bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracoronary Radiation for Prevention of Restenosis
Authors: Amols H. I. , Trichter F. , Weinberger J.
Published: June 2012

Background
—Intravascular irradiation with β-emitters has been proposed for inhibition of restenosis in coronary arteries after balloon angioplasty or stent implantation. Previous studies have shown the effectiveness of γ-radiation to prevent recurrent restenosis, even in the presence of an implanted stent. The limited range of β-particles compared with γ-radiation, however, opens the question of whether absorption and scattering of β-particles by stent struts will cause significant perturbations in the uniformity and magnitude of the radiation dose, which may in turn compromise treatment.

Methods and Results
—Nine different stents were deployed with a balloon filled with a β-emitting radioactive liquid. Dose distributions were measured with Gafchromic film. Stents varied significantly in their absorption of β-particles. Some stents, constructed of fine meshed wires, produced minimal dose perturbations. Others, with thicker, high-atomic-number struts, induced cold spots in the dose distribution adjacent to the wires of ≤35%. Average dose reduction varied from 4% to 14% in the presence of various stents.

Conclusions
—Radiation strategy may have to be tailored to stent design. Stents that minimally perturb the dose distribution may be deployed before irradiation. Those that significantly alter the radiation dose might be better deployed after irradiation. Dose prescriptions may require modification if such perturbations prove clinically significant. Observed dose perturbations, however, decreased rapidly with increasing distance from the stent, which may mitigate the clinical impact of these findings. This, as well as the effects of stents on γ-dose distributions, requires further investigation.
Long-Term Patency Rate of Right Internal Thoracic Artery Bypass Via the Transverse Sinus
Authors: Ura Masashi , Sakata Ryuzo , Nakayama Yoshihiro , Arai Yoshio , Saito Taro
Published: June 2012

Background
—Although concern regarding patency and possible compromise of graft blood flow by routing the right internal thoracic artery (RITA) through the transverse sinus has been raised, little is known about long-term patency.

Methods and Results
—To evaluate long-term patency of in situ RITA bypass via the transverse sinus, our first 115 patients (94 men, 21 women; mean age, 62.5 years; range, 13 to 77 years) who were alive in 1998 were enrolled for angiographic study. Only good-caliber grafts with no occlusion, string sign, or significant stenosis were considered patent. Early postoperative angiography had been performed 2 to 3 weeks after surgery in 114 patients. The early patency rates were 97.1% for RITA and 95.4% for left internal thoracic artery (LITA) grafts. Of 109 long-term survivors, 73 (67.0%) consented to have late angiographic restudy at a mean of 59 months (range, 9 to 93 months); 89.9% of RITA and 92.3% of LITA grafts were patent. Cumulative patency rates (actuarial curves) at 6 years were 89.3% (95% CI, 85% to 94%) for RITA and 94.5% (95% CI, 92% to 97%) for LITA, the differences not reaching statistical significance (multivariate Cox analysis).

Conclusions
—Our study demonstrated good long-term patency of in situ RITA bypass grafting via the transverse sinus for revascularization of the circumflex and diagonal arteries and supports its continued use.
Endocardial Activation Mapping of Ventricular Tachycardia in Patients
Authors: Schalij Martin J. , van Rugge F. Paul , Siezenga Machiel , van der Velde Enno T.
Published: June 2012

Background
—Localization of early activated endocardial areas during ventricular tachycardia (VT) is mandatory for performance of surgical or radiofrequency catheter interventions. The use of a multielectrode catheter may shorten the procedure time and increase the accuracy of the procedure compared with single-electrode mapping techniques. This study was performed to evaluate the safety and efficacy of a 32-bipolar-electrode mapping catheter in patients.

Methods and Results
—The basket-shaped mapping catheter (BMC), integrated with a computerized mapping system, allowed on-line reconstruction of endocardial activation maps. Twenty patients with VT were studied before surgery (n=4) or radiofrequency catheter ablation (n=16). End-diastolic left ventricular (LV) volume was 280±120 mL, with an LV ejection fraction of 33±14%. The volume encompassed by the BMC was 164±27 mL (130 to 200 mL); the deployment time was 46±11 minutes. Endocardial activation time during sinus rhythm was 105±34 ms; 14±5 electrodes could be used to stimulate the heart. Cycle length of VT was 325±83 ms. Earliest endocardial activation was recorded 58±42 ms before the onset of the surface ECG. Complications were pericardial effusion (n=2) and transient cerebral disorientation (n=1).

