in 47 consecutive patients with first acute MI and 16 control subjects. Serum PIIINP analysis was measured daily during hospitalization and on days 90, 180, and 360. LV function was assessed by echocardiography on days 1, 5, 90, and 360. Patients with MI were stratified according to their serum PIIINP value at day 4 (group A, ≤5.0 μg/L; group B, >5.0 μg/L). On arrival, LV function and size were comparable between groups A (n=31) and B (n=16). LV ejection fraction, initially depressed (day 1: group A, 47±7% versus group B, 47±8%;
P
=NS), increased significantly in group A (day 360: 54±8%,
P
<0.001) but was unchanged in group B (day 360: 43±8%,
P
=NS). LV volumes increased significantly in group B (
P
<0.05) but not in group A. Furthermore, patients in group B developed signs of restrictive LV diastolic filling. Multivariate regression analysis identified PIIINP >5.0 μg/L and deceleration ≤140 ms as independent predictors of cardiac death or complicating heart failure during follow-up.

Conclusions
—PIIINP assessed in the subacute phase of MI relates to long-term changes of LV function and provides clinical prognostic information.
Roles for Insulin Receptor, PI3-Kinase, and
Akt
in Insulin-Signaling Pathways Related to Production of Nitric Oxide in Human Vascular Endothelial Cells
Authors: Zeng Guangyuan , Nystrom Frederick H. , Ravichandran Lingamanaidu V. , Cong Li-Na , Kirby Martha , Mostowski Howard , Quon Michael J.
Published: June 2012

Background
—Previously, we demonstrated that insulin stimulates production of nitric oxide (NO) in endothelial cells. However, specific insulin-signaling pathways mediating production of NO have not been elucidated.

Methods and Results
—We developed methods for transfection of human umbilical vein endothelial cells (HUVECs) and direct measurement of NO to begin defining insulin-signaling pathways related to NO production. HUVECs were cotransfected with enhanced Green Fluorescent Protein (
eGFP
) and another gene of interest. Transfection efficiencies >95% were obtained by selecting cells expressing
eGFP
. Overexpression of insulin receptors in HUVECs resulted in an ≈3-fold increase in production of NO in response to insulin. In contrast, HUVECs overexpressing a tyrosine kinase–deficient mutant insulin receptor had a dose-response curve similar to that of control cells. Overexpression of inhibitory mutants of either phosphatidylinositol 3-kinase (PI3K) or
Akt
resulted in nearly complete inhibition of insulin-stimulated production of NO. Overexpression of an inhibitory mutant of
Ras
had a much smaller effect.

Conclusions
—Receptor kinase activity is necessary to mediate production of NO through the insulin receptor. Both PI3K and
Akt
contribute importantly to this process, whereas the contribution of
Ras
is small.
Results of Maze Surgery for Lone Paroxysmal Atrial Fibrillation
Authors: Jessurun Emile R. , van Hemel Norbert M. , Defauw Jo A. M. T. , Stofmeel Monique A. M. , Kelder Johannes C. , Brutel de la Rivière Aart , Ernst Jef M. P. G.
Published: June 2012

Background
—If drug refractoriness to paroxysmal atrial fibrillation (PAF) occurs, arrhythmia surgery that involves channelling and the exclusion of specific atrial areas can abolish atrial fibrillation. The purpose of this study was to establish the effectiveness and safety of maze III surgery to abolish PAF.

Methods and Results
—Surgery was performed in 41 selected patients who had long-standing, symptomatic, drug-refractory, lone PAF. At discharge, 35 patients (85%) were arrhythmia free, and 6 patients (15%) showed PAF and paroxysmal atrial tachycardia. Death or stroke did not occur during a mean follow-up of 31±16 months. At the end of follow-up, 39 patients (95%) had no PAF; however, in 2 patients (5%), PAF persisted and eventually required His bundle ablation and pacing. Three months after surgery, nodal escape rhythm was observed in only 1 patient, whereas sick-sinus syndrome emerged late after surgery in 2 patients. Antiarrhythmic drugs were used in 20% of patients during follow-up. The quality of life improved markedly after surgery and remained unchanged afterward. Echocardiographic findings did not alter, but exercise capacity increased.

