bluuebunny/crossref_metadata_2025 huggingface dataset:
Two‐Dimensional Fracture Mechanics Analysis Using a Single‐Domain Boundary Element Method
Authors: Ke Chien-Chung , Kuo Cheng-Lung , Hsu Shih-Meng , Liu Shang-Chia , Chen Chao-Shi
Published: June 2012

This work calculates the stress intensity factors (SIFs) at the crack tips, predicts the crack initiation angles, and simulates the crack propagation path in the two‐dimensional cracked anisotropic materials using the single‐domain boundary element method (BEM) combined with maximum circumferential stress criterion.
The BEM formulation, based on the relative displacements of the crack tip, is used to determine the mixed‐mode SIFs and simulate the crack propagation behavior. Numerical examples of the application of the formulation for different crack inclination angles, crack lengths, degree of material anisotropy, and crack types are presented. Furthermore, the propagation path in Cracked Straight Through Brazilian Disc (CSTBD) specimen is numerically predicted and the results of numerical and experimental data compared with the actual laboratory observations. Good agreement is found between the two approaches. The proposed BEM formulation is therefore suitable to simulate the process of crack propagation. Additionally, the anisotropic rock slope failure initiated by the tensile crack can also be analyzed by the proposed crack propagation simulation technique.
Differences in the Treatment Response to Antithyroid Drugs versus Electroconvulsive Therapy in a Case of Recurrent Catatonia due to Graves’ Disease
Authors: Saito Takahiro , Saito Rie , Suwa Hiroshi , Yakushiji Fumiatsu , Takezawa Kenji , Nakamura Mitsuru
Published: June 2012

We reported a case which presented recurrent episodes of catatonia as a result of Graves’ disease with hyperthyroidism. The patient showed different treatment response in each episodes; in the first episode, psychiatric and physical symptoms were resolved by a combination of antithyroid and anxiolytic therapies, while in the second episode, the combination therapy did not ameliorate her symptoms and ECT was indicated. We postulated that decreased CSF level of TTR and the resulting susceptibility to the derangement of peripheral thyroid function might be involved in this different treatment response.
SERS Substrates by the Assembly of Silver Nanocubes: High-Throughput and Enhancement Reliability Considerations
Authors: Rabin Oded , Lee Seung Yong
Published: June 2012

Small clusters of nanoparticles are ideal substrates for SERS measurements, but the SERS signal enhancement by a particular cluster is strongly dependent on its structural characteristics and the measurement conditions. Two methods for high-throughput assembly of silver nanocubes into small clusters at predetermined locations on a substrate are presented. These fabrication techniques make it possible to study both the structure and the plasmonic properties of hundreds of nanoparticle clusters. The variations in SERS enhancement factors from cluster to cluster were analyzed and correlated with cluster size and configuration, and laser frequency and polarization. Using Raman instruments with 633 nm and 785 nm lasers and linear clusters of nanocubes, an increase in the reproducibility of the enhancement and an increase in the average enhancement values were achieved by increasing the number of nanocubes in the cluster, up to 4 nanocubes per cluster. By examining the effect of cluster configuration, it is shown that linear clusters with nanocubes attached in a face-to-face configuration are not as effective SERS substrates as linear clusters in which nanocubes are attached along an edge.
Synthesis and Biological Evaluation of Achiral Indole-Substituted Titanocene Dichloride Derivatives
Authors: Deally Anthony , Hackenberg Frauke , Lally Grainne , Tacke Matthias
Published: June 2012

Six new titanocene compounds have been isolated and characterised. These compounds were synthesised from their fulvene precursors using Super Hydride (LiBEt3H) followed by transmetallation with titanium tetrachloride to yield the corresponding titanocene dichloride derivatives. These complexes are bis-[((1-methyl-3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5a), bis-[((5-methoxy-1-methyl,3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5b), bis-[((1-methyl,3-diethylaminomethyl)indol-4-yl)methylcyclopentadienyl] titanium (IV) dichloride (5c), bis-[((5-bromo-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5d), bis-[((5-chloro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5e), and bis-[((5-fluoro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5f). All six titanocenes 5a–5f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines using DMSO and Soluphor P as solubilising agents in order to determine their IC50 values. Titanocenes 5a–5f were found to have IC50 values of 10 (±2), 21 (±3), 29 (±4), 140 (±6), and 450 (±10) μM when tested using DMSO.
Retinoid Differentiation Therapy for Common Types of Acute Myeloid Leukemia
Authors: Brown Geoffrey , Hughes Philip
Published: June 2012

Many cancers arise in a tissue stem cell, and cell differentiation is impaired resulting in an accumulation of immature cells. The introduction of all-transretinoic acid (ATRA) in 1987 to treat acute promyelocytic leukemia (APL), a rare subtype of acute myeloid leukemia (AML), pioneered a new approach to obtain remission in malignancies by restoring the terminal maturation of leukemia cells resulting in these cells having a limited lifespan. Differentiation therapy also offers the prospect of a less aggressive treatment by virtue of attenuated growth of leukemia cells coupled to limited damage to normal cells. The success of ATRA in differentiation therapy of APL is well known. However, ATRA does not work in non-APL AML. Here we examine some of the molecular pathways towards new retinoid-based differentiation therapy of non-APL AML. Prospects include modulation of the epigenetic status of ATRA-insensitive AML cells, agents that influence intracellular signalling events that are provoked by ATRA, and the use of novel synthetic retinoids.
Effects of Beta-Blocker Use on Volume Status in Hemodialysis Patients
Authors: Bi Shu-Hong , Linke Lori , Wu Jimmy , Cheng Li-Tao , Wang Tao , Ahmad Suhail
Published: June 2012

