bluuebunny/crossref_metadata_2025 huggingface dataset:
Pacing-Induced Heart Failure in Dogs Enhances the Expression of p53 and p53-Dependent Genes in Ventricular Myocytes
Authors: Leri Annarosa , Liu Yu , Malhotra Ashwani , Li Qiong , Stiegler Peter , Claudio Pier Paolo , Giordano Antonio , Kajstura Jan , Hintze Thomas H. , Anversa Piero
Published: June 2012

Background
—Rapid ventricular pacing in dogs is characterized by a dilated myopathy in which myocyte cell death by apoptosis may play a significant role in the impairment of cardiac pump function. However, the molecular mechanisms implicated in the modulation of programmed cell death under this setting remain to be identified. Moreover, questions have been raised on the specificity and sensitivity of the histochemical detection of DNA strand breaks in nuclei by the terminal deoxynucleotidyl transferase (TdT) reaction.

Methods and Results
—Changes in the expression of
Bcl
-2 and
Bax
and their transcriptional regulator, p53, were determined by Western blot analysis in myocytes isolated from dogs affected by pacing-induced heart failure. A mobility shift assay for p53 binding activity was also performed. In addition, apoptosis was measured by confocal microscopy, which allowed the simultaneous detection of chromatin alterations and DNA damage. p53 DNA binding activity to the
bax
promoter was increased in nuclear extracts from myocytes obtained from failing hearts, and this response was associated with enhanced expression of
Bax
protein, 52%, and attenuation of
Bcl
-2, −92%. Immunolabeling of p53 in myocyte nuclei, measured by confocal microscopy, was 100% higher in cells from paced hearts. The combination of the TdT assay and confocal microscopy demonstrated that 20 myocyte nuclei per 10
6
were undergoing apoptosis in control myocardium and 4000 per 10
6
after pacing. Moreover, DNA laddering was shown in myocytes by agarose gel electrophoresis of DNA fragments.

Conclusions
—The activation of p53 and p53-dependent genes may be critical in the modulation of myocyte apoptosis in pacing-induced heart failure.
Apoptosis and Related Proteins in Different Stages of Human Atherosclerotic Plaques
Authors: Kockx Mark M. , De Meyer Guido R. Y. , Muhring Johannes , Jacob Willem , Bult Hidde , Herman Arnold G.
Published: June 2012

Background
—The transition of a fatty streak into an atherosclerotic plaque is characterized by the appearance of focal and diffuse regions of cell death. We have investigated the distribution of apoptotic cell death and apoptosis-related proteins in early and advanced atherosclerotic lesions.

Methods and Results
—Human atherosclerotic plaques were studied by whole-mount carotid endarterectomy specimens (n=18). This approach allowed comparison of adaptive intimal thickenings, fatty streaks, and advanced atherosclerotic plaques of the same patient. The fatty streaks differed from adaptive intimal thickenings by the presence of BAX (
P
<0.01), a proapoptotic protein of the BCL-2 family. Both regions were composed mainly of smooth muscle cells (SMCs), and macrophage infiltration was low and not different. Apoptosis, as detected by DNA in situ end labeling (terminal deoxynucleotidyl transferase end labeling [TUNEL] and in situ nick translation) was not present in these regions. Apoptosis of SMCs and macrophages, however, was present in advanced atherosclerotic plaques that were present mainly in the carotid sinus. A dense infiltration of macrophages (5.8±3% surface area) was present in these advanced atherosclerotic plaques. Cytoplasmic remnants of apoptotic SMCs, enclosed by a cage of thickened basal lamina, were TUNEL negative and remained present in the plaques as matrix vesicles.

Conclusions
—We conclude that SMCs within human fatty streaks express BAX, which increases the susceptibility of these cells to undergo apoptosis. The localization of these susceptible SMCs in the deep layer of the fatty streaks could be important in our understanding of the transition of fatty streaks into atherosclerotic plaques, which are characterized by regions of cell death. Matrix vesicles are BAX-immunoreactive cytoplasmic remnants of fragmented SMCs that can calcify and may be considered the graves of SMCs that have died in the plaques.
Reduced Endothelial Nitric Oxide Synthase Expression and Production in Human Atherosclerosis
Authors: Oemar Barry S. , Tschudi Marcel R. , Godoy Nelson , Brovkovich Victor , Malinski Tadeusz , Lüscher Thomas F.
Published: June 2012

Background
—NO regulates vascular tone and structure, platelets, and monocytes. NO is synthesized by endothelial NO synthase (eNOS). Endothelial dysfunction occurs in atherosclerosis.

Methods and Results
—With a porphyrinic microsensor, NO release was measured in atherosclerotic human carotid arteries and normal mammary arteries obtained during surgery. eNOS protein expression was analyzed by immunohistochemistry. In normal arteries, the initial rate of NO release after stimulation with calcium ionophore A23187 (10 μmol/L) was 0.42±0.05 (μmol/L)/s (n=10). In contrast, the initial rate of NO release was markedly reduced in atherosclerotic segments, to 0.08±0.04 (μmol/L)/s (n=10,
P
<0.0001). NO peak concentration in normal arteries was 0.9±0.09 μmol/L (n=10) and in atherosclerotic segments, 0.1±0.03 μmol/L (n=10,
P
<0.0001). Reduced NO release in atherosclerotic segments was accompanied by marked reduction of immunoreactive eNOS in luminal endothelial cells, although specific endothelial cell markers (CD31) were present (n=13). Endothelial cells of vasa vasorum of atherosclerotic segments, however, remained positive for eNOS, as was the endothelium of normal arteries.