Conclusions
—Percutaneous multielectrode endocardial mapping in patients with VT is feasible and relatively safe. The use of this technique shortens the time patients have to endure VT.
Gene Polymorphisms for Plasminogen Activator Inhibitor-1/Tissue Plasminogen Activator and Development of Allograft Coronary Artery Disease
Authors: Benza Raymond L. , Grenett Hernan E. , Bourge Robert C. , Kirklin James K. , Naftel David C. , Castro Pablo F. , McGiffin David C. , George James F. , Booyse Francois M.
Published: June 2012

Background
—Impaired fibrinolytic activity has been linked to the presence and severity of allograft vasculopathy (Tx CAD). This impairment may be associated with the presence of certain fibrinolytic protein gene polymorphisms.

Methods and Results
—To investigate the relation between donor-specific fibrinolytic protein genotypes and Tx CAD, we identified donor plasminogen activator inhibitor-1 (PAI-1)
Hin
dIII and tissue plasminogen activator (TPA)
Eco
RI restriction fragment length polymorphisms–based genotypes by Southern blot analysis in 48 recipients of cardiac allografts and correlated these genotypes with the development of CAD. No association was found between donor TPA genotypes and the presence of Tx CAD. Among the 48 patients, 17% were homozygous for the 1/1 PAI-1 genotype, 51% for the 2/2 PAI-1 genotype, and 32% for the 1/2 PAI-1 genotype. The actuarial freedom from any CAD for the recipients with each respective donor PAI-1 genotype at 12 and 24 months was 100% and 100% for the 1/1 PAI-1 genotype, 92% and 92% for the 1/2 PAI-1 genotype, and 75% and 45% for the 2/2 PAI-1 genotype (
P
=0.03). Recipients with a diseased 2/2 PAI-1 genotyped allograft had longer ischemic times (
P
=0.02) than those recipients with a Tx CAD–free allograft.

Conclusions
—These data suggest that recipients with a 2/2 PAI-1 genotype are at a significant risk of developing Tx CAD. This genotype may serve as a useful screening tool for predicting the future development of Tx CAD.
Long-Term Beneficial Effect of Late Reperfusion for Acute Anterior Myocardial Infarction With Percutaneous Transluminal Coronary Angioplasty
Authors: Horie Hajime , Takahashi Masayuki , Minai Kazuo , Izumi Masafumi , Takaoka Atsushi , Nozawa Masato , Yokohama Hiroshi , Fujita Tamotsu , Sakamoto Taizo , Kito Osamu , Okamura Hiroshi , Kinoshita Masahiko
Published: June 2012

Background
—Although the short-term and long-term beneficial effects of early coronary revascularization by primary PTCA or thrombolytic therapy have been established for acute myocardial infarction, thrombolytic therapy >24 hours after the onset of acute myocardial infarction has not been shown to improve clinical outcome. The purpose of this study was to assess the effect of late revascularization by primary PTCA over a 5-year period.

Methods and Results
—Eighty-three patients with initial Q-wave anterior myocardial infarction >24 hours after onset were randomized into a PTCA group (n=44) and a no-PTCA group (n=39). Long-term follow-up was conducted with regard to end points, which included cardiac death, nonfatal recurrence of myocardial infarction, and development of congestive heart failure. Left ventricular ejection fraction and regional wall motion at 6 months after myocardial infarction were similar in the 2 groups. Left ventricular end-diastolic and end-systolic volume indexes were significantly smaller in the PTCA group than in the no-PTCA group (
P
<0.0001). With cardiac events as end points, a 5-year Kaplan-Meier event-free survival analysis revealed that the no-PTCA group had a worse prognosis than the PTCA group (
P
<0.0001). Patency of the infarct-related artery, left ventricular ejection fraction, end-diastolic volume index, and end-systolic volume index were significantly associated with cardiac events by a Cox proportional hazards analysis (hazard ratios 0.120, 0.845, 1.065, and 1.164, respectively).

Conclusions
—In initial Q-wave anterior myocardial infarction, we conclude that even with late reperfusion, PTCA had beneficial effects on cardiac events over the 5-year period after myocardial infarction, with the prevention of left ventricular dilation after myocardial infarction being a possible mechanism.
Mechanisms of Vasorelaxation Induced by Troglitazone, a Novel Antidiabetic Drug, in the Porcine Coronary Artery
Authors: Kawasaki Junya , Hirano Katsuya , Nishimura Junji , Fujishima Masatoshi , Kanaide Hideo
Published: June 2012

Background
—Troglitazone (TRO), a novel antidiabetic drug, has been reported to decrease blood pressure and relax vascular strips. The mechanism of relaxation induced by TRO was determined in terms of Ca
2+
signaling in smooth muscle cells.

