bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping of Atrial Activation With a Noncontact, Multielectrode Catheter in Dogs
Authors: Kadish Alan , Hauck John , Pederson Brian , Beatty Graydon , Gornick Charles
Published: June 2012

Background
—Endocardial mapping of sustained arrhythmias has traditionally been performed with a roving diagnostic catheter. Although this approach is adequate for many tachyarrhythmias, it has limitations. The purpose of this study was to evaluate a novel noncontact mapping system for assessing atrial tachyarrhythmias.

Methods and Results
—The mapping system consists of a 9F multielectrode-array balloon catheter that has 64 active electrodes and ring electrodes for emitting a locator signal. The locator signal was used to construct a 3-dimensional right atrial map; it was independently validated and was highly accurate. Virtual electrograms were calculated at 3360 endocardial sites in the right atrium. We evaluated right atrial activation by positioning the balloon catheter in the mid right atrium via a femoral venous approach. Experiments were performed on 12 normal mongrel dogs. The mean correlation coefficient between contact and virtual electrograms was 0.80±0.12 during sinus rhythm. Fifty episodes of atrial flutter induced in 11 animals were evaluated. In the majority of experiments, complete or almost complete reentrant circuits could be identified within the right atrium. Mean correlation coefficient between virtual and contact electrograms was 0.85±0.17 in atrial flutter. One hundred fifty-six episodes of pacing-induced atrial fibrillation were evaluated in 11 animals. Several distinct patterns of right atrial activation were seen, including single-activation wave fronts and multiple simultaneous-activation wave fronts. Mean correlation coefficient between virtual and contact electrograms during atrial fibrillation was 0.81±0.18. The accuracy of electrogram reconstruction was lower at sites >4.0 cm from the balloon center and at sites with a high spatial complexity of electrical activation.

Conclusions
—This novel noncontact mapping system can evaluate conduction patterns during sinus rhythm, demonstrate reentry during atrial flutter, and describe right atrial activation during atrial fibrillation. The accuracy of electrogram reconstruction was good at sites <4.0 cm from the balloon center, and thus the system has the ability to perform high-resolution multisite mapping of atrial tachyarrhythmias in vivo.
Sustained Suppression of Ischemic Complications of Coronary Intervention by Platelet GP IIb/IIIa Blockade With Abciximab
Authors: Lincoff A. Michael , Tcheng James E. , Califf Robert M. , Kereiakes Dean J. , Kelly Thomas A. , Timmis Gerald C. , Kleiman Neal S. , Booth Joan E. , Balog Craig , Cabot Catherine F. , Anderson Keaven M. , Weisman Harlan F. , Topol Eric J.
Published: June 2012

Background
—Blockade of the platelet glycoprotein IIb/IIIa receptor with the monoclonal antibody fragment abciximab was shown in a placebo-controlled randomized trial to reduce the incidence of acute ischemic complications within 30 days among a broad spectrum of patients undergoing percutaneous coronary revascularization. The durability of clinical benefit in this setting has not been established.

Methods and Results
—A total of 2792 patients enrolled in the Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial were followed with maintenance of double-blinding for 1 year. Patients had been assigned at the time of their index coronary interventional procedure to receive placebo with standard-dose, weight-adjusted heparin (100 U/kg initial bolus), abciximab with standard-dose, weight-adjusted heparin, or abciximab with low-dose, weight-adjusted heparin (70 U/kg initial bolus). The primary outcome was the composite of death, myocardial infarction, or urgent repeat revascularization by 30 days; this composite end point and its individual components were also assessed at 6 months and 1 year. Rates of any repeat revascularization (urgent or elective), target vessel revascularization, and a composite of death, myocardial infarction, or any repeat revascularization were also reported. Follow-up at 1 year was 99% complete for survival status and 97% complete for other end points. By 1 year, the incidence of the primary composite end point was 16.1% in the placebo group, 9.6% in the abciximab with low-dose heparin group (
P
<0.001), and 9.5% in the abciximab with standard-dose heparin group (
P
<0.001). Each of the components of this composite end point was reduced to a similar extent. Nonurgent or target vessel repeat revascularization rates were not significantly decreased by abciximab therapy. Mortality rates over 1 year increased with increasing levels of periprocedural creatine kinase MB fraction elevation.

Conclusions
—Acute reductions in ischemic events after percutaneous coronary intervention by abciximab are sustained over follow-up to at least 1 year. Early periprocedural myocardial infarctions suppressed by this therapy are associated with long-term mortality rates.
Decreased Activity of the
l
-Arginine–Nitric Oxide Metabolic Pathway in Patients With Congestive Heart Failure
Authors: Katz Stuart D. , Khan Tehreen , Zeballos Guillermo A. , Mathew Leena , Potharlanka Prathibha , Knecht Mathias , Whelan James
Published: June 2012

Background
—Impaired endothelium-dependent, nitric oxide (NO)–mediated vasodilation may contribute to increased vasomotor tone in patients with heart failure. Whether decreased endothelium-dependent, NO-mediated vasodilation in patients with heart failure is due to decreased synthesis or increased degradation of NO is unknown.