Conclusions
—This pilot study demonstrates the effectiveness and safety of maze III surgery for lone PAF. In patients without sick-sinus syndrome, this intervention offers a sensible alternative to His bundle ablation and lifelong pacemaker dependency.
Enhanced Cardiac Contractility After Gene Transfer of V2 Vasopressin Receptors In Vivo by Ultrasound-Guided Injection or Transcoronary Delivery
Authors: Weig Hans-Jörg , Laugwitz Karl-Ludwig , Moretti Alessandra , Kronsbein Kai , Städele Christian , Brüning Stefan , Seyfarth Melchior , Brill Thomas , Schömig Albert , Ungerer Martin
Published: June 2012

Background
—Systemic levels of arginine vasopressin (AVP) are increased in congestive heart failure, resulting in vasoconstriction and reduced cardiac contractility via V
1
vasopressin receptors. V
2
vasopressin receptors (V2Rs), which promote activation of adenylyl cyclase, are physiologically expressed only in the kidney and are absent in the myocardium. Heterologous expression of V2Rs in the myocardium could result in a positive inotropic effect by using the endogenous high concentrations of AVP in heart failure.

Methods and Results
—We tested gene transfer with a recombinant adenovirus for the human V2R (Ad-V2R) to stimulate contractility of rat or rabbit myocardium in vivo. Ultrasound-guided direct injection or transcoronary delivery of adenovirus in vivo resulted in recombinant receptor expression in the myocardial target area, leading to a substantial increase in [
3
H]AVP binding. In 50% of the cardiomyocytes isolated from the directly injected area, single-cell shortening measurements detected a significant increase in contraction amplitude after exposure to AVP or the V2R-specific desmopressin (DDAVP). Echocardiography of the target myocardial area documented a marked increase in local fractional shortening after systemic administration of DDAVP in V2R-expressing animals but not in control virus–treated hearts. Simultaneous measurement of global contractility (dP/dt
max
) confirmed a positive inotropic effect of DDAVP on left ventricular function in the Ad-V2R–injected animals.

Conclusions
—Adenoviral gene transfer of the V2R into the myocardium increases cardiac contractility in vivo. Heterologous expression of cAMP-forming receptors in the myocardium could lead to novel strategies in the therapy of congestive heart failure by bypassing the desensitized β-adrenergic receptor–signaling cascade.
Early and Delayed Consequences of β
2
-Adrenergic Receptor Overexpression in Mouse Hearts
Authors: Liggett Stephen B. , Tepe Nicole M. , Lorenz John N. , Canning Amy M. , Jantz Tamara D. , Mitarai Sayaka , Yatani Atsuko , Dorn Gerald W.
Published: June 2012

Background
—Transgenic cardiac β
2
-adrenergic receptor (AR) overexpression has resulted in enhanced signaling and cardiac function in mice, whereas relatively low levels of transgenically expressed G
αs
or β
1
AR have resulted in phenotypes of ventricular failure. Potential relationships between the levels of βAR overexpression and biochemical, molecular, and physiological consequences have not been reported.

Methods and Results
—We generated transgenic mice expressing β
2
AR at 3690, 7120, 9670, and 23 300 fmol/mg in the heart, representing 60, 100, 150, and 350 times background βAR expression. All lines showed enhanced basal adenylyl cyclase activation but a decrease in forskolin- and NaF-stimulated adenylyl cyclase activities. Mice of the highest-expressing line developed a rapidly progressive fibrotic dilated cardiomyopathy and died of heart failure at 25±1 weeks of age. The 60-fold line exhibited enhanced basal cardiac function without increased mortality when followed for 1 year, whereas 100-fold overexpressors developed a fibrotic cardiomyopathy and heart failure, with death occurring at 41±1 weeks of age. Adenylyl cyclase activation did not correlate with early or delayed decompensation. Propranolol administration reduced baseline +dP/dt
max
to nontransgenic levels in all β
2
AR transgenics except the 350-fold overexpressors, indicating that spontaneous activation of β
2
AR was present at this level of expression.