Background: Removal and control of excess fluid with dialysis is considered critical for protection against cardiovascular sequelae. Antihypertensive agents including beta-blockers may influence hemodynamics, which may limit fluid removal during hemodialysis (HD). Methods: Fifty chronic HD patients underwent bioimpedance measurement before and after a midweek dialysis session. Data on volume status, blood pressure, antihypertensive medications, and bioimpedance were analyzed. Results: Patients in the high-volume status group used a significantly higher percentage of beta-blockers than patients in the low-volume status group (54.2 vs. 19.2%, respectively, p = 0.01). Multivariable regression revealed that the use of beta-blockers was independently positively associated with fluid overload (p < 0.05). Intradialytic muscle cramping occurred more often in the beta-blocker group than the control group (44.4 vs. 12.5%, respectively, p = 0.02). Conclusions: Our results suggest that the use of beta-blockers was associated with fluid overload in HD patients, and patients being treated with them experienced more intradialytic muscle cramping during dialysis.
Two Missense Mutations in the Primary Autosomal Recessive Microcephaly Gene MCPH1 Disrupt the Function of the Highly Conserved N-Terminal BRCT Domain of Microcephalin
Authors: Ghani-Kakhki M. , Robinson P.N. , Morlot S. , Mitter D. , Trimborn M. , Albrecht B. , Varon R. , Sperling K. , Neitzel H.
Published: June 2012

Primary microcephaly MCPH1 is an extremely rare autosomal recessive disorder associated with congenital microcephaly, mental retardation and a distinctive cellular phenotype of misregulated chromosome condensation. The MCPH1 gene encodes an 835-amino acid protein, microcephalin, which contains 1 N-terminal and 2 C-terminal BRCT (BRCA1 C-terminus) domains. BRCT domains are predominantly found in proteins involved in cell cycle control and DNA repair. Here we describe 1 novel and 1 previously reported MCPH1 missense mutation, p.Trp75Arg and p.Ser72Leu, respectively, in the N-terminal BRCT domain of microcephalin associated with severe congenital microcephaly. Both residues are entirely conserved in the MCPH1 orthologs of all vertebrate species and Drosophila. Proliferating lymphocytes of the patients with p.Trp75Arg and p.Ser72Leu show the unique cellular MCPH1 phenotype of misregulated chromosome condensation, indicating that these missense alterations disrupt the function of the N-terminal BRCT domain of the protein. Interestingly, both residues are strictly conserved in BRCT domains of BRCA1. ClustalW alignments show that the residue p.Ser72 of microcephalin corresponds to p.Ser1715 of the N-terminal BRCT domain of BRCA1, while the microcephalin residue p.Trp75 is analogous to p.Trp1718 in the N-terminal BRCT and to p.Trp1837 in C-terminal BRCT domains of BRCA1. Missense alterations for all 3 corresponding BRCA1 residues were described and are predicted to be deleterious resulting in the destabilization of the BRCA1 protein. Our data on the 2 MCPH1 missense alterations provide further evidence for the functional significance of these residues in BRCT domains.
Identification of a Novel 14q13.3 Deletion Involving the SLC25A21 Gene Associated with Familial Synpolydactyly
Authors: Meyertholen K. , Ravnan J.B. , Matalon R.
Published: June 2012

Synpolydactyly is a relatively rare malformation. Recently, we came across a male infant with a familial synpolydactyly of the hands and feet. As most familial synpolydactyly syndromes have not been linked to any specific mutations, we felt further investigation was warranted. Using microarray and fluorescent in situ hybridization analysis, we identified a novel mutation of the SLC25A21 gene on chromosome 14.
Impact of Prophylactic Immediate Posttransplant Ganciclovir on Development of Transplant Atherosclerosis
Authors: Valantine Hannah A. , Gao Shao-Zhou , Menon Santosh G. , Renlund Dale G. , Hunt Sharon A. , Oyer Philip , Stinson Edward B. , Brown Byron W. , Merigan Thomas C. , Schroeder John S.
Published: June 2012

Background
—Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD.

Methods and Results
—One hundred forty-nine consecutive patients (131 men and 18 women aged 48±13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7±1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43±8% versus 60±10% (
P
<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5;
P
<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3;
P
=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32±11% (n=28) for ganciclovir versus 62±16% (n=25) for placebo (
P
<0.03); calcium blockers (n=68), 50±14% (n=33) for ganciclovir versus 45±12% (n=35) for placebo (
P
=NS).

Conclusions
—TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.
Promotion of Atrial Fibrillation by Heart Failure in Dogs
Authors: Li Danshi , Fareh Samir , Leung Tack Ki , Nattel Stanley
Published: June 2012

Background
—Studies of atrial fibrillation (AF) due to atrial tachycardia have provided insights into the remodeling mechanisms by which “AF begets AF” but have not elucidated the substrate that initially supports AF before remodeling occurs. We studied the effects of congestive heart failure (CHF), an entity strongly associated with clinical AF, on atrial electrophysiology in the dog and compared the results with those in dogs subjected to rapid atrial pacing (RAP; 400 bpm) with a controlled ventricular rate (AV block plus ventricular pacemaker at 80 bpm).