Methods and Results
—Front-surface fluorometry and fura 2–loaded medial strips of porcine coronary artery were used to examine the effects of TRO on cytosolic Ca
2+
concentrations ([Ca
2+
]
i
) and contractions. The sustained contraction induced by 100 nmol/L U46619 was similar to that induced by 60 mmol/L K
+
depolarization (60K
+
). TRO concentration dependently decreased [Ca
2+
]
i
and the force of these contractions. The concentration of TRO required to induce 50% inhibition of U46619-induced force (2.9 μmol/L) was significantly lower than that required in the case of 60K
+
-induced force (7.3 μmol/L). Replacing extracellular Ca
2+
with Mn
2+
gradually quenched fluorescence at 360 nm excitation. This decline was accelerated by 100 nmol/L U46619 and 30K
+
to a similar extent, indicating a similar activation of Ca
2+
influx. TRO completely inhibited U46619-activated influx but partly inhibited depolarization-activated influx. Cumulative applications of extracellular Ca
2+
during stimulations with U46619 or 118K
+
induced stepwise increases in [Ca
2+
]
i
and force. TRO shifted the [Ca
2+
]
i
-force relation to the right during both stimulations.

Conclusions
—TRO relaxes coronary artery by decreasing [Ca
2+
]
i
and Ca
2+
sensitivity of contractile apparatus. Inhibition of Ca
2+
influx was important in decreasing [Ca
2+
]
i
. TRO more effectively inhibits receptor-operated Ca
2+
influx than voltage-operated Ca
2+
channels.
Intravenous Coronary Angiography by Electron Beam Computed Tomography
Authors: Rensing Benno J. , Bongaerts Alfons , van Geuns Robert-Jan , van Ooijen Peter , Oudkerk Matthijs , de Feyter Pim J.
Published: June 2012

Background
—Noninvasive detection of coronary stenoses with electron beam CT (EBCT) after intravenous injection of contrast medium has recently emerged. We sought to determine the diagnostic accuracy of EBCT angiography in the clinical setting using conventional coronary angiography as the “gold standard.”

Methods and Results
—Thirty-seven patients (30 men) were investigated. After intravenous injection of 150 mL of contrast medium, 40 to 60 consecutive transaxial tomograms, covering the proximal and middle parts of the coronary arteries, were obtained with ECG triggering at end diastole during breath-holding. Three-dimensional reconstructions of the proximal and middle parts of the arteries were compared with the conventional angiograms. Of the 259 proximal and middle coronary segments, 211 (81%) were analyzable by EBCT. Of the left anterior descending coronary artery (LAD) segments, 95% were assessable. Right coronary artery (RCA) and left circumflex artery (LCx) segments were assessable in 66% and 76%, respectively. Overall sensitivity and specificity to detect a >50% diameter stenosis were 77% and 94%, respectively. This was 82% and 92% for the LAD, 60% and 97% for the RCA, and 83% and 89% for the LCx (all figures based on assessable lesions).

Conclusions
—Intravenous EBCT coronary angiography is a promising coronary imaging technique. The technique is not yet robust enough to be an alternative to conventional coronary angiography. It can detect and rule out significant coronary artery disease of the left main proximal and mid portions of the LAD with good accuracy.
Thrombolytic Therapy in Acute Myocardial Infarction
Authors: Hoffmeister Hans Martin , Szabo Sebastian , Kastner Christof , Beyer Martin E. , Helber Uwe , Kazmaier Silke , Wendel Hans Peter , Heller Wolfgang , Seipel Ludger
Published: June 2012

Background
—Thrombolytic therapy in patients with acute myocardial infarction (AMI) is hampered by procoagulant effects. In vitro studies have indicated that plasmin stimulation activates the kallikrein–contact-phase system, resulting in thrombin activation. This prospective comparative study was designed to examine the procoagulant effects of streptokinase or alteplase in AMI.

Methods and Results
—Sixty-one patients with AMI received 1.5 million U of streptokinase or front-loaded alteplase (up to 100 mg) and systemic heparin. Twenty-four patients with AMI and no thrombolytic therapy and 30 control subjects were examined for comparison. Molecular markers of thrombin, plasmin activation, and coagulation activities were determined before therapy and serially for up to 10 days. Moderate thrombin (initial thrombin-antithrombin [TAT] complex 18±5 versus 4±0.3 μg/L,
P
<0.05) and kallikrein (up to 45±4 versus 30±1 U/L at 3 hours,
P
<0.01) activation occurs in patients with AMI.
d
-Dimers are increased (
P
<0.01), and plasmin is stimulated (
P
<0.01). Streptokinase and alteplase increase TAT to 50±17 and 51±18 μg/L at 3 hours and to 50±17 and 33±14 μg/L at 6 hours, respectively (
P
<0.01). Kallikrein activity is elevated (
P
<0.01) to 76±5 and 71±7 U/L at 3 hours and 64±6 and 47±5 U/L by streptokinase and alteplase, respectively, at 6 hours. Reductions in fibrinogen and increases in
d
-dimers and plasmin-antiplasmin complexes are more marked (
P
<0.05 and 0.01) after streptokinase versus alteplase. Correlations were found among TAT, kallikrein activity, and plasmin activation (
P
<0.01).