Methods and Results
—To specifically assess the synthetic activity of the
l
-arginine–NO metabolic pathway, urinary excretion of [
15
N]nitrates and [
15
N]urea was determined after a primed continuous intravenous infusion of
l
-[
15
N]arginine (40 μmol/kg) in 16 patients with congestive heart failure and 9 age-matched normal control subjects at rest and during submaximal treadmill exercise. After infusion of
l
-[
15
N]arginine, 24-hour urinary excretion of [
15
N]nitrates was decreased in patients with congestive heart failure at rest (2.2±0.5 versus 8.0±2.3 μmol/24 h) and during submaximal exercise (2.4±1.2 versus 11.4±4.0 μmol/24 h) compared with control subjects (both
P
<0.01). After infusion of
l
-[
15
N]arginine, 24-hour urinary excretions of [
15
N]urea at rest in patients with congestive heart failure and control subjects were not different (1.1±0.3 versus 1.2±0.2 mmol/24 h,
P
>0.20).

Conclusions
—A specific decrease in synthetic activity of the
l
-arginine–NO metabolic pathway contributes to decreased endothelium-dependent vasodilation in patients with congestive heart failure.
Lack of Association Between a Polymorphism of the Aldosterone Synthase Gene and Left Ventricular Structure
Authors: Schunkert Heribert , Hengstenberg Christian , Holmer Stephan R. , Broeckel Ulrich , Luchner Andreas , Muscholl Michael W. , Kürzinger Susanne , Döring Angela , Hense Hans-Werner , Riegger Günter A. J.
Published: June 2012

Background
—Cardiac growth and function may be modulated in part by trophic effects of neurohormones. Specifically, aldosterone has been shown to stimulate the growth of cardiac myocytes and the accumulation of cardiac extracellular matrix proteins. Moreover, a variant of the aldosterone synthase gene (a cytosine/thymidine exchange at position −344 in the transcriptional regulatory region) has been associated with enlargement and disturbed filling of the left ventricle (LV) in a small sample of young white adults. The aim of the present study was to reinvestigate the implications of aldosterone synthase −344C/T allele status for serum aldosterone levels, blood pressure, and LV structure and function in large population-based samples.

Methods and Results
—Individuals who participated in the echocardiographic substudy of the third MONICA (MONitoring trends and determinants in CArdiovascular disease) survey (n=1445) or in the second follow-up of the first MONICA survey (n=562) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for aldosterone synthase −344C/T allele status. In both surveys, the distribution of sex, age, arterial blood pressure, and body mass index was homogeneous in the aldosterone synthase genotype groups. Echocardiographic LV wall thicknesses, dimensions, and mass indexes were not significantly associated with a specific aldosterone synthase genotype. Likewise, no association was detectable with echocardiographic measures of LV systolic or diastolic function. Data were consistent in both samples and not materially different in subgroups defined by age, sex, or intake of antihypertensive medication. Finally, no significant association was observed for aldosterone synthase allele status and serum aldosterone levels in the group of 562 individuals.

Conclusions
—The data are not in favor of a significant contribution of the C/T exchange at position −344 in the aldosterone synthase transcriptional regulatory region to the variability of serum aldosterone levels, blood pressure, or cardiac size or function as found in 2 white population-based samples.
Calcium Channel Blockers Activate the Interleukin-6 Gene Via the Transcription Factors NF-IL6 and NF-κB in Primary Human Vascular Smooth Muscle Cells
Authors: Eickelberg Oliver , Roth Michael , Mussmann Rainer , Rüdiger Jochen J. , Tamm Michael , Perruchoud André P. , Block Lutz-Henning
Published: June 2012

Background
—Calcium channel blockers (CCB) of all subclasses: the dihydropyridines, benzothiazepines, and phenylalkylamines, at nanomolar concentrations, have been shown to up-regulate interleukin-6 (IL-6) mRNA. We investigated the underlying molecular mechanism responsible for IL-6 induction in response to the CCB amlodipine, diltiazem, and verapamil in primary human vascular smooth muscle cells (VSMC).

Methods and Results
—All 3 CCB directly activated transcription of the human IL-6 gene in primary human VSMC in a time- and dose-dependent manner, as demonstrated by luciferase reporter gene assays using a 651-bp fragment of the human IL-6 gene promoter. Deletion analysis of the IL-6 promoter revealed that CCB inducible promoter activity was localized to a 160-bp fragment directly upstream of the transcriptional start site of the IL-6 gene. Known transcription factor consensus sequences within this fragment include a NF-IL6 and a NF-κB site. Site-directed mutagenesis suggested that both transcription factors had positive regulatory activity and cooperatively transmitted induction of the IL-6 gene by CCB. The data are confirmed by electrophoretic mobility shift analyses using nuclear extracts from CCB-stimulated and control primary VSMC. CCB of all subclasses increased DNA binding of NF-IL6 and NF-κB as early as 30 minutes after stimulation with the drugs. This effect was independent of intracellular calcium concentrations because calcium-free medium did not increase NF-IL6 or NF-κB activity.

Conclusions
—The results demonstrate that CCB of all 3 subclasses are capable of activating NF-IL6 and NF-κB. CCB may thus directly regulate cellular functions by affecting the activity of transcription factors independent of changes of intracellular calcium concentrations, an observation that is of interest considering the biological effects induced by CCB.
Prevention of Cardiac Allograft Arteriosclerosis by Protein Tyrosine Kinase Inhibitor Selective for Platelet-Derived Growth Factor Receptor
Authors: Sihvola Roope , Koskinen Petri , Myllärniemi Marjukka , Loubtchenkov Michael , Häyry Pekka , Buchdunger Elisabeth , Lemström Karl
Published: June 2012

Background
—Increased immunoreactivity of platelet-derived growth factor (PDGF)-AA, -Rα, and -Rβ in intimal cells correlates with the development of cardiac allograft arteriosclerosis, a condition for which there is little or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease.