Conclusions
—In clinically relevant human atherosclerosis, eNOS protein expression and NO release are markedly reduced. This may be involved in the progression of atherosclerosis.
Lower Expression of Neutrophil Adhesion Molecule Indicates Less Vessel Wall Injury and Might Explain Lower Restenosis Rate After Cutting Balloon Angioplasty
Authors: Inoue Teruo , Sakai Yoshihiko , Hoshi Kazuhiro , Yaguchi Isao , Fujito Tsuneo , Morooka Shigenori
Published: June 2012

Background
—The Cutting Balloon is a novel dilatation catheter for coronary angioplasty (InterVentional Technologies Inc). It produces longitudinal, microsurgical incisions in the vessel wall before the actual dilatation. It is assumed that these controlled surgical incisions relieve hoop stress and reduce vessel wall injury and eventually restenosis. However, no clinical indicator to support the theory of reduced injury has been described. Certain clusters of differentiation (eg, CD11, CD18 on the leukocytes) are implicated in leukocyte adhesion, increased permeability, and opsonization. Therefore, they might serve as clinical indicators of the injury level of the vessels after angioplasty.

Methods and Results
—We randomly selected 64 patients with isolated left anterior descending coronary artery disease for either Cutting Balloon angioplasty or conventional balloon angioplasty. The expression of CD18 and CD11b on the surface of neutrophils was determined by flow cytometric analysis. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) were also measured. The expression of both the CD18 and CD11b in the coronary sinus blood gradually increased and reached its maximum at 48 hours after angioplasty. The sICAM-1 levels in the coronary sinus serum also increased after angioplasty. Percentage increases of CD18 and CD11b expression and the increase of the sICAM-1 levels at 48 hours after angioplasty (as ratios to baseline values before angioplasty) were less in the Cutting Balloon angioplasty group than in the conventional balloon angioplasty group (CD18, 1.10±0.05 versus 1.31±0.05,
P
<0.05; CD11b, 1.23±0.06 versus 1.72±0.10,
P
<0.001; sICAM-1, 1.12±0.05 versus 1.25±0.02,
P
<0.05). In all patients, the late lumen loss at follow-up angiogram positively correlated with the increased levels of CD11b (
R
=0.59,
P
<0.001) and sICAM-1 (
R
=0.38,
P
<0.05) at 48 hours after angioplasty.

Conclusions
—Balloon angioplasty upregulated Mac-1 (CD11b/CD18) on the surface of the neutrophils and increased sICAM-1 levels in association with late loss increase. These changes were significantly smaller in the Cutting Balloon angioplasty group than in the conventional balloon angioplasty group. This suggests that Cutting Balloon angioplasty may produce less vessel wall injury and, consequently, less neutrophil activation, which may account for the lower rate of restenosis.
Association of Remnant Lipoprotein Levels With Impairment of Endothelium-Dependent Vasomotor Function in Human Coronary Arteries
Authors: Kugiyama Kiyotaka , Doi Hideki , Motoyama Takeshi , Soejima Hirofumi , Misumi Kenji , Kawano Hiroaki , Nakagawa Osamu , Yoshimura Michihiro , Ogawa Hisao , Matsumura Toshiyuki , Sugiyama Seigo , Nakano Takamitsu , Nakajima Katsuyuki , Yasue Hirofumi
Published: June 2012

Background
—It remains undetermined whether triglyceride-rich lipoproteins are an independent risk factor for atherosclerosis.

Methods and Results
—The correlation of responses of coronary arterial diameter (quantitative coronary angiography) and coronary blood flow (intracoronary flow wire technique) to intracoronary infusion of acetylcholine (10 and 50 μg/min) with coronary risk factors including remnant lipoprotein levels was statistically analyzed in 106 consecutive subjects with normal coronary angiograms. Remnant lipoproteins were isolated from fasting blood with an immunoaffinity mixed gel containing anti–apolipoprotein (apo) A-1 and anti–apoB-100 monoclonal antibodies. In multivariate stepwise regression analysis, remnant lipoprotein levels had the most significant correlation with abnormal epicardial coronary vasomotor responses to acetylcholine infusion, reflected by impaired dilation or constriction of the epicardial coronary arteries, and the levels also had an inverse and independent correlation with the coronary blood flow increase in response to acetylcholine. In a subgroup of 53 consecutive subjects, constrictor responses of epicardial coronary diameters to intracoronary infusion of
N
G
-monomethyl-
l
-arginine (50 μmol/min for 4 minutes) at baseline, reflecting the presence of coronary nitric oxide bioactivity, had an inverse and independent correlation with remnant lipoprotein levels by use of multivariate analysis.

Conclusions
—Remnant lipoprotein levels were independently associated with abnormal endothelium-dependent vasomotor function in large and resistance coronary arteries in humans, indicating that remnant lipoproteins may impair endothelial vasomotor function in human coronary arteries. The decrease in coronary nitric oxide bioactivity may be responsible in part for the inhibitory effects of remnant lipoproteins.
Final Results of the Balloon vs Optimal Atherectomy Trial (BOAT)
Authors: Baim Donald S. , Cutlip Donald E. , Sharma Samin K. , Ho Kalon K. L. , Fortuna Richard , Schreiber Theodore L. , Feldman Robert L. , Shani Jacob , Senerchia Cynthia , Zhang Yan , Lansky Alexandra J. , Popma Jeffrey J. , Kuntz Richard E.
Published: June 2012

Background
—Previous directional coronary atherectomy (DCA) trials have shown no significant reduction in angiographic restenosis, more in-hospital complications, and higher 1-year mortality than conventional balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). DCA, however, has subsequently evolved toward a more “optimal” technique (larger devices, more extensive tissue removal, and routine postdilation to obtain diameter stenosis <20%).