Conclusions
—The data indicate a more marked procoagulant action of the streptokinase regimen compared with front-loaded alteplase, thus supporting the hypothesis of a plasmin-mediated kallikrein activation with consecutive procoagulant action in vivo.
Identification of a Novel Genetic Locus for Familial Cardiac Myxomas and Carney Complex
Authors: Casey Mairead , Mah Caroline , Merliss Andrew D. , Kirschner Lawrence S. , Taymans Susan E. , Denio Alfred E. , Korf Bruce , Irvine Alan D. , Hughes Anne , Carney J. Aidan , Stratakis Constantine A. , Basson Craig T.
Published: June 2012

Background
—Intracardiac myxomas are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. In the autosomal dominant syndrome Carney complex, intracardiac myxomas arise in the setting of lentiginosis and other lesions associated with cutaneous hyperpigmentation, extracardiac myxomas, and nonmyxomatous tumors. Genetic factors that regulate cardiac tumor growth remain unknown.

Methods and Results
—We used the molecular genetic techniques of linkage analysis to study 4 kindreds affected by Carney complex to determine the genetic basis of this syndrome. Our investigation confirmed genetic heterogeneity of Carney complex. Moreover, genetic linkage analysis with polymorphic short tandem repeats on the long arm of chromosome 17 revealed maximal pairwise LOD scores of 5.9, 1.5, 1.8, and 2.9 for families YA, YB, YC01, and YC11, respectively. Haplotype analysis excluded a founder effect at this locus. These data identify a major 17 cM locus on chromosome 17q2 that contains the Carney complex disease gene.

Conclusions
—The ultimate identification and analysis of the Carney complex disease gene at this human chromosome 17q2 locus will facilitate diagnosis and treatment of cardiac myxomas and will foster new concepts in regulation of cardiac cell growth and differentiation.
Location of Diastolic Potentials in Reentrant Circuits Causing Sustained Ventricular Tachycardia in the Infarcted Canine Heart
Authors: Cabo Candido , Schmitt Heiko , Masters Gregory , Coromilas James , Wit Andrew L. , Scheinman Melvin M.
Published: June 2012

Background
—The complete reentrant circuit for ablation of reentrant ventricular tachycardia (VT) in humans can rarely be localized by mapping. As a result, surrogate markers, such as diastolic electrical activity, subsequently confirmed by entrainment, have been used. However, ablation at those sites has had variable efficacy. The reasons for this variability are not clear.

Methods and Results
—We correlated activation maps of reentrant circuits in the epicardial border zone of 4-day old infarcted dog hearts with the corresponding ECGs for 45 VTs to determine the regions of the reentrant circuits activated during diastole. In VTs with a figure-8 reentrant pattern, the center point of the central common pathway, the part of the circuit critical for the maintenance of reentry, was activated in early diastole in 32 of 35 VTs (91.4%), in late diastole in 1 (2.9%), and in systole in 2 (5.7%). Regions outside the circuit were rarely activated in diastole. In 10 VTs, the reentrant circuit was characterized by a single reentrant loop. In these circuits, no one region was predicted to be critical for maintenance of reentry, and a segment of the circuits was activated during diastole. However, regions peripheral to the circuit were also activated during diastole.

Conclusions
—The pattern of reentrant activation determines the specificity of diastolic activity for locating critical sites for ablation of VT.
Contrast Magnetic Resonance Imaging in the Assessment of Myocardial Viability in Patients With Stable Coronary Artery Disease and Left Ventricular Dysfunction
Authors: Ramani Kishin , Judd Robert M. , Holly Thomas A. , Parrish Todd B. , Rigolin Vera H. , Parker Michele A. , Callahan Cathy , Fitzgerald Steven W. , Bonow Robert O. , Klocke Francis J.
Published: June 2012

Background
—The utility of contrast MRI for assessing myocardial viability in stable coronary artery disease (CAD) with left ventricular dysfunction is uncertain. We therefore performed cine and contrast MRI in 24 stable patients with CAD and regional contractile abnormalities and compared MRI findings with rest-redistribution
201
Tl imaging and dobutamine echocardiography.