Methods and Results
—The hypothesis was tested in a rat model of heterotopic cardiac and aortic allografts using dark agouti (AG-B4, RT1
a
) donors and Wistar-Furth (AG-B2, RT1
u
) recipients. The recipients received CGP 53716, a selective PDGF-R protein tyrosine kinase inhibitor, 50 mg · kg
−1
· d
−1
, or vehicle for 60 days. Cardiac allograft recipients also received background cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac and aortic allograft recipients. When rat coronary smooth muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1β or tumor necrosis factor-α, CGP 53716 significantly inhibited only AA-ligand–induced but not BB-ligand–induced replication. Concomitantly, in quantitative reverse transcriptase–polymerase chain reaction, interleukin-1β or tumor necrosis factor-α stimulation specifically upregulated the expression of PDGF-Rα mRNA but not of other ligand or receptor genes in cultured smooth muscle cells.

Conclusions
—We conclude that a PDGF-AA/Rα–dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.
Mortality Prediction in Cardiac Surgery Patients
Authors: Martínez-Alario J. , Tuesta I. D. , Plasencia E. , Santana M. , Mora M. L.
Published: June 2012

Background
—Our purpose was to assess the performance of general severity systems (Acute Physiology and Chronic Health Evaluation [APACHE], Simplified Acute Physiology Score [SAPS], and Mortality Probability Models [MPM]) and to compare them with the Parsonnet score to predict mortality after cardiac surgery.

Methods and Results
—This was a prospective observational study of 465 cardiac surgery patients in a tertiary referral center. Probabilities of hospital death for patients were estimated by applying the 4 models and were compared with actual mortality rates. Performance of the 4 systems was assessed by evaluating calibration with the Hosmer-Lemeshow goodness-of-fit test and discrimination with receiver operating characteristic (ROC) curves. χ
2
values were 3.71 for Parsonnet, 4.52 for MPM II
0
, 4.30 for MPM II
24
, 5.16 for SAPS II, and 10.57 for APACHE II. The area under the ROC curve was 0.857 for Parsonnet, 0.783 for MPM II
0
, 0.796 for MPM II
24
, 0.771 for SAPS II, and 0.803 for APACHE II.

Conclusions
—In our experience, the Parsonnet score performs very well, with calibration and discrimination very high, better than general severity systems, and it is an appropriate tool to assess mortality in cardiac surgery patients. In our experience, the general severity systems perform well to predict mortality after cardiac surgery, with high calibration of MPM II
24
, MPM II
0
, and SAPS II; minor calibration for APACHE II; and high discrimination for 3 general systems, but not as well as the Parsonnet score.
Inotropic and Sympathetic Responses to the Intracoronary Infusion of a β
2
-Receptor Agonist
Authors: Newton Gary E. , Azevedo Eduardo R. , Parker John D.
Published: June 2012

Background
—On the basis of the presence of β
2
-receptors within the sympathetic nervous system, β
2
-stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory β
2
-receptors are present in the human left ventricle.

Methods and Results
—The β
2
-agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no β-blocker therapy), group 2 (n=7, β
1
-selective blockade with atenolol), and group 3 (n=6, nonselective β-blockade with nadolol). Left ventricular +dP/dt in response to increasing concentrations of salbutamol was measured in all groups, and cardiac norepinephrine spillover was measured in group 1. There were no systemic hemodynamic changes in any group. Salbutamol resulted in a 44±6% increase in +dP/dt in group 1, a 25±6% increase in group 2 (
P
<0.05 versus group 1), and no increase in group 3. Salbutamol also resulted in a 124±37% increase in cardiac norepinephrine spillover in group 1 (
P
<0.05).

Conclusions
—Evidence that salbutamol increased norepinephrine release from cardiac sympathetic nerves was provided by the observations that atenolol suppressed the salbutamol inotropic response, demonstrating that this response was mediated in part by β
1
-receptors and that salbutamol also resulted in an increase in cardiac norepinephrine spillover. This result provides in vivo evidence, in humans, for the role of sympathoexcitatory cardiac β
2
-receptors.
Contribution of Head-Up Tilt Testing and ATP Testing in Assessing the Mechanisms of Vasovagal Syndrome
Authors: Flammang Daniel , Erickson Mark , McCarville Sally , Church Timothy , Hamani Djamel , Donal Erwan
Published: June 2012

Background
—In patients with vasovagal syndrome, head-up tilt testing may reproduce symptoms generally associated with vasodepression. Recent research suggests ATP testing identifies patients with abnormal vagal cardiac inhibition. This preliminary study examined the joint contribution of both tests in identifying underlying mechanisms in the general population with vasovagal syndrome.

Methods and Results
—Both tests were performed in random order during 1 session and outside of predominant sympathetic periods in 72 patients hospitalized for syncope (n=56) or presyncope (n=16) for whom no cardiac or extracardiac cause was found. For passive and isoproterenol-provocative tilt testing by standard protocol, reproduction of symptoms defined a positive test. The ATP test consisted of injecting ATP 20 mg IV at bedside, continuously monitoring ECG and blood pressure; a vagal cardiac pause >10 seconds defined a positive test. For most patients (64%), ≥1 test was positive. Of the 41 patients (57%) with a positive tilt test (either passive or provoked by isoproterenol), 32% had cardiac disease; none had significant bradycardia (<50 bpm). Of the 8 patients (11%) with a positive ATP test, 62% had cardiac disease; the probability of a positive result increased with age (
P
=0.015). Both tests were positive in 3 patients and negative in 26 patients; the tilt and ATP test results were uncorrelated (
P
=0.28).