Methods and Results
—The Balloon vs Optimal Atherectomy Trial (BOAT) was conducted to evaluate whether optimal DCA provides short- and long-term benefits compared with balloon angioplasty. One thousand patients with single de novo, native vessel lesions were randomized to either DCA or PTCA at 37 participating centers. Lesion success was obtained in 99% versus 97% (
P
=.02) of patients to a final residual diameter stenosis of 15% versus 28% (
P
<.0001) for DCA and PTCA, respectively, the latter including stents in 9.3% of the patients. There was no increase in major complications (death, Q-wave myocardial infarction, or emergent coronary artery bypass graft surgery [2.8% versus 3.3%]), although creatine kinase–MB >3× normal was more common with DCA (16% versus 6%;
P
<.0001). Angiographic restudy (in 79.6% of eligible patients at 7.2±2.6 [median, 6.9] months) showed a significant reduction in the prespecified primary end point of angiographic restenosis by DCA (31.4% versus 39.8%;
P
=.016). Clinical follow-up to 1 year showed nonsignificant 13% to 17% reductions in the DCA arm of the study for mortality rate (0.6% versus 1.6%;
P
=.14), target-vessel revascularization (17.1% versus 19.7%;
P
=.33), target-site revascularization (15.3% versus 18.3%;
P
=.23), and target-vessel failure (death, Q-wave myocardial infarction, or target-vessel revascularization, 21.1% versus 24.8%;
P
=.17).

Conclusions
—Optimal DCA provides significantly higher short-term success, lower residual stenosis, and lower angiographic restenosis than conventional PTCA, despite failing to reach statistical significance for reducing late clinical events compared with PTCA with stent backup.
Three-Dimensional Electrophysiological Imaging of the Intact Canine Left Ventricle Using a Noncontact Multielectrode Cavitary Probe: Study of Sinus, Paced, and Spontaneous Premature Beats
Authors: Khoury Dirar S. , Berrier Keith L. , Badruddin Shamim M. , Zoghbi William A.
Published: June 2012

Background
—The feasibility of measuring cavitary electrograms using a noncontact probe and reconstructing endocardial surface electrograms and activation sequences during paced beats was previously demonstrated in the isolated canine left ventricle (LV). The objective of the present study was to develop and test a high-resolution, three-dimensional, endocardial electrophysiological imaging technique that simultaneously reconstructs endocardial surface electrograms and their corresponding activation sequences during normal and abnormal beats with the use of cavitary electrograms measured with a noncontact multielectrode probe in the intact canine LV.

Methods and Results
—A 128-electrode probe was inserted into the intact canine LV. Probe unipolar electrograms were simultaneously acquired during sinus, artificially paced, and spontaneous premature beats. Representative endocardial electrograms were measured directly using eight needle electrodes (the “gold standard”). A probe-cavity realistic, three-dimensional geometric model was constructed using two-dimensional epicardial echocardiography. Boundary element methods and numeric regularization were used to compute electrograms at 194 sites on the endocardium. In eight pacing protocols, computed endocardial electrograms correlated well with directly measured electrograms (
r
=.88). Corresponding activation times were also in agreement with those determined from measured endocardial electrograms (activation error, 4.7 ms). The earliest region of activation was invariably in the vicinity of the pacing needle (spatial error, 9.2 mm). Subsequently, the site of origin of ischemia-induced spontaneous ventricular premature beats and the ensuing sequence of depolarization was identified.

Conclusions
—Noncontact mapping provides realistic, three-dimensional electrophysiological images of the endocardium, on a beat-by-beat basis, that localize the sites of origin of premature beats and reconstruct their activation sequences.
Downregulation of Immunodetectable Connexin43 and Decreased Gap Junction Size in the Pathogenesis of Chronic Hibernation in the Human Left Ventricle
Authors: Kaprielian Raffi R. , Gunning Mark , Dupont Emmanuel , Sheppard Mary N. , Rothery Stephen M. , Underwood Richard , Pennell Dudley J. , Fox Kim , Pepper John , Poole-Wilson Philip A. , Severs Nicholas J.
Published: June 2012

Background
—The regional wall motion impairment and predisposition to arrhythmias in human ventricular hibernation may plausibly result from abnormal intercellular propagation of the depolarizing wave front. This study investigated the hypothesis that altered patterns of expression of connexin43, the principal gap junctional protein responsible for passive conduction of the cardiac action potential, contribute to the pathogenesis of hibernation.

Methods and Results
—Patients with poor ventricular function and severe coronary artery disease underwent thallium scanning and MRI to predict regions of normally perfused, reversibly ischemic, or hibernating myocardium. Twenty-one patients went on to coronary artery bypass graft surgery, during which biopsies representative of each of the above classes were taken. Hibernation was confirmed by improvement in segmental wall motion at reassessment 6 months after surgery. Connexin43 was studied by quantitative immunoconfocal laser scanning microscopy and PC image software. Analysis of en face projection views of intercalated disks revealed a significant reduction in relative connexin43 content per unit area in reversibly ischemic (76.7±34.6%,
P
<.001) and hibernating (67.4±24.3%,
P
<.001) tissue compared with normal (100±30.3%); ANOVA
P
<.001. The hibernating regions were further characterized by loss of the larger gap junctions normally seen at the disk periphery, reflected by a significant reduction in mean junctional plaque size in the hibernating tissues (69.5±20.8%) compared with reversibly ischemic (87.4±31.2%,
P
=.012) and normal (100±31.5%,
P
<.001) segments; ANOVA
P
<.001.