Methods and Results
—Delayed MRI contrast enhancement patterns were examined from 3 to 15 minutes after injection of 0.1 mmol/kg IV gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). Comparable MRI and
201
Tl basal and midventricular short-axis images were subdivided into 6 segments. Segments judged nonviable by quantitative and qualitative assessment of
201
Tl scans showed persistent, systematically greater MRI contrast signal intensity than segments judged viable (
P
≤0.002). Delayed contrast hyperenhancement also occurred in segments judged nonviable by dobutamine echocardiography (
P
≤0.03). The presence or absence of hyperenhancement correlated most closely with nonviability and viability, respectively, in segments that were akinetic or dyskinetic under resting conditions (83% concordance with
201
Tl in both cases). In segments with resting hypokinesis, 58% of segments showing hyperenhancement were judged viable by
201
Tl and may have represented an admixture of scar tissue and viable myocardium.

Conclusions
—Delayed (by 3 to 15 minutes) hyperenhancement of Gd-DTPA contrast–enhanced MRI images occurs frequently in dysfunctional areas of the left ventricle in patients with stable CAD. Hyperenhancement is associated with nonviability by rest-redistribution
201
Tl scintigraphy and dobutamine echocardiography, particularly in regions exhibiting resting akinesis/dyskinesis. The absence of hyperenhancement correlates with radionuclide and echocardiographic determinations of viability, regardless of resting contractile function.
Electrophysiological Mechanisms and Determinants of Vagal Maneuvers for Termination of Paroxysmal Supraventricular Tachycardia
Authors: Wen Zu-Chi , Chen Shih-Ann , Tai Ching-Tai , Chiang Chern-En , Chiou Chuen-Wang , Chang Mau-Song
Published: June 2012

Background
—The vagal maneuvers used for termination of paroxysmal supraventricular reentrant tachycardia (PSVT) appear to involve more complex mechanisms than we have known, and further study should be done to explore the possible mechanisms.

Methods and Results
—In this study, 133 patients with PSVT and 30 age- and sex-matched control subjects were included. We assessed the effects of different vagal maneuvers on termination of PSVT and compared baroreflex sensitivity and β-adrenergic sensitivity between the patients with PSVT and control subjects. Out of 85 patients with atrioventricular reciprocating tachycardia (AVRT), vagal maneuvers terminated in 45 (53%). Of these, 28 (33%) terminated in the antegrade limb and 17 (20%) terminated in the retrograde limb. Out of 48 patients with atrioventricular nodal reentrant tachycardia (AVNRT), vagal maneuvers terminated the tachycardia in the antegrade slow pathway (14%) or in the retrograde fast pathway (19%). Baroreflex sensitivity was poorer but isoproterenol sensitivity test better in patients with AVNRT. Poorer antegrade atrioventricular node conduction properties and better vagal response determined successful antegrade termination of AVRT by vagal maneuvers. Poorer retrograde accessory pathway conduction property but better vagal response determined successful retrograde termination of AVRT. Better sympathetic and vagal response associated with poorer retrograde atrioventricular node conduction determined retrograde termination of AVNRT by the Valsalva maneuver.

Conclusions
—Both the vagal response and conduction properties of the reentrant circuit determine the tachycardia termination by vagal maneuvers. Improved understanding of the interaction of autonomic and electrophysiological mechanisms in maintaining or terminating PSVT may provide important insight into the pathophysiology of these two tachycardias.
Expression of Hirudin Fusion Proteins in Mammalian Cells
Authors: Riesbeck Kristian , Chen Daxin , Kemball-Cook Geoffrey , McVey John H. , George Andrew J. T. , Tuddenham Edward G. D. , Dorling Anthony , Lechler Robert I.
Published: June 2012

Background
—Intravascular thrombosis occurs in disorders of diverse pathogeneses, including allograft and xenograft rejection. In this in vitro study, we describe an approach for tethering the specific thrombin inhibitor hirudin to plasma membranes as part of a genetic strategy for regulating intravascular coagulation.

Methods and Results
—An HLA class I leader sequence was fused with hirudin linked to domains 3 and 4 of human CD4 and intracytoplasmic sequence from either CD4 or human P-selectin. The constructs were transfected into mouse fibroblasts, Chinese hamster ovary (CHO)-K1 cells, immortalized porcine endothelial cells (IPECs), and a pituitary secretory cell line (D16/16). Thrombin binding to the hirudin fusion proteins expressed on fibroblasts and CHO-K1 cells could be blocked by an anti-hirudin monoclonal antibody and by pretreatment of thrombin with either the synthetic tripeptide thrombin inhibitor PPACK or native hirudin. Hirudin expression significantly modified the procoagulant phenotype of IPECs in human plasma, leading to prolongation of clotting times. Hirudin-CD4–P-selectin fusion proteins accumulated in adrenocorticotropic hormone–containing granules in D16/16 cells, with no cell surface expression except on activation with phorbol ester, when hirudin relocated to the outer membrane.