Conclusions
—Results suggest tilt and ATP tests individually and jointly determine the mechanism of vasovagal symptoms in most patients and that vagal cardiac inhibition increases with age.
Impact of Aortic Stiffness on Survival in End-Stage Renal Disease
Authors: Blacher Jacques , Guerin Alain P. , Pannier Bruno , Marchais Sylvain J. , Safar Michel E. , London Gérard M.
Published: June 2012

Background
—Damage to large arteries is a major factor in the high cardiovascular morbidity and mortality of patients with end-stage renal disease (ESRD). Increased arterial stiffness and intima-media thickness, together with increased pulse pressure, are the principal arterial alterations. Whether increased aortic pulse-wave velocity (PWV), a classic marker of increased arterial stiffness, may predict all-cause and/or cardiovascular mortality has never been investigated.

Methods and Results
—A cohort of 241 patients with ESRD undergoing hemodialysis was studied between April 1987 and April 1998. The mean duration of follow-up was 72±41 months (mean±SD). Mean age at entry was 51.5±16.3 years. Seventy-three deaths occurred, including 48 cardiovascular and 25 noncardiovascular fatal events. At entry, together with standard clinical and biochemical analyses, patients underwent echocardiography and aortic PWV measured by Doppler ultrasonography. On the basis of Cox analyses, 2 factors emerged as predictors of all-cause and cardiovascular mortality: age and aortic PWV. Hemoglobin and low diastolic pressure interfered to a smaller extent. After adjustment for all the confounding factors, an OR for PWV >12.0 versus <9.4 m/s was 5.4 (95% CI, 2.4 to 11.9) for all-cause mortality and 5.9 (95% CI, 2.3 to 15.5) for cardiovascular mortality. For each PWV increase of 1 m/s in our study population, all-cause mortality–adjusted OR was 1.39 (95% CI, 1.19 to 1.62).

Conclusions
—These results provide the first direct evidence that in patients with ESRD, increased aortic stiffness determined by measurement of aortic PWV is a strong independent predictor of all-cause and mainly cardiovascular mortality.
Effects of
I
Kr
and
I
Ks
Heterogeneity on Action Potential Duration and Its Rate Dependence
Authors: Viswanathan Prakash C. , Shaw Robin M. , Rudy Yoram
Published: June 2012

Background
—A growing body of evidence suggests that heterogeneity of ion channel expression and electrophysiological characteristics is an important property of the ventricular myocardium. The 2 components of the delayed rectifier potassium current,
I
Kr
(rapid) and
I
Ks
(slow), play a dominant role in the repolarization of the action potential and are important determinants of its duration.

Methods and Results
—In this report, the effects of heterogeneities of
I
Kr
and
I
Ks
on action potential duration (APD) and its rate dependence (adaptation) are studied with the use of the LRd model of a mammalian ventricular cell. Results demonstrate the importance of
I
Ks
density variations in heterogeneity of repolarization. Cells with reduced
I
Ks
(eg, mid-myocardial M cells) display long APD and steep dependence of APD on rate. Mechanistically, accumulation of
I
Ks
activation and increased sodium calcium exchange current,
I
NaCa
, secondary to Na
+
accumulation at a fast rate underlie the steep APD-rate relation of these cells. When cells are electrotonically coupled in a multicellular fiber through resistive gap junction, APD differences are reduced. The results demonstrate strong dependence of APD heterogeneity on the degree of intercellular coupling even in the normal physiological range. Highly reduced coupling maximizes APD heterogeneity.

Conclusions
—Heterogeneity of
I
Ks
:
I
Kr
density strongly influences APD and its rate dependence. However, in the intact myocardium, the degree of gap-junction coupling may be an important factor that determines the manifestation of APD heterogeneity and dispersion of repolarization. The clinical significance of this study is in the context of repolarization abnormalities and associated arrhythmias (eg, long QT syndrome and torsade de pointes).
Antibodies to Platelet Factor 4–Heparin After Cardiopulmonary Bypass in Patients Anticoagulated With Unfractionated Heparin or a Low-Molecular-Weight Heparin
Authors: Pouplard Claire , May Marc-Antoine , Iochmann Sophie , Amiral Jean , Vissac Anne-Marie , Marchand Michel , Gruel Yves
Published: June 2012

Background
—Cardiopulmonary bypass (CPB) induces platelet activation with release of platelet factor 4 (PF4), and patients are exposed to high doses of heparin (H). We investigated whether this contributes to the development of antibodies to H-PF4 and heparin-induced thrombocytopenia (HIT).

Methods and Results
—CPB was performed with unfractionated heparin (UFH) in 328 patients. After surgery, patients received UFH (calcium heparin, 200 IU · kg
−1
· d
−1
) (group 1, n=157) or low-molecular-weight heparin (LMWH, Dalteparin, 5000 IU once daily) (group 2, n=171). Eight days after surgery, antibodies to H-PF4 were present in 83 patients (25.3%), 46 in group 1 and 37 in group 2 (
P
=0.12). Most patients (61%) had IgG1 to H-PF4, but only 8 samples with antibodies induced platelet activation with positive results on serotonin release assay. HIT occurred in 6 patients in group 1, but no thrombocytopenia was observed in subjects receiving LMWH, although 2 had high levels of antibodies with positive serotonin release assay results. When antibodies to H-PF4 were present, mean platelet counts were lower only in patients with FcγRIIA R/R
131
platelets.