Conclusions
—These data demonstrate that the heart tolerates enhanced contractile function via 60-fold β
2
AR overexpression without detriment for a period of ≥1 year and that higher levels of expression result in either aggressive or delayed cardiomyopathy. The consequences for enhanced βAR function in the heart appear to be highly dependent on which signaling elements are increased and to what extent.
“Bystander” Chest Compressions and Assisted Ventilation Independently Improve Outcome From Piglet Asphyxial Pulseless “Cardiac Arrest”
Authors: Berg Robert A. , Hilwig Ronald W. , Kern Karl B. , Ewy Gordon A.
Published: June 2012

Background
—Bystander cardiopulmonary resuscitation (CPR) without assisted ventilation may be as effective as CPR with assisted ventilation for ventricular fibrillatory cardiac arrests. However, chest compressions alone or ventilation alone is not effective for complete asphyxial cardiac arrests (loss of aortic pulsations). The objective of this investigation was to determine whether these techniques can independently improve outcome at an earlier stage of the asphyxial process.

Methods and Results
—After induction of anesthesia, 40 piglets (11.5±0.3 kg) underwent endotracheal tube clamping (6.8±0.3 minutes) until simulated pulselessness, defined as aortic systolic pressure <50 mm Hg. For the 8-minute “bystander CPR” period, animals were randomly assigned to chest compressions and assisted ventilation (CC+V), chest compressions only (CC), assisted ventilation only (V), or no bystander CPR (control group). Return of spontaneous circulation occurred during the first 2 minutes of bystander CPR in 10 of 10 CC+V piglets, 6 of 10 V piglets, 4 of 10 CC piglets, and none of the controls (CC+V or V versus controls,
P
<0.01; CC+V versus CC and V combined,
P
=0.01). During the first minute of CPR, arterial and mixed venous blood gases were superior in the 3 experimental groups compared with the controls. Twenty-four-hour survival was similarly superior in the 3 experimental groups compared with the controls (8 of 10, 6 of 10, 5 of 10, and 0 of 10,
P
<0.05 each).

Conclusions
—Bystander CPR with CC+V improves outcome in the early stages of apparent pulseless asphyxial cardiac arrest. In addition, this study establishes that bystander CPR with CC or V can independently improve outcome.
The Value of Magnetic Resonance Imaging of the Left Ventricular Outflow Tract in Patients With Hypertrophic Obstructive Cardiomyopathy After Septal Artery Embolization
Authors: Schulz-Menger Jeanette , Strohm Oliver , Waigand Jürgen , Uhlich Frank , Dietz Rainer , Friedrich Matthias G.
Published: June 2012

Background
—We tested the value of magnetic resonance imaging (MRI) in the follow-up of patients with hypertrophic obstructive cardiomyopathy after septal artery embolization. MRI provides a noninvasive visualization of transplanar turbulent flow in order to quantify left ventricular outflow tract obstruction.

Methods and Results
—We followed 10 patients who were treated with septal artery embolization for 12 months. We used gradient echo sequences to document continuous improvement of the outflow tract area and T1- and T2-weighted spin echo sequences to visualize myocardial infarction. A continuous, but not linear, improvement of the outflow tract area occurred after septal artery embolization during the 12-month follow-up period. The improvement of the outflow tract area correlated well with the amelioration of symptoms (r
2
=0.86).

Conclusions
—We conclude that MRI reliably detects the degree of obstruction in patients with hypertrophic obstructive cardiomyopathy. This modality may be especially useful for follow-up after septal artery embolization.
Ciprofibrate Therapy Improves Endothelial Function and Reduces Postprandial Lipemia and Oxidative Stress in Type 2 Diabetes Mellitus
Authors: Evans Marc , Anderson Richard A. , Graham John , Ellis Gethin R. , Morris Keith , Davies Stephen , Jackson Simon K. , Lewis Malcolm J. , Frenneaux Michael P. , Rees Alan
Published: June 2012

Background
—Exaggerated postprandial lipemia (PPL) is a factor in atherogenesis, involving endothelial dysfunction and enhanced oxidative stress. We examined the effect of ciprofibrate therapy on these parameters in type 2 diabetes mellitus.