Conclusions
—Hirudin fusion proteins were expressed on mammalian cells, where they reduced local thrombin levels and inhibited fibrin formation. Regulated expression was achieved on activated cells by use of the cytoplasmic sequence from P-selectin. In vivo, these fusion proteins may prove useful transgenic or gene therapy agents for preventing intravascular thrombosis.
Gene Therapy for Myocardial Angiogenesis
Authors: Losordo Douglas W. , Vale Peter R. , Symes James F. , Dunnington Cheryl H. , Esakof Darryl D. , Maysky Michael , Ashare Alan B. , Lathi Kishor , Isner Jeffrey M.
Published: June 2012

Background
—We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia.

Methods and Results
—VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF
165
) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75±15/min versus post-GTx=80±16/min,
P
=NS), systolic BP (114±7 versus 118±7 mm Hg,
P
=NS), or diastolic BP (57±2 versus 59±2 mm Hg,
P
=NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm
3
, and total chest tube drainage was 110 to 395 cm
3
. Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8±0.4 versus postanesthesia=4.1±0.3 versus 24 hours postoperative=6.3±0.8,
P
=0.02). Time to extubation after closure was 18.4±1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9±10.0/wk pre-GTx versus 9.8±6.9/wk post-GTx,
P
<0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients.

Conclusions
—This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.
Platelet-Derived 12-Hydroxyeicosatetraenoic Acid Plays an Important Role in Mediating Canine Coronary Thrombosis by Regulating Platelet Glycoprotein IIb/IIIa Activation
Authors: Katoh Atsushi , Ikeda Hisao , Murohara Toyoaki , Haramaki Nobuya , Ito Hideki , Imaizumi Tsutomu
Published: June 2012

Background
—In the thrombotic process of acute coronary syndromes, the pathophysiological role of thromboxane A
2
via cyclooxygenase is well established; however, the role of 12-HETE via 12-lipoxygenase is little known. Therefore, we used OPC-29030, a novel specific inhibitor of 12-HETE synthesis, to test whether platelet-derived 12-HETE is involved in mediating cyclic flow variations (CFVs) and platelet aggregation in stenosed and endothelium-injured canine coronary arteries.

Methods and Results
—After developing CFVs, dogs received a vehicle or OPC-29030 intravenously. Plasma and intraplatelet 12-HETE levels increased after CFVs. OPC-29030 but not vehicle reduced CFVs, which was associated with decreases in plasma and intraplatelet 12-HETE levels. Cessation of OPC-29030 restored CFVs in association with increases in plasma and intraplatelet 12-HETE levels. ADP and U46619 induced ex vivo platelet 12-HETE production and aggregation. After OPC-29030 administration, the ADP- and U46619-induced increases in ex vivo platelet 12-HETE production and aggregation were inhibited significantly. Platelet aggregation was linearly correlated with platelet 12-HETE production. OPC-29030 suppressed activation of human platelet glycoprotein IIb/IIIa.

Conclusions
—OPC-29030 reduced intraplatelet 12-HETE levels, resulting in the inhibition of coronary thrombosis in vivo in dogs. OPC-29030 inhibited human platelet glycoprotein IIb/IIIa activation in vitro. Thus, platelet-derived 12-HETE may play an important role in mediating thrombotic process.
Prospective Study of Coronary Heart Disease Incidence in Relation to Fasting Total Homocysteine, Related Genetic Polymorphisms, and B Vitamins
Authors: Folsom Aaron R. , Nieto F. Javier , McGovern Paul G. , Tsai Michael Y. , Malinow M. René , Eckfeldt John H. , Hess David L. , Davis C. E.
Published: June 2012

Background
—Elevated plasma total homocysteine (tHcy), low B-vitamin intake, and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease (CHD). More prospective studies are needed.

Methods and Results
—We used a prospective case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center–adjusted CHD incidence was associated positively (
P
<0.05) with tHcy in women but not men, and CHD was associated negatively (
P
<0.05) with plasma folate (women only), plasma pyridoxal 5′-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5′-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5′-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C
677
T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine β-synthase gene.

Conclusions
—Our prospective findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major, independent, causative risk factor for CHD. Our findings point more strongly to the possibility that vitamin B
6
offers independent protection. Randomized trials, some of which are under way, are needed to better clarify the interrelationships of tHcy, B vitamins, and cardiovascular disease.
Evaluation of Regional Differences in Right Ventricular Systolic Function by Acoustic Quantification Echocardiography and Cine Magnetic Resonance Imaging
Authors: Geva Tal , Powell Andrew J. , Crawford Elizabeth C. , Chung Taylor , Colan Steven D.
Published: June 2012

Background
—Accurate quantitative evaluation of right ventricular (RV) function has been limited by its complex structural geometry. Although embryological and anatomic observations suggest that the RV is composed of 2 distinct components, the RV sinus and infundibulum, most studies on RV dimensions and function viewed it as a single chamber. This study was designed to determine the volumes, relative contribution to global systolic function, and temporal course of contraction and relaxation of the RV sinus and infundibulum.