Conclusions
—These results provide evidence that the development of antibodies to H-PF4 after CPB performed with UFH is not influenced by the postoperative heparin treatment. The antibodies associated with high risk of HIT are mainly IgG1, which is present at high titers in the plasma of patients continuously treated with UFH.
C-Reactive Protein, a Sensitive Marker of Inflammation, Predicts Future Risk of Coronary Heart Disease in Initially Healthy Middle-Aged Men
Authors: Koenig Wolfgang , Sund Malte , Fröhlich Margit , Fischer Hans-Günther , Löwel Hannelore , Döring Angela , Hutchinson Winston L. , Pepys Mark B.
Published: June 2012

Background
—Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events.

Methods and Results
—We used a sensitive immunoradiometric assay to examine the association of serum C-reactive protein (CRP) with the incidence of first major coronary heart disease (CHD) event in 936 men 45 to 64 years of age. The subjects, who were sampled at random from the general population, participated in the first MONICA Augsburg survey (1984 to 1985) and were followed for 8 years. There was a positive and statistically significant unadjusted relationship, which was linear on the log-hazards scale, between CRP values and the incidence of CHD events (n=53). The hazard rate ratio (HRR) of CHD events associated with a 1-SD increase in log-CRP level was 1.67 (95% CI, 1.29 to 2.17). After adjustment for age, the HRR was 1.60 (95% CI, 1.23 to 2.08). Adjusting further for smoking behavior, the only variable selected from a variety of potential confounders by a forward stepping process with a 5% change in the relative risk of CRP as the selection criterion, yielded an HRR of 1.50 (95% CI, 1.14 to 1.97).

Conclusions
—These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.
Differentiation of Viable and Nonviable Myocardium by the Use of Three-Dimensional Tagged MRI in 2-Day-Old Reperfused Canine Infarcts
Authors: Croisille P. , Moore C. C. , Judd R. M. , Lima J. A. C. , Arai M. , McVeigh E. R. , Becker L. C. , Zerhouni E. A.
Published: June 2012

Background
—To limit ischemic myocardial injury, it is important to differentiate viable from infarcted myocardium. Three dimensional (3D) tagged MRI has the ability to quantify myocardial 3D deformation and strain (noninvasively and precisely), and can achieve a true comparison of contraction not only from region to region, but also at different levels of function. In this study, we investigated whether regional strain mapping obtained by 3D-tagged MRI can differentiate between viable but stunned myocardium and nonviable myocardium.

Methods and Results
—We examined 7 dogs 2 days after a 90-minute closed-chest left anterior descending coronary artery occlusion followed by 48 hours of reperfusion. 3D-tagged MR images spanning the entire left ventricle were acquired both at rest and during dobutamine infusion (5 μg · kg
−1
· min
−1
IV). Regional blood flow was measured with radioactive microspheres and used to define risk regions. Infarcted regions were defined as 2,3,5 triphenyltetrazolium chloride negative regions. Strains in infarcted regions were greatly impaired compared with remote regions (
P
<0.001) and remained unchanged during dobutamine stress. Risk regions showed a dysfunction at rest, with improved function during dobutamine infusion. Receiver operating characteristics analysis showed that radial strain was more accurate for identifying viable regions.

Conclusions
—When coupled with a stress test, 3D strain mapping by the use of tagged MRI is a sensitive and noninvasive method for characterizing ischemic injury. Regional strain can be used to differentiate between viable but stunned and nonviable myocardium within the postischemic injured myocardium.
The Role of Endothelin-Converting Enzyme-1 in the Development of α
1
-Adrenergic-Stimulated Hypertrophy in Cultured Neonatal Rat Cardiac Myocytes
Authors: Kaburagi Satoshi , Hasegawa Koji , Morimoto Tatsuya , Araki Makoto , Sawamura Tatsuya , Masaki Tomoh , Sasayama Shigetake
Published: June 2012

Background
—Accumulating evidence suggests that the local synthesis of endothelin-1 (ET-1) plays a role in the development of heart failure in vivo. We investigated the role of endothelin-converting enzyme-1 (ECE-1), which mediates the conversion of big ET-1 to mature ET-1, in the development of α
1
-adrenergic–stimulated hypertrophy in cultured neonatal rat cardiac myocytes.

Methods and Results
—Phenylephrine (PE) induced the expression of ET-1 in rat cardiac myocytes and accelerated the conversion of big ET-1 to ET-1. The
ECE-1
mRNA levels were markedly increased 3 hours after PE stimulation (3.6-fold compared with saline stimulation,
P
<0.005). A specific ECE-1 antagonist, FR901533, inhibited the PE-stimulated increase in protein synthesis rate by 45% (
P
<0.05). As genetic markers for the hypertrophic response, FR901533 inhibited the PE-stimulated transcriptional activities of the 3.5-kb
β-myosin heavy chain
promoter by 79% (
P
<0.01) but did not affect that of the 3.4-kb
atrial natriuretic factor
(
ANF
) promoter. In Bio14.6 Syrian cardiomyopathic hamsters, ventricular ET-1 and
ANF
mRNA levels did not correlate at 2 different stages.