Methods and Results
—CHF induced by 5 weeks of rapid ventricular pacing (220 to 240 bpm) increased the duration of AF induced by burst pacing (from 8±4 seconds in control dogs to 535±82 seconds;
P
<0.01), similar to the effect of 1 week of RAP (713±300 seconds). In contrast to RAP, CHF did not alter atrial refractory period, refractoriness heterogeneity, or conduction velocity at a cycle length of 360 ms; however, CHF dogs had a substantial increase in the heterogeneity of conduction during atrial pacing (heterogeneity index in CHF dogs, 2.76±0.16 versus 1.46±0.10 for control and 1.51±0.06 for RAP dogs;
P
<0.01) owing to discrete regions of slow conduction. Histological examination revealed extensive interstitial fibrosis (connective tissue occupying 12.8±1.9% of the cross-sectional area) in CHF dogs compared with control (0.8±0.3%) and RAP (0.9±0.2%) dogs.

Conclusions
—Experimental CHF strongly promotes the induction of sustained AF by causing interstitial fibrosis that interferes with local conduction. The substrates of AF in CHF are very different from those of atrial tachycardia–related AF, with important potential implications for understanding, treating, and preventing AF related to CHF.
Incremental Prognostic Value of Post-Stress Left Ventricular Ejection Fraction and Volume by Gated Myocardial Perfusion Single Photon Emission Computed Tomography
Authors: Sharir Tali , Germano Guido , Kavanagh Paul B. , Lai Shenhan , Cohen Ishac , Lewin Howard C. , Friedman John D. , Zellweger Michael J. , Berman Daniel S.
Published: June 2012

Background
—The incremental prognostic value of post-stress left ventricular ejection fraction (EF) and volume over perfusion has not been investigated.

Methods and Results
—We identified 1680 consecutive patients who underwent rest Tl-201/stress Tc-99m sestamibi gated single photon emission computed tomography (SPECT) and who were followed-up for 569±106 days. Receiver-operator characteristics analysis defined an EF<45%, an end-systolic volume (ESV) >70 mL, and an end-diastolic volume >120 mL as optimal thresholds, yielding moderate sensitivity and high specificity in the prediction of cardiac death. Patients with an EF≥45% had mortality rates <1%/year, despite severe perfusion abnormalities, whereas patients with an EF<45% had high mortality rates, even with only mild/moderate perfusion abnormalities (9.2%/year;
P
<0.00001). Similarly, an ESV≤70 mL was related to a low cardiac death rate (<1.2%/year), even for patients with severe perfusion abnormalities, whereas patients with an ESV>70 mL and only mild/moderate perfusion abnormalities had high death rates (8.2%/year;
P
<0.00001). Patients with an EF<45% and an ESV≤70 mL had low cardiac death rates (1.7%/year); those with an EF<45% but an ESV>70 mL had high death rates (7.9%/year;
P
<0.02). Multivariate Cox proportional hazards regression showed that perfusion variables and ESV were independent predictors of overall coronary events, whereas EF and ESV demonstrated incremental prognostic values over prescan and perfusion information in predicting cardiac death and cardiac death or myocardial infarction.

Conclusions
—Post-stress EF and ESV by gated-SPECT have incremental prognostic values over prescan and perfusion information in predicting cardiac death, and they provide clinically useful risk stratification.
Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans
Authors: Kanani Prapti M. , Sinkey Christine A. , Browning Roger L. , Allaman Margaret , Knapp Howard R. , Haynes William G.
Published: June 2012

Background
—Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress.

Methods and Results
—Oral administration of
l
-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia (≈25 μmol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477±82%; placebo, 673±110%;
P
=0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3±2.7%) compared with placebo (8.2±1.6%,
P
=0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (
P
=0.03).

Conclusions
—Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.
New Method for Detection of Heart Allograft Rejection
Authors: Morgan David C. , Wilson Janet E. , MacAulay Calum E. , MacKinnon Nicholas B. , Kenyon Jennifer A. , Gerla Paul S. , Dong Chunming , Zeng Haishan , Whitehead Peter D. , Thompson Christopher R. , McManus Bruce M.
Published: June 2012

Background
—Patients with inflammatory heart muscle diseases would benefit from a safe, convenient, rapidly performed diagnostic technique with real-time results not involving tissue removal. We have performed a detailed evaluation of detection of heart allograft rejection by autofluorescence in a heterotopic abdominal rat heart allograft model ex vivo.