Methods and Results
—Twenty patients entered a 3-month, double-blind, placebo-controlled study. Each subject was studied fasting and after a fatty meal, at baseline, and after 3 months of treatment. Glucose and lipid profiles were measured over an 8-hour postprandial period. Endothelial function (flow-mediated endothelium-dependent vasodilatation [FMD]) and oxidative stress (electron paramagnetic resonance spectroscopy) were measured after fasting and 4 hours postprandially. At baseline, both groups exhibited similar PPL and deterioration in endothelial function. After ciprofibrate, fasting and postprandial FMD values were significantly higher (from 3.8±1.8% and 1.8±1.3% to 4.8±1.1% and 3.4±1.1%;
P
<0.05). This was mirrored by a fall in fasting and postprandial triglycerides (3.1±2.1 and 6.6±4.1 mmol/L to 1.5±0.8 and 2.8±1.3 mmol/L,
P
<0.05). Fasting and postprandial HDL cholesterol was also elevated (0.9±0.1 and 0.8±0.1 mmol/L and 1.2±0.2 and 1.2±0.1 mmol/L,
P
<0.05). There were no changes in total or LDL cholesterol. Fasting and postprandial triglyceride enrichment of all lipoproteins was attenuated, with cholesterol depletion of VLDL and enrichment of HDL. There were similar postprandial increases in oxidative stress in both groups at baseline, which was significantly attenuated by ciprofibrate (0.3±0.6 versus 1.5±1.1 U,
P
<0.05).

Conclusions
—This study demonstrates that fibrate therapy improves fasting and postprandial endothelial function in type 2 diabetes. Attenuation of PPL and the associated oxidative stress, with increased HDL cholesterol levels, may be important.
Endothelial Dysfunction Is Detectable in Young Normotensive First-Degree Relatives of Subjects With Type 2 Diabetes in Association With Insulin Resistance
Authors: Balletshofer Bernd M. , Rittig Kilian , Enderle Markus D. , Volk Anette , Maerker Elke , Jacob Stephan , Matthaei Stephan , Rett Kristian , Häring Hans U.
Published: June 2012

Background
—-Endothelial dysfunction (ED) is regarded as an early step in the development of atherosclerosis. Among the pathogenetic factors leading to atherosclerosis, the role of insulin resistance and hyperinsulinemia as independent risk factors is still under debate. In this study, we examined the association between ED and insulin resistance in normotensive and normoglycemic first-degree relatives (FDRs) of patients with type 2 diabetes mellitus (DM).

Methods and Results
—-Endothelium-dependent and -independent vasodilation of the brachial artery was measured with high-resolution ultrasound (13 MHz) in 53 normotensive FDRs (21 men, 32 women; mean age, 35 years) with normal oral glucose tolerance, 10 age- and sex-matched normal control subjects, and 25 DM patients (mean age, 57 years). According to the tertiles of the clamp-derived glucose metabolic clearance rate (MCR), the FDRs were further classified as insulin resistant with an MCR ≤5.8 mL · kg
−1
· min
−1
, insulin sensitive (IS) with an MCR ≥7.8 mL · kg
−1
· min
−1
, and borderline with an MCR of 5.9 to 7.7 mL · kg
−1
· min
−1
. Flow-associated dilation was 4.1±0.9% in insulin-resistant FDRs, 6.7±1.1% in borderline FDRs, 9.0±1.2% in insulin-sensitive FDRs (
P
=0.002), 7.7±2.9% in control subjects (
P
=NS versus FDRs), and 3.8±1.0% in DM patients (
P
=0.03). In multiple regression analysis, low MCR was significantly correlated with ED independent of age, sex, smoking, body mass index, percent body fat, serum insulin, and lipids.

Conclusions
—–There is a significant association between ED and insulin resistance in young FDRs of DM subjects independent of the classic cardiovascular risk factors.
Dilated Cardiomyopathy and Sensorineural Hearing Loss
Authors: Schönberger Jost , Levy Hara , Grünig Ekkehard , Sangwatanaroj Somkiat , Fatkin Diane , MacRae Calum , Stäcker Hinrich , Halpin Christopher , Eavey Roland , Philbin Edward F. , Katus Hugo , Seidman J. G. , Seidman Christine E.
Published: June 2012

Background
—Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNHL) are prevalent disorders that occur alone or as components of complex multisystem syndromes. Multiple genetic loci have been identified that, when mutated, cause DCM or SNHL. However, the isolated coinheritance of these phenotypes has not been previously recognized.