Conclusions
—These results indicate progressive reduction and disruption of connexin43 gap junctions in reversible ischemia and hibernation. Abnormal impulse propagation resulting from such changes may contribute to the electromechanical dysfunction associated with hibernation.
Disparate Effects of Deficient Expression of Connexin43 on Atrial and Ventricular Conduction
Authors: Thomas Suma A. , Schuessler Richard B. , Berul Charles I. , Beardslee Michael A. , Beyer Eric C. , Mendelsohn Michael E. , Saffitz Jeffrey E.
Published: June 2012

Background
—Myocardial conduction depends on intercellular transfer of currrent at gap junctions. Atrial myocytes express three different gap junction channel proteins—connexin43 (Cx43), connexin45 (Cx45), and connexin40 (Cx40)—whereas ventricular myocytes express only Cx43 and Cx45. However, the physiological roles of individual connexins are unknown. We have previously shown that mice heterozygous for a null mutation in the gene encoding Cx43 (Cx43
+/−
mice) express 50% of the normal amount of Cx43 in ventricular myocardium and exhibit marked slowing of ventricular conduction.

Methods and Results
—To determine whether atrial conduction is affected in Cx43
+/−
mice, we measured atrial conduction velocity in isolated hearts, performed detailed ECG and electrophysiological studies in intact animals, and determined the amount of cardiac connexins in atrial and ventricular tissue. Ventricular conduction velocity was reduced by 38% in Cx43
+/−
mice compared with wild-types, but atrial conduction velocity in the same hearts was normal. QRS duration was significantly greater in Cx43
+/−
mice than in wild-types, but P-wave duration and amplitude did not differ. Atrial expression of Cx43 was reduced by 50%.

Conclusions
—These results indicate that Cx43 is a principal conductor of intercellular current in the ventricle because ventricular conduction is significantly slowed when Cx43 content is reduced by only 50%. In contrast, a similar reduction in Cx43 content in atrial muscle has no effect on atrial conduction, suggesting that Cx40 (which is expressed in atrial but not ventricular myocytes) is a major electrical coupling protein in atrial muscle. Thus, Cx43 and Cx40 may be chamber-specific determinants of myocardial conduction.
Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries
Authors: Hata Katsuya , Whittaker Peter , Kloner Robert A. , Przyklenk Karin
Published: June 2012

Background
—Recent studies suggest that patients with angina before myocardial infarction exhibit improved recovery of coronary perfusion after thrombolysis by an as-yet-unknown mechanism. We therefore proposed that brief antecedent ischemia/reperfusion may, via release of adenosine, improve vessel patency in damaged and stenotic coronary arteries.

Methods and Results
—Anesthetized dogs underwent coronary injury+stenosis, resulting in repeated cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgment of platelet-rich thrombi. Vessel patency was assessed for 3 hours after stenosis by quantification of the nadir of the CFVs, duration of total thrombotic occlusion (flow=0), and area of the flow-time profile (expressed as percent of baseline flow×180 minutes). In protocol 1, dogs received 10 minutes of coronary occlusion+10 minutes of reflow or a comparable 20-minute control period before injury+stenosis. The median nadir of the CFVs was higher (4.0 versus 0.3 mL/min), median zero flow duration per 30-minute time interval was shorter (0.4 versus 15.1 minutes), and mean percent flow-time area was greater (54±8% versus 28±9%) in dogs that received antecedent ischemia versus controls (
P
<.05). These benefits of antecedent ischemia/reperfusion were largely mimicked by a 10-minute intracoronary adenosine infusion (400 μg/min) in lieu of brief ischemia (protocol 2) and were abolished by administration of the adenosine A
1
/A
2
receptor antagonist PD 115,199 (3 mg/kg IV) before brief antecedent coronary occlusion (protocol 3).

Conclusions
—Brief antecedent ischemia attenuates subsequent platelet-mediated thrombosis in damaged and stenotic canine coronary arteries, due, in large part, to an adenosine-mediated mechanism.
Risk Factors for In-hospital Nonhemorrhagic Stroke in Patients With Acute Myocardial Infarction Treated With Thrombolysis
Authors: Mahaffey Kenneth W. , Granger Christopher B. , Sloan Michael A. , Thompson Trevor D. , Gore Joel M. , Weaver W. Douglas , White Harvey D. , Simoons Maarten L. , Barbash Gabriel I. , Topol Eric J. , Califf Robert M.
Published: June 2012

Background
—Nonhemorrhagic stroke occurs in 0.1% to 1.3% of patients with acute myocardial infarction who are treated with thrombolysis, with substantial associated mortality and morbidity. Little is known about the risk factors for its occurrence.

Methods and Results
—We studied the 247 patients with nonhemorrhagic stroke who were randomly assigned to one of four thrombolytic regimens within 6 hours of symptom onset in the GUSTO-I trial. We assessed the univariable and multivariable baseline risk factors for nonhemorrhagic stroke and created a scoring nomogram from the baseline multivariable modeling. We used time-dependent Cox modeling to determine multivariable in-hospital predictors of nonhemorrhagic stroke. Baseline and in-hospital predictors were then combined to determine the overall predictors of nonhemorrhagic stroke. Of the 247 patients, 42 (17%) died and another 98 (40%) were disabled by 30-day follow-up. Older age was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by higher heart rate, history of stroke or transient ischemic attack, diabetes, previous angina, and history of hypertension. These factors remained statistically significant predictors in the combined model, along with worse Killip class, coronary angiography, bypass surgery, and atrial fibrillation/flutter.

Conclusions
—Nonhemorrhagic stroke is a serious event in patients with acute myocardial infarction who are treated with thrombolytic, antithrombin, and antiplatelet therapy. We developed a simple nomogram that can predict the risk of nonhemorrhagic stroke on the basis of baseline clinical characteristics. Prophylactic anticoagulation may be an important treatment strategy for patients with high probability for nonhemorrhagic stroke, but further study is needed.
Genes for Apolipoprotein B and Microsomal Triglyceride Transfer Protein Are Expressed in the Heart
Authors: Nielsen Lars B. , Véniant Murielle , Borén Jan , Raabe Martin , Wong Jinny S. , Tam Carmen , Flynn Laura , Vanni-Reyes Teresa , Gunn Michael D. , Goldberg Ira J. , Hamilton Robert L. , Young Stephen G.
Published: June 2012

Background
—Expression of both the apolipoprotein B (apoB) gene and the microsomal triglyceride transfer protein (MTP) gene is required for the assembly and secretion of triglyceride-rich lipoproteins in the liver and intestine. Both genes have been assumed to be silent in the heart.