Methods and Results
—Recipient rats with allograft (Lewis to Fisher 344; n=71) and isograft (Lewis to Lewis; n=33) hearts, treated with cyclosporine or untreated, were killed at days 2, 4, 7, 14, 21, 28, and 56 after transplant. Nontransplant controls with (n=24) or without (n=24) immunosuppressive therapy were also studied. When the rats were killed, autofluorescence spectra were acquired under blue-light excitation from midtransverse ventricular sections of native and transplanted hearts. Corresponding sections were then evaluated pathologically by a modified International Society for Heart and Lung Transplantation (ISHLT) grading schema. The spectral differences between rejecting and nonrejecting hearts were quantified by linear discriminant functions, producing scores that decreased progressively with increasing severity of tissue rejection. Mean±SD discriminant function scores were 2.9±1.6, 1.8±2.2, −0.1±2.8, −1.2±2.3, and −2.3±3.0 for isografts and allograft ISHLT grades 0, I, II, and III, respectively (Spearman rank-order correlation −0.6;
P
<0.001, test for trend). Cyclosporine had no detectable effect on the spectra.

Conclusions
—The correlation between changes in autofluorescence spectra and ISHLT rejection grade strongly supports the possibility of catheter-based, fluorescence-guided surveillance of rejection.
Homozygous Premature Truncation of the HERG Protein
Authors: Hoorntje Theo , Alders Marielle , van Tintelen Peter , van der Lip Karin , Sreeram Narayanswami , van der Wal Allard , Mannens Marcel , Wilde Arthur
Published: June 2012

Background
—In long-QT syndrome (LQTS), heterozygosity for a mutation in 1 of the K
+
channel genes leads to prolongation of the cardiac action potential, because the aberrant protein exhibits “loss of function.” HERG, which is involved in LQT2, is the gene encoding the rapid component of the delayed rectifier, I
Kr
.

Methods and Results
—In a consanguineous family, a stillbirth was followed by the premature birth of a child in distress due to ventricular arrhythmia in the presence of QT prolongation. LQTS was diagnosed, β-blocker therapy was begun, and a pacemaker was implanted. She developed well and remained symptom-free for 1.5 years. In the index patient, we identified a duplication of bp 558 to 600 in exon 4 of HERG on both alleles. This will result in a frameshift and a premature stop codon before the S1 domain of the HERG protein. Because it is present on both alleles, no functional I
Kr
is anticipated. The same mutation was found heterozygously in both parents and homozygously in the stillborn brother.

Conclusions
—It is concluded that absence of I
Kr
gives rise to a severe cardiac phenotype, with no indication of malfunction of any other organ.
Failure to Improve Left Ventricular Function After Coronary Revascularization for Ischemic Cardiomyopathy Is Not Associated With Worse Outcome
Authors: Samady Habib , Elefteriades John A. , Abbott Brian G. , Mattera Jennifer A. , McPherson Craig A. , Wackers Frans J. Th.
Published: June 2012

Background
—Preoperative identification of viable myocardium in patients with ischemic cardiomyopathy is considered important because CABG can result in recovery of left ventricular (LV) function. However, the hypothesis that lack of improvement of LV function after CABG is associated with poorer patient outcome is untested.

Methods and Results
—Outcome was compared in patients with ischemic LV dysfunction (LVEF ≤0.30) with and without improvement in LVEF after CABG. Of 135 consecutive patients, 128 (95%) survived CABG and 104 (77%) had pre- and post-CABG LVEF assessment. Of these 104 patients, 68 (65%) had >0.05 increase in LVEF (group A) and 36 (35%) had no significant change, or ≤0.05 decrease in LVEF (group B) compared with pre-CABG LVEF. No significant differences existed in age, gender, comorbidities, baseline symptoms, baseline LVEF, or intraoperative variables between groups A and B. Group A increased LVEF from 0.24±0.05 to 0.39±0.1 (
P
<0.005). In Group B, LVEF did not change significantly postoperatively, 0.24±0.05 to 0.23±0.06 (
P
=NS). Postoperative improvement in angina and heart failure scores were similar between the 2 groups. Survival free of cardiac death was similar for both groups (93% in group A and 94% in group B,
P
=NS) at a mean follow-up of 32±23 months.

Conclusions
—Lack of improvement of global LVEF after CABG is not associated with poorer outcome compared with that of patients with improved LVEF, presumably because effective revascularization of ischemic myocardium, even without improvement in ventricular function, protects against future infarction and death.
Hemodynamic Effects of Basal and Stimulated Release of Endogenous Nitric Oxide in Isolated Human Lungs
Authors: Cremona George , Higenbottam Timothy W. , Bower Edward A. , Wood Alison M. , Stewart Susan
Published: June 2012

Background
—We compared the hemodynamic responses to inhibition or stimulation of endothelial nitric oxide (NO) release of isolated explanted lungs from transplantation recipients with pulmonary hypertension and in normotensive unallocated donor lungs.

Methods and Results
—Lungs from 10 patients with severe pulmonary hypertension (SPH) and from 16 patients with severe chronic obstructive lung disease (COLD) were studied. Fourteen normotensive lungs were studied as controls. The lungs were perfused at a constant flow. In protocol 1
N
G
-nitro-
l
-arginine methyl ester caused a similar rise in baseline pulmonary artery pressure (PAP) that was similar in SPH (+17.1±4.2 mm Hg; n=5), COLD (+15.5±4.8 mm Hg; n=8), and control lungs (+14.5±1.5 mm Hg; n=7). Arterial occlusion demonstrated that most of the changes with
N
G
-nitro-
l
-arginine methyl ester were precapillary. The response to sodium nitroprusside (10
−8
to 10
−4
mol/L) was similar in all groups. In protocol 2, the lungs were preconstricted, and acetylcholine (10
−9
to 10
−5
mol/L) caused a lesser fall in PAP in both COLD and SPH lungs compared with control (−41.9±8.6%, −55.7±7.6%, and −73.2±2.5%, respectively;
P
<0.05), whereas sodium nitroprusside (10
−5
mol/L) decreased PAP to initial levels in all lungs.