Methods and Results
—Clinical evaluations of 2 kindreds demonstrated autosomal-dominant transmission and age-related penetrance of both SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss was evident by late adolescence, whereas ventricular dysfunction produced progressive congestive heart failure after the fourth decade. DNA samples from the larger kindred (29 individuals) were used to perform a genome-wide linkage study. Polymorphic loci on chromosome 6q23 to 24 were coinherited with the disease (maximum logarithm of odds score, 4.88 at locus
D6S2411
). The disease locus must lie within a 2.8 cM interval between loci
D6S975
and
D6S292
, a location that overlaps an SNHL disease locus (
DFNA10
). However,
DFNA10
does not cause cardiomyopathy. The
epicardin
gene, which encodes a transcription factor expressed in the myocardium and cochlea, was assessed as a candidate gene by nucleotide sequence analysis; no mutations were identified.

Conclusions
—A syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at 6q23 to 24 (locus designated
CMD1J
). Recognition of this cardioauditory disorder allows for the identification of young adults at risk for serious heart disease, thereby enabling early intervention. Definition of the molecular cause of this syndrome may provide new information about important cell physiology common to both the ear and heart.
Assessment of Aortic Line of Elasticity Using Polynomial Regression Analysis
Authors: Stefanadis Christodoulos , Dernellis John , Tsiamis Eleftherios , Diamantopoulos Leonidas , Michaelides Andreas , Toutouzas Pavlos
Published: June 2012

Background
—The aim of this study was to assess the sigmoid line of elasticity in the human aorta.

Methods and Results
—The pressure-diameter relation was measured in the descending aorta in 120 subjects. In an additional group of 6 subjects, transient vena caval occlusion produced 5 sets of pressure-diameter data. We found that the best fit curve of the pooled pressure-diameter data was a third-order polynomial. A polynomial equation was used to calculate the sigmoid line of elasticity in the entire population and after the administration of diltiazem (15 patients) or enalaprilat (10 patients). The sigmoid line of elasticity was significantly different with respect to age (
P
<0.001), history of hypertension (
P
<0.004), and hypercholesterolemia (
P
<0.02). The difference between the transition point and the peak systolic pressure was increased in normal subjects compared with patients (
P
<0.0001). The sigmoid line shifted leftward and upward with diltiazem, but it remained unchanged with enalaprilat. During an average of 3 years of follow-up, 19 of 88 patients developed stroke (n=4), unstable angina (n=8), acute myocardial infarction (n=4), or acute pulmonary edema (n=3).

Conclusions
—This approach provides a quantitative evaluation of the aortic line of elasticity, which can differentiate the intrinsic from the extrinsic aortic elastic properties. Furthermore, it is a powerful and independent risk factor for cardiovascular events.
Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to β-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Shinke Toshiro , Takaoka Hideyuki , Takeuchi Motoshi , Hata Katsuya , Kawai Hiroya , Okubo Hideaki , Kijima Yoichi , Murata Takeomi , Yokoyama Mitsuhiro
Published: June 2012

Background
—The results of recent studies suggest that NO synthase may increase in the failing myocardium and that NO modulates the myocardial contractile response to β-adrenergic stimulation. However, there are few data regarding the physiological role of NO in patients with heart failure. The aim of the present study was to address the role of NO in left ventricular (LV) contractile response to β-adrenergic stimulation and corresponding oxygen expenditure in human heart failure.