Methods and Results
—Northern blot and RNase protection analyses showed that the apoB and MTP genes were expressed in the hearts of mice and humans. In situ hybridization studies revealed that the apoB mRNA was produced in cardiac myocytes. Electron microscopy of human cardiac myocytes revealed lipid-staining particles of relatively small diameter (≈250 Å) within the Golgi apparatus.

Conclusions
—These studies strongly suggest that the heart synthesizes and secretes apoB-containing lipoproteins.
Noninvasive Diagnosis of Dual AV Node Physiology in Patients With AV Nodal Reentrant Tachycardia by Administration of Adenosine-5′-Triphosphate During Sinus Rhythm
Authors: Belhassen Bernard , Fish Roman , Glikson Michael , Glick Aharon , Eldar Michael , Laniado Shlomo , Viskin Sami
Published: June 2012

Background
—Atrioventricular nodal reentry tachycardia (AVNRT) represents the most commonly encountered type of regular paroxysmal supraventricular tachycardia. This study determined whether administration of adenosine-5′-triphosphate (ATP) during sinus rhythm may be useful in the noninvasive diagnosis of dual AV nodal pathways.

Methods and Results
—During electrophysiological study, we intravenously administered incremental doses of ATP (from 10 to 50 mg) during sinus rhythm to patients with spontaneous and inducible sustained AVNRT (study group, n=42) and to patients with no evidence of dual AV nodal physiology or inducible AVNRT (control group, n=21). Signs suggestive of dual AV node physiology after ATP administration during sinus rhythm (“jump” of AH ≥50 ms between 2 consecutive beats, ≥1 AV nodal echo beat, or initiation of AVNRT) were observed in 32 (76%) of 42 study patients but in only 1 (5%) of the 21 control patients (
P
<0.001). Similar results were observed when only surface lead recordings (without intracardiac recordings) were evaluated. Signs suggestive of dual AV node physiology by the ATP test were observed in 29 (80.5%) of 36 patients who had electrophysiological demonstration of dual AV node physiology and in 3 (50%) of 6 patients without AV nodal duality (
P
=NS). Signs suggestive of dual physiology according to the ATP test disappeared in 11 (92%) of the 12 patients who underwent successful slow AV nodal ablation but persisted in 8 (62%) of 13 patients who underwent AV nodal modification
.

Conclusions
—Administration of ATP during sinus rhythm may be a useful bedside test for identifying patients with dual AV nodal pathways who are prone to AVNRT. This simple test should be considered as a screening test for patients with symptoms suggestive of paroxysmal supraventricular tachycardia but no documented arrhythmias or for patients with documented narrow complex tachycardia of unclear mechanism.
Ischemic Preconditioning in Pigs: A Graded Phenomenon
Authors: Schulz Rainer , Post Heiner , Vahlhaus Christian , Heusch Gerd
Published: June 2012

Background
—A threshold concept for ischemic preconditioning (IPc) has been proposed. It is unclear, however, whether IPc, above a certain threshold, is an all-or-nothing or a graded phenomenon.

Methods and Results
—In 71 enflurane-anesthetized swine, severe left anterior descending coronary artery hypoperfusion for 90 minutes followed by 2 hours of reperfusion resulted in an infarct size (IS, by triphenyltetrazolium chloride) of 16.7±3.4% (SEM) of the area at risk. IPc by 2 minutes of low-flow ischemia and 15 minutes of reperfusion before the 90-minute target ischemia did not reduce IS (21.9±7.0%). IS was decreased to 9.0±2.6% (
P
<0.05) by 3 minutes of IPc and reduced further to 1.9±0.9% (
P
<0.05) by 10 minutes of IPc. The interstitial adenosine concentration (microdialysis, high-performance liquid chromatography) was unchanged with 2 and 3 minutes of IPc but increased with 10 minutes of IPc (by 573±144%). The interstitial bradykinin concentration (microdialysis, radioimmunoassay) remained unchanged with 2 minutes of IPc but increased to a similar extent with 3 minutes (by 198±32%) and 10 minutes (by 224±30%) of IPc. The IS reduction by 3 minutes of IPc was abolished by blockade of the bradykinin B
2
receptor with intracoronary HOE 140 (16.6±4.3%) but not with intracoronary infusion of adenosine deaminase (8.4±2.5%,
P
<0.05). HOE 140, however, did not affect the IS reduction (3.5±1.1%,
P
<0.05) by 10 minutes of IPc. Combined infusion of HOE 140 and adenosine deaminase abolished the IS reduction by 10 minutes of IPc (15.4±6.7%).

Conclusions
—IS reduction by IPc is a graded phenomenon. Whereas bradykinin is essential during preconditioning ischemia of shorter duration, adenosine is more important during preconditioning ischemia of longer duration.
Enhancement of Fibrinolysis With 40-kHz Ultrasound
Authors: Suchkova Valentina , Siddiqi Farhan N. , Carstensen Edwin L. , Dalecki Diane , Child Sally , Francis Charles W.
Published: June 2012

Background
—Ultrasound at frequencies of 0.5 to 1 MHz and intensities of ≥0.5 W/cm
2
accelerates enzymatic fibrinolysis in vitro and in some animal models, but unacceptable tissue heating can occur, and limited penetration would restrict application to superficial vessels. Tissue heating is less and penetration better at lower frequencies, but little information is available regarding the effect of lower-frequency ultrasound on enzymatic fibrinolysis. We therefore examined the effect of 40-kHz ultrasound on fibrinolysis, tissue penetration, and heating.