Conclusions
—Stimulated release of NO is impaired in arteries of lungs with plexogenic or hypoxemic pulmonary hypertension. In contrast, basal release of NO appears to be maintained.
Dynamic Behavior and Autonomic Regulation of Ectopic Atrial Pacemakers
Authors: Huikuri Heikki V. , Poutiainen Aino-Maija , Mäkikallio Timo H. , Koistinen M. Juhani , Airaksinen K. E. Juhani , Mitrani Raul D. , Myerburg Robert J. , Castellanos Agustin
Published: June 2012

Background
—Heart rate (HR) variability reflects the neural regulation of normal pacemaker tissue, but the autonomic nervous regulation of abnormal atrial foci originating outside the sinus node has not been well characterized. We compared the HR variability of tachycardias originating from the ectopic foci and the sinus node.

Methods and Results
—R-R–interval variability was analyzed from 24-hour Holter recordings in 12 patients with incessant ectopic atrial tachycardia (average HR 107±14 bpm), 12 subjects with sinus tachycardia (average HR 106±9 bpm), and 24 age- and sex-matched subjects with normal sinus rhythm (average HR 72±8 bpm). Time- and frequency-domain HR variability measures, along with approximate entropy, short- and long-term correlation properties of R-R intervals (exponents α
1
and α
2
), and power-law scaling (exponent β), were analyzed. Time- and frequency-domain measures of HR variability did not differ between subjects with ectopic and sinus tachycardia. Fractal scaling exponents and approximate entropy were similar in sinus tachycardia and normal sinus rhythm, but the short-term scaling exponent α
1
was significantly lower in ectopic atrial tachycardia (0.71±0.16) than in sinus tachycardia (1.16±0.13;
P
<0.001) or normal sinus rhythm (1.19±0.11;
P
<0.001). Abrupt prolongations in R-R intervals due to exit blocks from the ectopic foci or instability in beat-to-beat R-R dynamics were the major reasons for altered short-term HR behavior during ectopic tachycardias.

Conclusions
—HR variability obtained by time- and frequency-domain methods does not differ between ectopic and sinus tachycardias, which suggests that abnormal atrial foci are under similar long-term autonomic regulation as normal pacemaker tissue. Short-term R-R–interval dynamics are altered toward more random behavior in ectopic tachycardia, which may result from a specific autonomic disturbance or an intrinsic abnormality of ectopic atrial pacemakers.
A Positive Family History of Premature Coronary Artery Disease Is Associated With Impaired Endothelium-Dependent Coronary Blood Flow Regulation
Authors: Schächinger Volker , Britten Martina B. , Elsner Mathias , Walter Dirk H. , Scharrer Inge , Zeiher Andreas M.
Published: June 2012

Background
—The aim of the study was to determine whether a positive family history of coronary artery disease is related to impaired coronary blood flow regulation.

Methods and Results
—In 150 patients with angiographically normal or minimally diseased coronary vessels, risk factors for coronary artery disease, the extent of atherosclerosis and endothelium-dependent vasomotor responses to acetylcholine, and endothelium-independent blood flow regulation by papaverine or adenosine were assessed. Coronary blood flow responses to acetylcholine were reduced in a dose-dependent manner in patients with a positive family history (
P
=0.030). By multivariate analysis, hypercholesterolemia (
P
=0.001), age (
P
=0.002), and a positive family history (
P
=0.008) remained predictors of coronary blood flow increase to acetylcholine. The extent of atherosclerotic coronary artery disease was, by multivariate analysis, an additional independent predictor of acetylcholine-induced blood flow (
P
=0.014), but also of endothelium-independent blood flow regulation (
P
=0.001). A positive family history had additive effects in addition to the other risk factors, such as hypercholesterolemia or increased age. Angiotensin-converting-enzyme genotype polymorphism had no influence either on endothelium-dependent or endothelium-independent coronary blood flow responses. However, in a subset of 28 patients, homocysteine (which is, in part, genetically determined) was inversely related to maximal acetylcholine-induced blood flow regulation (
r
=−0.47,
P
=0.012).

Conclusions
—The results of this study demonstrate, for the first time, that a positive family history of coronary artery disease is an important predictor of impaired endothelium-dependent coronary blood flow regulation in humans. The influence of a positive family history is independent of other well known risk factors but instead aggravates endothelial vasodilator dysfunction associated with hypercholesterolemia and increased age, suggesting important interacting effects between genetic and environmental risk factors.
Cytomegalovirus Infection of Rats Increases the Neointimal Response to Vascular Injury Without Consistent Evidence of Direct Infection of the Vascular Wall
Authors: Zhou Yi Fu , Shou Matie , Guetta Esther , Guzman Raul , Unger Ellis F. , Yu Zu Xi , Zhang Jun , Finkel Toren , Epstein Stephen E.
Published: June 2012

Background
—Previous studies suggest that infection may play a role in restenosis and atherogenesis; cytomegalovirus (CMV) is one of the implicated pathogens. To determine a potential causal role of CMV in these disease processes, we assessed whether CMV infection increases the neointimal response to injury of the rat carotid artery.