Conclusions
—ET-1-independent pathways may mediate activation of the
ANF
gene program in ventricular myocytes both in vitro and in vivo. These results also indicate that the conversion of big ET-1 to ET-1 in rat cardiac myocytes is required for the development of α
1
-adrenergic-stimulated hypertrophy and
β-myosin heavy chain
gene transcription.
Enhanced Contractility and Decreased β-Adrenergic Receptor Kinase-1 in Mice Lacking Endogenous Norepinephrine and Epinephrine
Authors: Cho Myeong-Chan , Rao Madhu , Koch Walter J. , Thomas Steven A. , Palmiter Richard D. , Rockman Howard A.
Published: June 2012

Background
—Elevated circulating norepinephrine (NE) has been implicated in causing the profound β-adrenergic receptor (βAR) downregulation and receptor uncoupling that are characteristic of end-stage human dilated cardiomyopathy, a process mediated in part by increased levels of β-adrenergic receptor kinase (βARK1). To explore whether chronic sustained NE stimulation is a primary stimulus that promotes deterioration in cardiac signaling, we characterized a gene-targeted mouse in which activation of the sympathetic nervous system cannot lead to an elevation in plasma NE and epinephrine.

Methods and Results
—Gene-targeted mice that lack dopamine β-hydroxylase (
dbh
−/−
), the enzyme needed to convert dopamine to NE, were created by homologous recombination. In vivo contractile response to the β
1
AR agonist dobutamine, measured by a high-fidelity left ventricular micromanometer, was enhanced in mice lacking the
dbh
gene. In unloaded adult myocytes isolated from
dbh
−/−
mice, basal contractility was significantly increased compared with control cells. Furthermore, the increase in βAR responsiveness and enhanced cellular contractility were associated with a significant reduction in activity and protein level of βARK1 and increased high-affinity agonist binding without changes in βAR density or G-protein levels.

Conclusions
—Mice that lack the ability to generate NE or epinephrine show increased contractility associated primarily with a decrease in the level of βARK1 protein and kinase activity. This animal model will be valuable in testing whether NE is required for the pathogenesis of heart failure through mating strategies that cross the
dbh
−/−
mouse into genetically engineered models of heart failure.
Rate-Dependent Conduction Block of the Crista Terminalis in Patients With Typical Atrial Flutter
Authors: Arenal Angel , Almendral Jesus , Alday Jesus M. , Villacastín Julian , Ormaetxe Jose M. , Sande Jose Luis M. , Perez-Castellano Nicasio , Gonzalez Sergio , Ortiz Mercedes , Delcán Juan Luis
Published: June 2012

Background
—The crista terminalis (CT) has been identified as the posterior boundary of typical atrial flutter (AFL) in the lateral wall (LW) of the right atrium (RA). To study conduction properties across the CT, rapid pacing was performed at both sides of the CT after bidirectional conduction block was achieved in the cavotricuspid isthmus by radiofrequency catheter ablation.

Methods and Results
—In 22 patients (aged 61±7 years) with AFL (cycle length, 234±23 ms), CT was identified during AFL by double electrograms recorded between the LW and posterior wall (PW). After the ablation procedure, decremental pacing trains were delivered from 600 ms to 2-to-1 local capture at the LW and PW or coronary sinus ostium (CSO). At least 5 bipolar electrograms were recorded along the CT from the high to the low atrium next to the inferior vena cava. No double electrograms were recorded during sinus rhythm in that area. Complete transversal conduction block all along the CT (detected by the appearance of double electrograms at all recording sites and craniocaudal activation sequence on the side opposite to the pacing site) was observed in all patients during pacing from the PW or CSO (cycle length, 334±136 ms), but it was fixed in only 4 patients. During pacing from the LW, complete block appeared at a shorter pacing cycle length (281±125 ms;
P
<0.01) and was fixed in 2 patients. In 3 patients, complete block was not achieved.

Conclusions
—These data suggest the presence of rate-dependent transversal conduction block at the crista terminalis in patients with typical AFL. Block is usually observed at longer pacing cycle lengths with PW pacing than with LW pacing. This difference may be a critical determinant of the counterclockwise rotation of typical AFL.
Reduction in Lipopolysaccharide-Induced Thrombocytopenia by Triflavin in a Rat Model of Septicemia
Authors: Sheu Joen-Rong , Hung Wei-Chung , Wu Ching-Hsiang , Ma Ming-Chieh , Kan Ya-Chen , Lin Chien-Huang , Lin Ming-Shyan , Luk Hsiung-Ning , Yen Mao-Hsiung
Published: June 2012

Background
—Thrombocytopenia frequently occurs early in the course of Gram-negative bacterial infections. Triflavin, an Arg-Gly-Asp–containing disintegrin, has been suggested to interfere with the interaction of fibrinogen with the glycoprotein IIb/IIIa complex. The present study was undertaken to determine whether triflavin could prevent thrombocytopenia in lipopolysaccharide (LPS)-treated rats.

Methods and Results
—In this study,
51
Cr-labeled platelets were used to assess blood and tissue platelet accumulation after LPS challenge. The administration of LPS (4 mg/kg IV bolus) for 4 hours induced a reduction in radiolabeled platelets in blood and an obvious accumulation of platelets in liver. Triflavin (500 μg/kg) but not GRGDS (20 mg/kg) significantly prevented the alteration of radiolabeled platelet distribution in blood and liver when induced by LPS. Furthermore, triflavin but not GRGDS markedly suppressed the elevation in plasma thromboxane B
2
concentration within the 4-hour period of LPS administration. In LPS-treated rats, the 5-hydroxytryptamine level was lower in the blood and higher in the liver compared with levels in normal saline–treated rats. Pretreatment with triflavin (500 μg/kg) significantly reversed the 5-hydroxytryptamine concentration in blood and liver of LPS-treated rats. In histological examinations and platelet adhesion assay, triflavin markedly inhibited the adhesion of platelets to subendothelial matrixes in vivo and in vitro.