Methods and Results
—
125
I-fibrin–radiolabeled plasma clots in thin-walled tubes were overlaid with plasma containing tissue plasminogen activator (tPA) and exposed to ultrasound. Enzymatic fibrinolysis was measured as solubilization of radiolabel. Tissue attenuation and heating were examined in samples of porcine rib cage. Fibrinolysis was increased significantly in the presence of 40-kHz ultrasound at 0.25 W/cm
2
, reaching 39±7% and 93±11% at 60 minutes and 120 minutes, compared with 13±8% and 37±4% in the absence of ultrasound (
P
<0.0001). The acceleration of fibrinolysis increased at higher intensities. Attenuation of the ultrasound field was only 1.7±0.5 dB/cm through the intercostal space and 3.4±0.9 dB/cm through rib. Temperature increments in rib were <1°C/(W/cm
2
).

Conclusions
—These findings indicate that 40-kHz ultrasound significantly accelerates enzymatic fibrinolysis at intensities of ≥0.25 W/cm
2
with excellent tissue penetration and minimal heating. Externally applied 40-kHz ultrasound at low intensities is a potentially useful therapeutic adjunct to enzymatic fibrinolysis with sufficient tissue penetration for both peripheral vascular and coronary applications.
Spiral Computed Tomography
Authors: Corti Roberto , Ferrari Claudio , Roberti Marzio , Alerci Mario , Pedrazzi Pier Luigi , Gallino Augusto
Published: June 2012

Background
—For the detection of atherosclerotic lesions of the extracranial cerebral arteries, duplex ultrasonography (US) is an established operator-dependent method, whereas arteriography is associated with the not-insignificant risk of embolic complications. Spiral CT is a promising novel diagnostic tool that allows noninvasive, operator-independent diagnosis of obstruction of extracranial cerebral arteries. The aim of our prospective study was to evaluate in a clinical setting the complementary role of duplex US and spiral CT.

Methods and Results
—We compared the results obtained independently by spiral CT and duplex US in 59 consecutive patients with clinical suspicion of an obstructive lesion affecting the carotid arteries. We analyzed a total of 354 segments from the extracranial carotid arteries, including the common, internal, and external carotid arteries. A total of 4 complete occlusions, 38 severe stenoses (70% to 99%), and 32 moderate stenoses (30% to 69%) were concordantly identified by means of duplex US and spiral CT. In 5 cases in which duplex US did not allow sufficient evaluation of the carotid artery because of a poor US window or severe calcification, spiral CT allowed identification and correct measurement of the stenotic lesion. The comparison of the percentage of stenosis with both methods was good (
r
=0.91,
P
=0.024).

Conclusions
—Our results indicate that spiral CT of the extracranial cerebral arteries is a promising noninvasive complementary and non–operator-dependent examination. Its application is particularly attractive in cases in which duplex US is not reliable (ie, severe kinking, severe calcification, short neck, and high bifurcation) and particularly when an overall view of the vascular field is required.
Prognostic Value of Dipyridamole-Thallium Myocardial Scintigraphy in Patients With Kawasaki Disease
Authors: Miyagawa Masao , Mochizuki Teruhito , Murase Kenya , Tanada Shuji , Ikezoe Junpei , Sekiya Michihito , Hamamoto Ken , Matsumoto Shuhei , Niino Masaharu
Published: June 2012

Background
—Although coronary artery lesions are critical complications of Kawasaki disease, their long-term outcome is still unclear. It is sometimes difficult to monitor progressive changes from aneurysms to stenotic lesions because coronary angiography (CAG) cannot be repeated very often, especially in infants. Our prospective study was designed to evaluate the prognostic value of dipyridamole-thallium single-photon-emission CT (SPECT) in the long-term follow-up of patients with Kawasaki disease.

Methods and Results
—Of 459 consecutive patients with Kawasaki disease, coronary aneurysms were detected in 90 cases by echocardiography during the acute stage. After paired studies of selective CAG and SPECT were conducted, all patients were followed up and monitored for the occurrence of any cardiac events for ≥8 years. During the follow-up interval, there were 15 cardiac events (1 death, 5 infarctions, 2 coronary artery bypass graft operations, and 7 occurrences of unstable angina). Of patients who had some event, thallium redistribution was found on SPECT in 14 (93%,
P
<0.001). Of the various clinical and scintigraphic image variables, the presence of thallium redistribution was the best multivariate independent predictor of a late cardiac event (χ
2
=57.8,
P
<0.0001). The number of aneurysms detected on CAG added minimal statistical improvement to the model (χ
2
=1.9,
P
=0.0009).

Conclusions
—Dipyridamole-thallium SPECT is safely performed and is useful and important for risk stratification in the long-term follow-up of patients with Kawasaki disease.
Predictors of Early- and Late-Onset Supraventricular Tachyarrhythmias After Fontan Operation
Authors: Durongpisitkul Kritvikrom , Porter Co-burn J. , Cetta Frank , Offord Kenneth P. , Slezak Jeffrey M. , Puga Francisco J. , Schaff Hartzell V. , Danielson Gordon K. , Driscoll David J.
Published: June 2012

Background
—The objectives of our study were to determine the frequency of supraventricular tachyarrhythmias (SVTAs) among modifications of the Fontan operation and identify risk factors for developing SVTA.