Methods and Results
—Carotid injury was performed on 60 rats; immediately thereafter, 30 rats were infected with rat CMV, and the other 30 were mock-infected. Six weeks later, rats were euthanized, and the salivary glands, spleen, and carotid arteries were harvested. CMV infection was associated with significant exacerbation of the neointimal response to injury (neointimal to medial ratio 0.81±0.59 versus 0.31±0.38 in CMV-infected versus control rats;
P
<0.0001). This occurred despite absence of infectious virus from vascular tissues and detection of CMV DNA by polymerase chain reaction in the injured artery only at day 3 after infection. Persistent distant infection, associated with systemic cytokine response, was evidenced by isolation of infectious virus from homogenates of both salivary glands and spleen and by higher serum levels of interleukin (IL)-2 and IL-4 (but not interferon-γ and tumor necrosis factor-α) in infected versus noninfected rats.

Conclusions
—CMV infection of immunocompetent adult rats increases the neointimal response to vascular injury, suggesting that CMV may play a causal role in atherosclerosis/restenosis. Importantly, this CMV-induced response occurs even without the presence of virus in the vascular wall, suggesting that inflammatory and immune responses to infection of nonvascular tissues may contribute to the vascular response to injury.
Firing Properties of Single Muscle Vasoconstrictor Neurons in the Sympathoexcitation Associated With Congestive Heart Failure
Authors: Macefield Vaughan G. , Rundqvist Bengt , Sverrisdottir Yrsa B. , Wallin B. Gunnar , Elam Mikael
Published: June 2012

Background
—Congestive heart failure (CHF) in humans is associated with a marked sympathoexcitation, including an augmented muscle sympathetic nerve activity (MSNA) in intraneural multiunit recordings. In the present study, single-unit recording was used to evaluate whether the firing properties of individual muscle vasoconstrictor neurons can reveal underlying mechanisms for this increase in MSNA.

Methods and Results
—Eight patients with CHF (NYHA class II to IV; left ventricular ejection fraction, 29±5%, mean±SEM) were studied. In standard multiunit recordings, MSNA burst incidence (bursts/100 heartbeats) ranged from 65% to 100% (88±5%). Using selective tungsten microelectrodes, we made recordings from 16 single muscle vasoconstrictor axons. Mean unit firing probability (ie, the percentage of cardiac intervals in which a single axon fired) was 54.5±5.2% (range, 21 to 89%), and mean firing frequency was 0.98±0.22 Hz (0.14 to 3.86 Hz), both of which were higher than seen previously in healthy subjects (
P
<0.001). Although single neurons occasionally generated multiple spikes per sympathetic burst, such multiple firing was rare and was not different from that seen in healthy subjects.

Conclusions
—An increased firing frequency of individual vasoconstrictor neurons is one mechanism for the increased number of multiunit MSNA bursts at rest in CHF. The neurons discharge in more diastoles than in healthy subjects (ie, firing probability is increased), but the likelihood of discharging >1 impulse per sympathetic burst is not increased. Despite the intense multiunit activity at rest, the firing characteristics of individual vasoconstrictor axons indicate a remaining capacity for transient increases of MSNA in CHF.
Developmental Changes in Prostaglandin E
2
Receptor Subtypes in Porcine Ductus Arteriosus
Authors: Bhattacharya Mousumi , Asselin Pierre , Hardy Pierre , Guerguerian Anne-Marie , Shichi Hitoshi , Hou Xin , Varma Daya R. , Bouayad Asmàa , Fouron Jean-Claude , Clyman Ronald I. , Chemtob Sylvain
Published: June 2012

Background
—Prostaglandin E
2
(PGE
2
) is important in ductus arteriosus (DA) patency, but the types of functional PGE
2
receptors (EP) in the developing DA are not known. We postulated that age-dependent alterations in EP and/or their subtypes may possibly contribute to the reduced responsiveness of the newborn DA to PGE
2
.

Methods and Results
—We determined PGE
2
receptor subtypes by competition binding and immunoblot studies on the DA of fetal (≈75% and 90% gestation) and newborn (<45 minutes old) pigs. We studied the effects of EP receptor stimulation on cAMP signaling in vitro and on term newborn (<3 hours old) DA patency in vivo. Fetal pig DA expressed EP
2
, EP
3
, and EP
4
receptors equivalently, but not EP
1
. In neonatal DA, EP
1
, EP
3
, and EP
4
were undetectable, whereas EP
2
density was similar in fetus and newborn. Prostaglandin-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE
2
and 11-deoxy PGE
1
(EP
2
/EP
3
/EP
4
agonist) produced more cAMP in fetus than newborn, but butaprost (selective EP
2
agonist) caused similar cAMP increases in both; EP
3
and EP
4
ligands (M&B28767 and AH23848B, respectively) affected cAMP production only in fetus. After birth, administration of butaprost alone was as effective as 11-deoxy PGE
1
and 16,16-dimethyl PGE
2
in dilating DA in vivo.