Conclusions
—The results indicate that triflavin effectively prevents thrombocytopenia, possibly through the following 2 mechanisms: (1) Triflavin markedly inhibits platelet aggregation, resulting in decreased thromboxane A
2
formation. (2) It inhibits the adhesion of platelets to subendothelial matrixes, thereby leading to a reversal in the distribution of platelets in blood and liver in LPS-treated rats.
Opening of Potassium Channels
Authors: Kevelaitis Egidijus , Peynet Jacqueline , Mouas Christian , Launay Jean-Marie , Menasché Philippe
Published: June 2012

Background
—The tolerance of hibernating mammals to cold hypoxia is related to a factor similar to agonists of δ-opioid receptors. This study was designed to assess whether activation of these receptors could reproduce the protection conferred by ischemic preconditioning and whether such cardioprotection was similarly mediated by an opening of ATP-sensitive potassium (K
ATP
) channels.

Methods and Results
—Thirty-two isolated rat hearts were arrested with and stored in Celsior at 4°C for 5 hours before being reperfused for 2 hours. They were divided into 4 equal groups. Group 1 hearts served as controls. In group 2, ischemic preconditioning was elicited by two 5-minute global ischemia periods interspersed with 5 minutes of reperfusion before arrest. In group 3, hearts were pharmacologically preconditioned with a 15-minute infusion of the δ-opioid receptor agonist
d
-Ala2-
d
-Leu5-enkephalin (DADLE; 200 μmol/L). In group 4, the protocol was similar to group 3 except that infusion of DADLE was preceded by infusion of the K
ATP
blocker glibenclamide (50 μmol/L). The salutary effects of both forms of preconditioning were primarily manifest as a better preservation of diastolic function, a reduced myocardial edema, and reduced creatine kinase leakage. This protection was abolished by administration of glibenclamide before DADLE.

Conclusions
—These data suggest that activation of δ-opioid receptors improves recovery of cold-stored hearts to a similar extent as ischemic preconditioning, most likely through an opening of K
ATP
channels. This provides a rationale for improving the preservation of hearts for transplantation by pharmacologically duplicating the common pathway to natural hibernation and preconditioning.
Cardiac-Directed Adenylyl Cyclase Expression Improves Heart Function in Murine Cardiomyopathy
Authors: Roth David M. , Gao Mei Hua , Lai N. Chin , Drumm Jeff , Dalton Nancy , Zhou Jin Yao , Zhu Jian , Entrikin Daniel , Hammond H. Kirk
Published: June 2012

Background
—We tested the hypothesis that increased cardiac myocyte adenylyl cyclase (AC) content increases cardiac function and response to catecholamines in cardiomyopathy.

Methods and Results
—Transgenic mice with cardiac-directed expression of AC type VI (AC
VI
) were crossbred with mice with cardiomyopathy induced by cardiac-directed G
q
expression. G
q
mice had dilated left ventricles, reduced heart function, decreased cardiac responsiveness to catecholamine stimulation, and impaired β-adrenergic receptor (βAR)–dependent and AC-dependent cAMP production. G
q
/AC mice showed improved basal cardiac function in vivo (
P
=0.01) and ex vivo (
P
<0.0005). When stimulated through the βAR, cardiac responsiveness was increased (
P
=0.02), and cardiac myocytes showed increased cAMP production in response to isoproterenol (
P
=0.03) and forskolin (
P
<0.0001).

Conclusions
—Increasing myocardial AC
VI
content in cardiomyopathy restores cAMP-generating capacity and improves cardiac function and responsiveness to βAR stimulation.
C(−260)→T Polymorphism in the Promoter of the CD14 Monocyte Receptor Gene as a Risk Factor for Myocardial Infarction
Authors: Hubacek Jaroslav A. , Pit’ha Jan , Škodová Zdena , Stanĕk Vladimír , Poledne Rudolf
Published: June 2012

Background
—The CD14 receptor of monocytes is an important mediator for the activation of monocytes/macrophages by endotoxins from the envelope of Gram-negative bacteria (lipopolysaccharides). We identified a polymorphism in the CD14 receptor and examined whether this genetic marker influenced the expression of the CD14 receptor on monocytes and affected the predisposition to myocardial infarction.

Methods and Results
—We identified a C(−260)→T nucleotide change, creating a
Hae
III polymorphism in the promoter of the CD14 gene. The polymorphism was determined in 178 male patients <65 years old (cases; average age, 55.9±6.3 years) at the time of their first myocardial infarction and in 135 representative selected male control subjects (controls; average age, 55.2±11.5 years). The frequency of the T allele (absence of the cutting site) was 0.49 in cases and 0.35 in controls (
P
=0.0005; OR, 1.781; 95% CI, 1.286 to 2.465). Subsequently, we measured the expression of monocyte CD14 by flow cytometry in 18 volunteers with different CD14 genotypes. A significantly higher density of the CD14 receptor was shown in the T/T homozygotes than in the others (
P
=0.0028).