Methods and Results
—We studied 15 patients with heart failure due to idiopathic dilated cardiomyopathy (mean ejection fraction 0.33). We examined LV contractility (E
max
, the slope of end-systolic pressure-volume relation), LV external work (EW), myocardial oxygen consumption (MV̇
o
2
), and mechanical efficiency (measured as EW/MV̇
o
2
) with the use of conductance and coronary sinus thermodilution catheters before and during dobutamine (DOB) infusion via a peripheral vein (4.8±0.3 μg · kg
−1
· min
−1
IV). Heart rate was kept constant with atrial pacing. We carried out a similar protocol during the intracoronary infusion of the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA; 200 μmol). DOB increased E
max
, EW, and MV̇
o
2
(by 77±17%, 39±5%, and 21±5%, respectively), leading to an increase in mechanical efficiency (25.4±3.1% to 29.6±4.1%). L-NMMA alone did not significantly change these variables. Although the concurrent infusion of DOB with L-NMMA increased E
max
, EW, and MV̇
o
2
(by 140±21%, 64±9%, and 35±5%, respectively) more than DOB alone, mechanical efficiency did not increase further (24.3±3.3% to 29.5±4.5%) because EW and MV̇
o
2
increased in parallel.

Conclusions
—These data suggest that in patients with idiopathic dilated cardiomyopathy, endogenous NO spares MV̇
o
2
through attenuation of LV contractile response to β-adrenergic stimulation while maintaining LV energy-converting efficiency.
Endovascular Irradiation From β-Particle–Emitting Gold Stents Results in Increased Neointima Formation in a Porcine Restenosis Model
Authors: Schulz Christian , Niederer Christina , Andres Christian , Herrmann Robert A. , Lin Xilei , Henkelmann Richard , Panzer Werner , Herrmann Clemens , Regulla Dieter F. , Wolf Ingo , Ulm Kurt , Alt Eckhard
Published: June 2012

Background
—Recent studies have shown that ionizing radiation reduces neointima formation after balloon angioplasty and stent implantation in experimental models of restenosis and first clinical trials. The objective of this study was to determine the dose distribution of a new β-particle–emitting radioactive gold stent and to evaluate the dose-dependent vascular response in the coronary overstretch pig model.

Methods and Results
—Sixteen Göttinger minipigs underwent placement of 11 nonradioactive and 36 β-particle–emitting stents with activity levels of 10.4±0.6, 14.9±2.4, 22.8±1.3, 35.8±2.8, and 55.4±5.3 μCi of
198
Au. Three months after implantation, the percent area stenosis, neointimal thickness, neointimal area, and vessel injury were analyzed by quantitative histomorphometry. The lifetime radiation doses at a depth of 1 mm were 3.3±0.2, 4.7±0.5, 7.2±0.4, 11.4±0.9, and 17.6±1.7 Gy for the different activity groups. No dose-response relationship was observed in the radioactive stents with respect to percent area stenosis (
P
=0.297), mean neointimal thickness (
P
=0.82), or mean neointimal area (
P
=0.65). Significantly lower neointima formation and less luminal narrowing was seen in the control group than in the β-particle–emitting stents (
P
<0.001). Multilinear regression analysis revealed that only radioactivity made a significant independent contribution to the degree of percent area stenosis (
P
<0.001).

Conclusions
—Neointima formation in pigs is markedly increased by β-particle–emitting stents with
198
Au as the radioisotope. This study provides evidence that dosages of 3 to 18 Gy of low-dose-rate β-particle irradiation via endovascular stents cause pronounced luminal narrowing in the animal model at 3 months.
Low Fasting Plasma Glucose Level as a Predictor of Cardiovascular Disease and All-Cause Mortality
Authors: Wei Ming , Gibbons Larry W. , Mitchell Tedd L. , Kampert James B. , Stern Michael P. , Blair Steven N.
Published: June 2012

Background
—Although medical textbooks usually classify fasting plasma glucose <70 or 80 mg/dL (<3.89 or 4.44 mmol/L) as abnormal, the prognosis for patients with low fasting plasma glucose is unclear.

Methods and Results
—We conducted prospective cohort studies among 40 069 men and women to investigate the association between fasting plasma glucose levels and cardiovascular disease and all-cause mortality. We documented a U-shaped relation between fasting plasma glucose and mortality. In addition to diabetes and impaired fasting glucose levels, low fasting plasma glucose levels were also associated with high mortality. After multivariate adjustment for age, sex, study population, ethnicity, current smoking status, high blood pressure, total cholesterol, body mass index, triglycerides, history of cardiovascular disease and cancer, and a family history of cardiovascular disease, patients with fasting plasma glucose <70 mg/dL (<3.89 mmol/L) had a 3.3-fold increased risk of cardiovascular disease mortality, and patients with fasting plasma glucose 70 to 79 mg/dL (3.89 to 4.43 mmol/L) had a 2.4-fold increased risk compared with the risk in patients with fasting plasma glucose 80 to 109 mg/dL (4.44 to 6.05 mmol/L) (tests for trend
P
<0.0001). Participants with low fasting plasma glucose levels also had increased risk of all-cause mortality (test for trend
P
<0.0001).