Conclusions
—The data reveal fewer PGE
2
receptors in the DA of the newborn than in that of the fetus; this may contribute to the decreased responsiveness of the DA to PGE
2
in newborn. Because EP
2
receptors seem to mediate the effects of PGE
2
on the newborn DA, one may propose that a selective EP
2
agonist may be preferred as a pharmacological agent to maintain DA patency in infants with certain congenital heart diseases.
Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice
Authors: Tangirala Rajendra K. , Tsukamoto Kazuhisa , Chun Sam H. , Usher David , Puré Ellen , Rader Daniel J.
Published: June 2012

Background
—The ability of apolipoprotein (apo)A-I to induce regression of preexisting atherosclerotic lesions has not been determined, and a mouse model of atherosclerosis regression has not yet been reported.

Methods and Results
—LDL receptor–deficient mice were fed a western-type diet for 5 weeks to induce atherosclerotic lesions. A second-generation recombinant adenovirus encoding human apoA-I or a control adenovirus were injected intravenously in order to express apoA-I in the liver. Three days after injection, total apoA-I levels in mice injected with the apoA-I–expressing adenovirus were 216±16.0 mg/dL, compared with 68.0±3.0 mg/dL in control virus–injected mice (
P
<0.001). HDL cholesterol levels in mice injected with the AdhapoA-I vector 7 days after injection were 189±21.0 mg/dL, compared with 123±8.0 mg/dL in control virus-injected mice (
P
<0.02). Total and non-HDL cholesterol levels did not differ between the 2 groups. Atherosclerotic lesion area was quantified by en face analysis of the aorta and cross-sectional analysis of the aortic root. Compared with baseline mice, atherosclerosis progressed in mice injected with the control adenovirus. In contrast, in mice expressing apoA-I compared with baseline mice, total en face aortic lesion area was reduced by 70% and aortic root lesion was reduced by 46%. Expression of apoA-I was associated with a significant reduction in the fraction of lesions occupied by macrophages and macrophage-derived foam cells.

Conclusions
—Liver-directed gene transfer of human apoA-I resulted in significant regression of preexisting atherosclerotic lesions in LDL receptor–deficient mice as assessed by 2 independent methods.
Local
l
-Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis
Authors: Niebauer Josef , Schwarzacher Severin P. , Hayase Motoya , Wang Bingyin , Kernoff Robert S. , Cooke John P. , Yeung Alan C.
Published: June 2012

Background
—Local administration of
l
-arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of
l
-arginine inhibits lesion formation.

Methods and Results
—New Zealand White rabbits (n=56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either
l
-arginine (800 mg/5 mL with and without 100 μCi
l
-[2,3-
3
H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled
l
-arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676±223 versus 453±93 cpm/mg;
P
<0.02); this was associated with significantly higher NO levels in the
l
-arginine–treated segments (394.4±141.6 versus 86.3±34.3 nmol/mg;
P
<0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with
l
-arginine as compared with saline infusion (
P
<0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of
l
-arginine as compared with the saline-treated segments (
P
<0.05).

Conclusions
—Intramural delivery of
l
-arginine immediately after angioplasty causes a sustained increase in tissue
l
-arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.
Transatlantic Conference on Clinical Trial Guidelines in Peripheral Arterial Disease
Authors: Labs Karl-Heinz , Dormandy John A. , Jaeger Kurt A. , Stuerzebecher Claus-Steffen , Hiatt William R.
Published: June 2012

Abstract
—Guidelines for the clinical development of drugs in peripheral arterial disease (PAD) have been issued by the Food and Drug Administration for the United States and by the regulatory agency of the European Union for Europe. With increasing globalization, transatlantic cooperation in drug research and development is essential for the future and would be substantially facilitated by the existence of transatlantic guidelines. A conference was held in Basel, Switzerland, in November 1997 to discuss the scientific background of the existing guidelines on the basis of published evidence and the extensive knowledge of clinical investigators and experienced regulators. The meeting was attended by 52 invited experts from the United States and Europe, as well as by representatives from the 2 regulatory authorities. The main conclusions from the meeting are presented and may serve as a reference for the future development of transatlantic guidelines for the evaluation of pharmacotherapy in PAD.
Demonstration of the Proarrhythmic Preconditioning of Single Premature Extrastimuli by Use of the Magnitude, Phase, and Distribution of Repolarization Alternans
Authors: Narayan Sanjiv M. , Lindsay Bruce D. , Smith Joseph M.
Published: June 2012

Background
—We hypothesized that single premature extrastimuli (S
2
) insufficient to induce reentry produce proarrhythmic effects (proarrhythmic preconditioning) that are measurable by use of the magnitude, phase, and temporal distribution of repolarization alternans (RPA; alternate-beat fluctuations in ECG repolarization).

Methods and Results
—Before programmed electrical stimulation (PES), surface ECG leads I, aVF, and V
1
were recorded in 30 patients during simultaneous atrial and ventricular pacing at 500 ms with S
2
coupling intervals (CIs) decreasing from 400 to 240 ms in 20-ms steps. We determined RPA magnitude (V
alt
) as the 0.5-cycle/beat peak after spectral decomposition of consecutive STU intervals over 64 beats immediately preceding and following each S
2
, RPA phase reversals as discontinuities in the even/odd phase of STU alternation, and RPA distribution as the time point of median RPA magnitude within repolarization. Eighteen patients were induced into ventricular tachycardia (VT), whereas 12 were not. Extrastimuli dynamically modulated each characteristic of RPA. S
2
augmented V
alt
in inducible (8.2±2.3 versus 6.2±1.6 μV;
P
=0.003) but not noninducible patients. S
2
reversed RPA phase more in inducible than in noninducible patients (56.7% versus 45.3%;
P
=0.02 by χ
2
), particularly when CI was ≤300 ms (66.3% versus 46.5%;
P
=0.006). Finally, S
2
redistributed RPA significantly later within repolarization in inducible patients. Each effect was more marked for CI ≤300 ms.