Conclusions
—A higher frequency of allele T(−260) in the promoter of the CD14 receptor gene was found in myocardial infarction survivors than in controls. At the same time, this variation was associated with a higher density of CD14 receptors in healthy volunteers. Therefore, we can conclude that in addition to the well-established risk factors, a genetically determined reaction of monocytes/macrophages to infectious stimuli could play an important role in the process of atherosclerosis.
Tumor Necrosis Factor-α–Converting Enzyme and Tumor Necrosis Factor-α in Human Dilated Cardiomyopathy
Authors: Satoh Mamoru , Nakamura Motoyuki , Saitoh Hidenori , Satoh Hidetoshi , Maesawa Chihaya , Segawa Ikuo , Tashiro Atsushi , Hiramori Katsuhiko
Published: June 2012

Background
—Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). TNF-α–converting enzyme (TACE) has recently been purified and its complementary DNA cloned. The expression of TACE results in the production of a functional enzyme that has precursor TNF-α in the mature form. The aim of this study was to determine whether TACE is expressed with TNF-α in myocardium and whether levels of TACE and TNF-α are related to clinical severity of DCM.

Methods and Results
—Endomyocardial tissues were obtained from 30 patients with DCM and 5 control subjects. TNF-α and TACE mRNA levels were measured by a novel real-time quantitative reverse transcriptase–polymerase chain reaction method. Expression of TNF-α and TACE proteins was determined by immunohistochemical analysis. TNF-α mRNA was expressed in DCM patients (TNF-α/GAPDH ratio 0.85±0.24) but not in control subjects. TACE mRNA expression was significantly greater in DCM patients than in control subjects (TACE/GAPDH ratio 2.52±0.59 vs 0.03±0.02,
P
<0.05). A positive correlation was found between TNF-α and TACE mRNA levels (
r
=0.779,
P
<0.001). TACE and TNF-α immunostaining was observed in myocytes in patients with DCM. When 2 subgroups of DCM were divided on the basis of left ventricular end-systolic diameter (LVESD) of 45 mm and left ventricular ejection fraction (LVEF) of 40%, the DCM subgroup with high LVESD (≥45 mm) showed significantly greater expression of TACE (
P
=0.02) and TNF-α (
P
=0.001) than did the low LVESD subgroup (<45 mm). In addition, the DCM subgroup with lower LVEF (<40%) showed higher expression of TACE (
P
=0.006) and TNF-α (
P
=0.01) than did the subgroup with high LVEF (≥40%).

Conclusions
—This study has shown that increased myocardial TACE expression is associated with elevated myocardial TNF-α expression in both mRNA and protein levels in clinically advanced DCM.
Origins of Heart Rate Variability
Authors: Roach Daniel , Malik Paul , Koshman Mary Lou , Sheldon Robert
Published: June 2012

Background
—We propose that heart period sequences are linearly organized, like sentences, and that there is a lexicon of recurrent, similarly shaped transient structures like words. Each word (or lexon) has a characteristic physiological basis. One potential lexon is the transient, reversible tachycardia that is induced by exercise initiation under laboratory conditions. We hypothesized that this lexon was inducible and observable on ambulatory ECGs of most or all subjects, was morphologically similar in both induced and detected bursts, and shared a plausible origin in both circumstances.

Methods and Results
—Ten healthy subjects (mean age, 36 years) underwent a protocol in which subjects rolled themselves from supine to lateral decubitus positions and back. Transient tachycardias (“bursts”) were seen in 36 of 40 rollovers. Bursts were characterized by an initial monoexponential heart period decay (
K
=0.39±0.23 s
−1
), a maximum heart period decrease of 277±109 ms after 10.8±4.5 seconds, and a subsequent return to baseline 23.3±10.8 seconds after roll initiation. The roll-induced bursts were detected with 97% sensitivity and 99% specificity with a search algorithm that incorporated morphological parameters. In 24-hour ambulatory ECGs of 10 healthy subjects (mean age, 38 years; range, 17 to 69 years), 117±59 bursts were detected. Induced and detected bursts were similar in most morphological parameters. Finally, many bursts occurred at night, when rolling over also occurs.

Conclusions
—Bursts are inducible, transient tachycardias that occur clinically and constitute a lexon with an understandable physiology.
Changes in Left Ventricular Diastolic Function 6 Months After Nonsurgical Septal Reduction Therapy for Hypertrophic Obstructive Cardiomyopathy
Authors: Nagueh Sherif F. , Lakkis Nasser M. , Middleton Katherine J. , Killip Donna , Zoghbi William A. , Quiñones Miguel A. , Spencer William H.
Published: June 2012

Background
—Nonsurgical septal reduction therapy (NSRT) decreases left ventricular outflow tract (LVOT) gradient and improves symptoms in patients with hypertrophic obstructive cardiomyopathy (HOCM). NSRT effects on LV/left ventricular diastolic function are currently unknown.

Methods and Results
—HOCM patients (n=29) had Doppler echocardiography at baseline and 6 months after NSRT to evaluate changes in LV volume, pre–A-wave pressure, early diastolic mitral annulus velocity (Ea) by tissue Doppler, and τ. At 6 months, a significant reduction in LVOT gradient (from 53.6±15 to 6±5 mm Hg;
P
<0.001) was accompanied by improvement in exercise duration (from 284±147 to 408±178 seconds;
P
=0.04) and New York Health Association class (from III to I;
P
<0.001). Pre-A pressure (18±6 to 14±5 mm Hg;
P
<0.01) and τ (62±8 to 51±8 ms;
P
<0.01) decreased, whereas Ea (5.8±1.8 to 8±1.8 cml/s;
P
<0.01) and LV end-diastolic volume (117±16 to 130±22 mL;
P
<0.01) increased.

Conclusions
—NSRT improves LV relaxation and compliance, which contributes to the symptomatic relief seen at 6 months.