Methods and Results
—The population consisted of all patients who had any modification of the Fontan operation at the Mayo Clinic between 1985 and 1993. Clinically significant SVTAs were those requiring initiation or change of antiarrhythmic treatment, and they were divided into early SVTAs (<30 days after the operation) and late SVTAs (≥30 days after the operation). Clinical histories were reviewed, and health status questionnaires were sent. Four hundred ninety-nine patients had various modifications of the Fontan operation. Frequency of early SVTA was 15%. Risk factors identified by multivariate analysis for early SVTA were AV valve regurgitation, abnormal AV valve, and preoperative SVTA. Frequency of late SVTA was 6% by 1 year, 12% by 3 years, and 17% by 5 years. Risk factors for late SVTA were age at operation (<3 or ≥10 years) and systemic AV valve replacement. By univariate and multivariate analysis, the type of Fontan operation was not a significant risk factor for late SVTA when all 6 modifications were considered. However, when we analyzed the frequency of late SVTA for the 2 recently used modifications, we found a lower frequency of late SVTA in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.

Conclusions
—Postoperative SVTA continues to be a significant problem. Risk factors for SVTA are AV valve regurgitation, abnormal AV valve, preoperative SVTA, and age at operation. Frequency of SVTA does not appear to be related to type of Fontan procedure except for slightly lower frequency in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.
New Insights and Observations in Three-Dimensional Echocardiographic Visualization of Ventricular Septal Defects
Authors: Kardon Richard E. , Cao Qi Ling , Masani Navroz , Sugeng Lissa , Supran Stacey , Warner Kenneth G. , Pandian Natesa G. , Marx Gerald R.
Published: June 2012

Background
—The positions, sizes, and shapes of ventricular septal defects (VSDs) can be difficult to assess by 2-dimensional echocardiography (2DE). Volume-rendered 3-dimensional echocardiography (3DE) can provide unique views of VSDs from the left ventricular (LV) side, allowing complete assessment of their circumference and spatial orientations to other anatomic structures.

Methods and Results
—Seventeen experimentally created defects of various locations, sizes, and shapes were imaged and reconstructed in 9 explanted porcine hearts. From an en face projection, major and minor axis diameters of the defects were measured, and these data were compared with direct anatomic measurements. Optimal reconstructions of the VSDs were obtained in all heart specimens, accurately depicting their positions and shapes. The correlations between 3DE and anatomy for the VSD major and minor axis diameters were
y
=1.0
x
+0.3 (
r
=0.88,
P
<0.001) and
y
=1.0
x
−1.4 (
r
=0.89,
P
<0.001), respectively. Good agreement between the 2 methods was demonstrated for all measurements. Our experience from the in vitro model was then applied to patient studies. Optimal LV en face reconstructions were obtained in 45 of 51 patients, permitting detailed assessment of the positions, sizes, and shapes of the VSDs. In the 25 patients with comparative surgical measurements, the correlations between 3DE and surgery for the VSD major and minor axis diameters were
y
=0.81
x
+2.1 (
r
=0.92,
P
<0.001) and
y
=0.73
x
+2.0 (
r
=0.91,
P
<0.001), respectively. Good agreement was demonstrated between measurements made by 3DE and those obtained at surgery.

Conclusions
—3DE provides excellent visualization of various types of VSDs. From an LV en face projection, the positions, sizes, and shapes of VSDs can be accurately determined. Such precise imaging will be beneficial for surgical and catheter-based closure of difficult perimembranous and singular or multiple muscular VSDs.
Risk Profile and Prediction of Long-Term Ischemic Stroke Mortality
Authors: Tanne David , Yaari Shlomit , Goldbourt Uri
Published: June 2012

Background
—Multinational comparisons demonstrate marked ethnic and regional variation in stroke mortality and risk-factor distribution. We assessed the role of ethnicity and estimated the cumulative effect of multiple risk factors on long-term ischemic stroke mortality.

Methods and Results
—Civil servants and municipal employees in Israel (n=9734 men; age, ≥42 years), chosen by stratified sampling in 6 prespecified areas of birth (those born in Israel and those who were immigrants from 5 other regional-ethnic strata), were included in the Israeli Ischemic Heart Disease (IIHD) Project. Over a 21-year follow-up period, age-adjusted mortality rates per 10 000 person-years attributed to ischemic stroke (n=282; International Classification of Diseases [ICD]-9 codes 433 to 438) were higher among immigrants to Israel from northern Africa and the Mideast (17.1 to 19.0), than from 3 parts of Europe (11.3 to 12.4). Crude rates per 1000 subjects observed in those born in Asia or Africa (29.4 to 31.2) exceeded rates predicted by risk-factor profiles (21.4 to 24.9). Adjusted hazard ratios were 3.00 for age (per 10 years), 2.15 for left ventricular hypertrophy, 1.69 for systolic blood pressure (BP, per 20 mm Hg), 1.86 for diabetes mellitus, 1.83 for peripheral vascular disease, 1.79 for smoking (>20 cigarettes per day), 1.51 for coronary heart disease, 1.16 for percent cholesterol contained in the HDL fraction (%HDL, per 5% decrease), and 1.88 for diastolic BP (per 12 mm Hg; assessed in an alternative model). Accounting for regression dilution bias and assessed from repeat measurements, we found that hazard ratio estimates associated with diastolic BP, systolic BP, and percent HDL (per increments described) increased to 3.22, 2.23, and 1.23, respectively. Ischemic stroke mortality rates were 30-fold greater among subjects at the highest versus the lowest quintile of predicted probability according to risk-factor profiles (81.2 versus 2.6 per 1000 subjects).

Conclusions
—Assessment of multiple risk factors provides useful quantitative prediction of long-term ischemic stroke mortality risk. Regional-ethnic variations are consistent with a hypothesis that other, undetermined inherent genetic or sociocultural factors act to increase ischemic stroke mortality rates in immigrants to Israel from the Mideast and northern Africa over that predicted by conventional risk factors.
S
-Nitrosoglutathione Reduces the Rate of Embolization in Humans
Authors: Molloy Jane , Martin John F. , Baskerville Paul A. , Fraser Simon C. A. , Markus Hugh S.
Published: June 2012

Background
—Antiplatelet agents presently used in the secondary prevention of cardiovascular disease fail to prevent the majority of cases of recurrent stroke and systemic embolization. An evaluation of the efficacy of new agents is hampered by a lack of in vivo models in humans. Asymptomatic cerebral embolic signals (ES) may be detected with the use of transcranial Doppler ultrasonography. These signals are particularly common after carotid endarterectomy, and this provides a situation in which new antiplatelet agents can be evaluated. With this model, we determined the effectiveness of
S
-nitrosoglutathione (GSNO), a nitric oxide donor with relative platelet specificity, in reducing cerebral embolization.