Conclusions
—Participants with low fasting plasma glucose levels had a high risk of cardiovascular disease and all-cause mortality.
Improvement in Exercise Capacity With Nitric Oxide Inhalation in Patients With Precapillary Pulmonary Hypertension
Authors: Hasuda Toshio , Satoh Toru , Shimouchi Akito , Sakamaki Fumio , Kyotani Shingo , Matsumoto Takahiro , Goto Yoichi , Nakanishi Norifumi
Published: June 2012

Background
—Patients with precapillary pulmonary hypertension (PH) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries. By causing the pulmonary artery to dilate, inhaled nitric oxide (NO) may allow an increase in exercise capacity in patients with PH.

Methods and Results
—On 2 separate days, 3 days apart, 14 patients with precapillary PH (10 primary PH, 4 residual PH after correction of an intracardiac shunt; age, 40±12 years; mean pulmonary artery pressure, 60±23 mm Hg) performed exercise, with and without inhalation of 20 ppm NO, on a cycle ergometer. The work rate was increased 15 W/min until their symptom-limited maximum, with breath-by-breath gas analysis. Patients were randomly and blindly selected to inhale NO on either their first or second test. Peak exercise load and anaerobic threshold tended to increase, but not significantly. Peak oxygen consumption (V̇
o
2
) and ΔV̇
o
2
/ΔW ratio increased significantly, by 18% and 22%, respectively (peak V̇
o
2
, 13.6±3.6 to 16.0±4.1 mL · kg
−1
· min
−1
; ΔV̇
o
2
/ΔW ratio, 5.8±2.4 to 7.1±2.3 mL · kg
−1
· min
−1
· W
−1
; both
P
<0.01). Peak V̇
o
2
increased >10% in 12 of the 14 patients. However, respiratory quotient at peak exercise decreased from 1.22±0.15 to 1.09±0.15 (
P
<0.01).

Conclusions
—Inhaled NO substantially increases oxygen consumption at the same workload during exercise. This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH.
Electron-Beam Computed Tomography in the Assessment of Coronary Artery Disease After Heart Transplantation
Authors: Knollmann Friedrich D. , Bocksch Wolfgang , Spiegelsberger Susanne , Hetzer Roland , Felix Roland , Hummel Manfred
Published: June 2012

Background
—Our aim was to compare the electron-beam CT (EBCT) features of coronary arteries in heart transplant recipients with those of biplane coronary angiography and intracoronary ultrasound (ICUS).

Methods and Results
—We examined 112 heart transplant recipients (25 female; age, 17 to 69 years; median, 52 years) 1 to 153 months (median, 46 months) after surgery by EBCT to detect coronary artery calcifications. Calcifications were quantified by the Agatston scoring system. EBCT scores were compared with coronary angiography in all patients and ICUS of the left anterior descending coronary artery (LAD) in 100 patients. Coronary artery calcifications were found in 84 patients (75%). Angiographically, 16 patients displayed >50% coronary artery stenoses, all of whom had some degree of coronary artery calcification and only 1 of whom had a score of <55 (
P
<0.0001). With this threshold, EBCT had a sensitivity of 94%, a specificity of 79%, a positive predictive value of 43%, and a negative predictive value of 99% for detecting stenosis. ICUS confirmed the presence of calcified plaques in all patients with an LAD score >9. EBCT total calcium score was associated with the degree of intimal proliferation in that patients without ICUS features of allograft vasculopathy had a median score of 0 (25th percentile, 0; 75th percentile, 0), whereas patients with Stanford class IV vasculopathy had a median score of 41 (9 to 98,
P
<0.0001).

Conclusions
—EBCT is a promising noninvasive test for the detection of coronary heart disease in cardiac transplant recipients.