Methods and Results
—Thirty-one individuals without heart disease (aged 1 month to 17 years, 16 boys and 15 girls) participated in this study. Instantaneous area over time, its derivatives, and the temporal course of contraction and relaxation were studied by acoustic quantification echocardiography and phonocardiography in 20 individuals. Global and regional RV volumes and ejection fraction were determined by cine MRI in 11 individuals. The RV sinus made up 81±6% of the combined RV end-diastolic volume and 87±4% of the combined stroke volume. The infundibulum accounted for the remaining 19±6% and 13±4%, respectively (
P
<0.0001). Compared with the infundibulum, the extent of RV sinus fiber shortening was significantly greater: for ejection fraction (56±11% versus 38±13%,
P
<0.001), fractional area change (42±14% versus 28±9%,
P
<0.0001), and dA/dt (27±17% versus 13±6%,
P
<0.0001). Analysis of temporal course of contraction and relaxation (expressed as percentage of the cardiac cycle to adjust for differences in heart rate) showed that the infundibulum follows the RV sinus: onset of contraction 53%±14 versus 19±11% of systole, time to peak systole 115±16% versus 97±19% (
P
≤0.01), indicating a peristalsis-like pattern of contraction and relaxation.

Conclusions
—The results of this study demonstrate significant regional differences between the sinus and infundibulum components of the RV with regard to contribution to stroke volume, extent of fiber shortening, and sequence of mechanical activation. These data from normal individuals can be used in future research on RV function in pathological conditions.
Low-Level Expression of a Mutant Coxsackieviral cDNA Induces a Myocytopathic Effect in Culture
Authors: Wessely Rainer , Henke Andreas , Zell Roland , Kandolf Reinhard , Knowlton Kirk U.
Published: June 2012

Background
—Enteroviral ribonucleic acids have been identified in heart muscle of a subset of patients with myocarditis and dilated cardiomyopathy as well as in a mouse model of persistent coxsackievirus B3 (CVB3) infection, suggesting that persistent viral infection along with activation of an immune response may contribute to the pathogenesis of ongoing cardiac disease and dilated cardiomyopathy in certain patients. It is still not known whether persistence of the viral genome contributes to the pathogenesis of dilated cardiomyopathy.

Methods and Results
—To determine whether low-level enteroviral gene expression similar to that observed with viral persistence can induce myocytopathic effects without formation of infectious virus progeny, the full-length infectious cDNA copy of CVB3 was mutated at the VP0 maturation cleavage site. This prevented formation of infectious virus progeny. In myocytes transfected with this mutated cDNA copy of the viral genome, both positive- and negative-strand viral RNAs were detected, demonstrating that there was replication of the viral genome by the RNA-dependent RNA polymerase. The level of viral protein expression was found to be below limits of detection by conventional methods of protein detection, thus resembling restricted virus replication. Nonetheless, the CVB3 mutant was found to induce a cytopathic effect in transfected myocytes, which was demonstrated by inhibition of cotransfected MLC-2v luciferase reporter activity and an increase in release of lactate dehydrogenase from transfected cells.

Conclusions
—This study demonstrates that restricted replication of enteroviral genomes in myocytes in a pattern similar to that observed in hearts with persistent viral infection can induce myocytopathic effects without generation of infectious virus progeny.
Evaluation of the Aortic Root by MRI
Authors: Summers Ronald M. , Andrasko-Bourgeois Jonathan , Feuerstein Irwin M. , Hill Suvimol C. , Jones Elizabeth C. , Busse Mary K. , Wise Betty , Bove Karen E. , Rishforth Beth A. , Tucker Eben , Spray Thomas L. , Hoeg Jeffrey M.
Published: June 2012

Background
—In homozygous familial hypercholesterolemia (HFH), the aortic root is prone to develop atherosclerotic plaque at an early age. However, the aortic wall and plaque have not yet been assessed in this condition by MRI. We evaluated the aortic root by use of MRI in 17 HFH patients and 12 normal control subjects in a prospective, blinded, controlled study.

Methods and Results
—Morphological assessment of the aortic root was done with spin-echo and gradient-echo MRI scanning. Comparisons were made with a number of measures of disease severity, including cholesterol-year score, calcium score on electron-beam CT (EBCT), and size of Achilles tendon xanthomas. Atherosclerotic plaque, visible on fat-suppressed images but never on water-suppressed images, was present in 9 HFH patients (53%). Supravalvular aortic stenosis was present in 7 patients with HFH (41%). Maximum supravalvular aortic wall thickness was significantly greater and OD and lumen cross-sectional area (CSA) were smaller in patients than in control subjects (
P
=0.006, 0.0005, and 0.06, respectively). Maximum wall thickness was associated with a greater calcium score on electron-beam CT (
P
=0.02). Although the cumulative exposure of the aortic root to cholesterol (the cholesterol-year score) was significantly correlated with the Achilles tendon CSA and vascular calcification, this score did not correlate with the wall thickness or aortic CSA.