Methods and Results
—Transcranial Doppler ultrasound recordings from the ipsilateral middle cerebral artery were made after carotid endarterectomy in 12 control patients and 12 patients receiving intravenous GSNO from the induction of anesthesia until 2 hours after skin closure. Recording times were 0.5 to 3.5, 6 to 7, and 24 to 25 hours after skin closure. The Doppler signal was recorded onto tape, and analysis for ES was performed, with the investigators blinded to treatment group. All patients received aspirin 300 mg/d before surgery and 5000 IU of heparin during surgery. The median (range) number of ES detected during the initial 3-hour postoperative recording was markedly reduced in the GSNO group compared with the control group: 7.5 (0 to 61) versus 38.5 (1 to 219) (
P
=0.018). This difference persisted until 6 hours after surgery.

Conclusions
—Despite the administration of aspirin and heparin, frequent embolization occurred and was markedly reduced after the administration of GSNO. This demonstrates the potential use of platelet-specific nitric oxide donors in the treatment of thromboembolic disease. This model of cerebral embolism may allow determination of the effectiveness of new antiplatelet agents in humans.
Prediction of 30-Day Mortality Among Patients With Thrombolysis-Related Intracranial Hemorrhage
Authors: Sloan Michael A. , Sila Cathy A. , Mahaffey Kenneth W. , Granger Christopher B. , Longstreth W. T. , Koudstaal Peter , White Harvey D. , Gore Joel M. , Simoons Maarten L. , Weaver W. Douglas , Green Cindy L. , Topol Eric J. , Califf Robert M.
Published: June 2012

Background
—Limited information exists on risk factors for mortality after thrombolysis-related intracranial hemorrhage. We wished to determine the characteristics associated with 30-day mortality after thrombolysis-related intracranial hemorrhage.

Methods and Results
—We performed an observational analysis within a randomized trial of 4 thrombolytic therapies, conducted in 1081 hospitals in 15 countries. Patients presented with ST-segment elevation within 6 hours of symptom onset. Our population was composed of the 268 patients who had primary intracranial hemorrhage after thrombolysis. With univariable and multivariable analyses, we identified clinical and brain imaging characteristics that would predict 30-day mortality among these patients. CT or MRI were available for 240 patients (90%). The 30-day mortality rate was 59.7%. Glasgow Coma Scale score, age, time from thrombolysis to symptoms of intracranial hemorrhage, hydrocephalus, herniation, mass effect, intraventricular extension, and volume and location of intracranial hemorrhage were significant univariable predictors. Multivariable analysis of 170 patients with complete data, 98 of whom died, identified the following independent, significant predictors: Glasgow Coma Scale score (χ
2
, 19.3;
P
<0.001), time from thrombolysis to intracranial hemorrhage (χ
2
, 15.8;
P
<0.001), volume of intracranial hemorrhage (χ
2
, 11.6;
P
<0.001), and baseline clinical predictors of mortality in the overall GUSTO-I trial (χ
2
, 10.3;
P
=0.001). The final model had a C-index of 0.931.

Conclusions
—This model provides excellent discrimination between patients who are likely to live and those who are likely to die after thrombolytic-related intracranial hemorrhage; this may aid in making decisions about the appropriate level of care for such patients.
Prospective Randomized Study of the Effect of “Add-Back” Hormone Replacement on Vascular Function During Treatment With Gonadotropin-Releasing Hormone Agonists
Authors: Yim S.F. , Lau T.K. , Sahota D.S. , Chung T.K.H. , Chang A.M.Z. , Haines C.J.
Published: June 2012

Background
—Gonadotropin-releasing hormone agonists (GnRHas) are a group of drugs that with long-term use induce a pseudomenopausal state in which estrogen production is suppressed. They are commonly used in the treatment of sex steroid–dependent conditions. “Add-back” hormone replacement therapy is used to prevent menopause-like symptoms and bone loss during GnRHa treatment, but it is also recognized that hypoestrogenism adversely affects vascular function. The aim of this study was to examine the effect of GnRHa and add-back therapy on vascular reactivity. This model serves as a paradigm for the effect of hormone replacement therapy in postmenopausal women.

Methods and Results
—Measurements of endothelium-dependent and endothelium-independent vascular reactivity were compared in 2 groups of women treated with a GnRHa for 6 months. One group received estrogen/progestogen add-back therapy during the second 3 months of GnRHa treatment. Vascular reactivity was examined by use of ultrasound measurements of changes in brachial artery diameter. Endothelium-dependent changes were assessed during reactive hyperemia, whereas endothelium-independent changes were measured after the administration of glyceryl trinitrate sublingual spray. Treatment with the GnRHa alone had an inhibitory effect on endothelium-dependent relaxation. However, endothelium-dependent relaxation significantly improved in the group receiving add-back therapy (14.6%) compared with the group treated with GnRHa alone (8.6%) (
P
<0.01). There were no significant endothelium-independent changes in either group.

Conclusions
—These results suggest that the administration of add-back therapy has a protective effect on vascular function in GnRHa-induced hypoestrogenism. As a model for the menopause, these results also suggest that the long-term administration of hormone replacement therapy would result in endothelium-dependent arterial relaxation, an observation previously attributed only to the acute administration of estrogen.