Conclusions
—A single S
2
increases RPA magnitude, reverses its phase, and redistributes it later in repolarization in patients with the substrates for VT. These effects become more pronounced with shorter coupling intervals. These results suggest that it is possible to track the dynamic proarrhythmic preconditioning of single premature depolarizations.
Contribution of Vasodilator Prostanoids and Nitric Oxide to Resting Flow, Metabolic Vasodilation, and Flow-Mediated Dilation in Human Coronary Circulation
Authors: Duffy Stephen J. , Castle Sally F. , Harper Richard W. , Meredith Ian T.
Published: June 2012

Background
—Endothelial dysfunction is associated with atherosclerosis and may contribute to ischemic syndromes. We assessed the contribution of endothelium-derived nitric oxide (NO) and vasodilator prostanoids to resting blood flow, metabolic vasodilation, and flow reserve in the human coronary circulation.

Methods and Results
—Coronary hemodynamics were assessed before and after inhibition of vasodilator prostanoids and NO with intracoronary aspirin (acetylsalicylic acid [ASA]) and
N
G
-monomethyl-
l
-arginine (L-NMMA), respectively. Angiographically smooth or mildly irregular vessels, with normal adenosine-induced coronary flow reserve, were studied in 25 patients undergoing clinically indicated procedures. Coronary blood velocity was measured by Doppler flow wire, and coronary blood flow (CBF) was calculated. ASA reduced resting conduit vessel diameter by 11% (
P
=0.003) and CBF by 27% (
P
=0.008) and increased coronary vascular resistance (CVR) by 24% (
P
<0.0001). ASA attenuated pacing-induced hyperemia by 28% (45.0±4.6 versus 32.6±3.4 mL/min,
P
=0.005) and increased minimum CVR by 39% (2.8±0.3 versus 3.9±0.5 mm Hg · mL
−1
· min
−1
,
P
=0.007). L-NMMA reduced resting conduit vessel diameter by 9% (
P
=0.05) and CBF by 20% (
P
=0.08) and increased CVR by 19% (
P
=0.03). L-NMMA attenuated pacing-induced hyperemia by 20% (42.4±5.1 versus 34.1±3.4 mL/min,
P
=0.04) and increased minimum CVR by 33% (2.9±0.4 versus 3.8±0.5 mm Hg · mL
−1
· min
−1
,
P
=0.02). ASA (7.7±2.3% versus −1.6±3.2%,
P
=0.06) and L-NMMA (12.1±3.9% versus 0.0±2.9%,
P
=0.02) abolished pacing-induced conduit vessel flow–mediated dilation.

Conclusions
—Tonic release of vasodilator prostanoids and NO contributes to resting conduit and resistance vessel tone and to peak functional hyperemia and flow-mediated dilation after metabolic stimulation. This underscores the importance of normal endothelial function for metabolic vasodilation and suggests that it may be a key mechanism for preventing myocardial ischemia in coronary artery disease.
Independent Prognostic Value of Elevated C-Reactive Protein in Unstable Angina
Authors: Ferreirós Ernesto R. , Boissonnet Carlos P. , Pizarro Rodolfo , Merletti Pablo F. García , Corrado Gianni , Cagide Arturo , Bazzino Oscar O.
Published: June 2012

Background
—There is growing evidence of the prognostic importance of C-reactive protein (CRP) in unstable angina. However, the independent value of CRP relative to other conventional markers at different stages of treatment has not been established. Therefore, we assessed the in-hospital and 90-day prognostic values of serum CRP in unstable angina. We also compared the relation of CRP at admission and discharge with 90-day outcome.

Methods and Results
—One hundred ninety-four consecutive patients were included in a derivation (n=105) and a validation set (n=89). Serum CRP was measured at admission, at 48 hours, and at hospital discharge. A cutoff point of 1.5 mg/dL for CRP provided optimum sensitivity and specificity for adverse outcome, based on the receiver operator curves. No association was found between CRP on admission and in-hospital outcome. CRP at admission, adjusted for age, ECG findings on admission, silent ischemia, left ventricular wall motion score, and high-risk clinical presentation, was related to the combined end point of refractory angina, myocardial infarction, or death at 90 days (hazard ratio [HR] 1.9, 95% CI 1.2 to 8.3,
P
=0.002). CRP at hospital discharge was the strongest independent marker of an adverse outcome (HR 3.16, 95% CI 2.0 to 5.2,
P
=0.0001). These results were confirmed in the validation set (CRP at discharge: HR 3.3, 95% CI 2.0 to 7.69,
P
=0.0001).

Conclusions
—In unstable angina, CRP is a strong independent marker of increased 90-day risk. Compared with CRP at admission, CRP at discharge is better related to later outcome and could be of great utility for risk stratification.