Conclusions
—This study not only demonstrates the utility of MRI for detecting and characterizing aortic root atherosclerotic plaque and supravalvular aortic stenosis in HFH patients but also suggests that the LDL receptor plays a direct or indirect role in aortic mural development and vascular growth.
Pulmonary Atresia With Intact Ventricular Septum
Authors: Daubeney P. E. F. , Sharland G. K. , Cook A. C. , Keeton B. R. , Anderson R. H. , Webber S. A.
Published: June 2012

Background
—Fetal echocardiography is widely established in the United Kingdom for prenatal diagnosis of congenital heart disease. This may result in a substantial reduction in incidence at birth because of selected termination of pregnancy. The objective of this population-based study was to determine the incidence of pulmonary atresia with intact ventricular septum (PAIVS) at birth, the impact of fetal echocardiography on this incidence, and to compare the outcome of cases with and those without prenatal diagnosis.

Methods and Results
—From 1991 to 1995, all infants born with PAIVS and all fetal diagnoses in the United Kingdom and Eire were studied. There were 183 live births (incidence 4.5/100 000 live births). The incidence was 4.1 cases per 100 000 live births in England and Wales, 4.7 in Scotland, 6.8 in Eire, and 9.6 in Northern Ireland (
P
=0.01). There were 86 fetal diagnoses made at a mean of 22.0 weeks of gestation leading to 53 terminations of pregnancy (61%), 4 intrauterine deaths (5%), and 29 live births (34%). The incidence at birth would be 5.6 per 100 000 births in England and Wales, 5.3 in Scotland, and unchanged in Eire and Northern Ireland, if there were no terminations of pregnancy and assuming no further spontaneous fetal deaths (
P
=0.28). An initial diagnosis of critical pulmonary stenosis was made in 6 cases, at a mean of 22.3 weeks of gestation with progression to PAIVS by 31.4 weeks. Probability of survival at 1 year was 65% and was the same for live-born infants whether or not a fetal diagnosis had been made.

Conclusions
—PAIVS is rare, occurring in 1 in 22 000 live births in the United Kingdom and Eire. Termination of pregnancy has resulted in an important reduction in the live-born incidence in mainland Britain.
Inhibitory Effects of Antioxidants on Neonatal Rat Cardiac Myocyte Hypertrophy Induced by Tumor Necrosis Factor-α and Angiotensin II
Authors: Nakamura Kazufumi , Fushimi Kazuo , Kouchi Hirosuke , Mihara Koichiro , Miyazaki Masahiro , Ohe Tohru , Namba Masayoshi
Published: June 2012

Background
—Tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II) modulate heart failure in part by provoking the hypertrophic response. Signal transduction pathways of those factors are implicated in reactive oxygen intermediates (ROIs). Therefore, we hypothesized that TNF-α and Ang II might cause myocyte hypertrophy via the generation of ROIs.

Methods and Results
—To test the hypothesis, we tested whether TNF-α and Ang II could induce the generation of ROIs and whether antioxidants such as butylated hydroxyanisole (BHA), vitamin E, and catalase might inhibit the hypertrophy in cultured neonatal rat cardiac myocytes. ROIs were measured by the ROI-specific probe 2′,7′-dichlorofluorescin diacetate in cultured cardiac myocytes. We demonstrated that TNF-α and Ang II induced the generation of ROIs in a dose-dependent manner. TNF-α (10 ng/mL) and Ang II (100 nmol/L) enlarged cardiac myocytes and increased [
3
H]leucine uptake, and BHA (10 μmol/L) significantly inhibited both effects. Other antioxidants, such as vitamin E (1 μg/mL) and catalase (100 U/mL), also inhibited the enlargement of cardiac myocytes induced by TNF-α.

Conclusions
—These results indicate that TNF-α and Ang II cause hypertrophy in part via the generation of ROIs in cardiac myocytes.
Assessment of Small-Diameter Aortic Mechanical Prostheses
Authors: Marcus Richard H. , Heinrich Russell S. , Bednarz James , Lupovitch Stephen , Abruzzo Joseph , Borok Raphael , Vandenberg Byron , Kerber Richard E. , Piccione William , Yoganathan Ajit P. , Lang Roberto M.
Published: June 2012

Background
—Noninvasive assessment of functionally stenotic small-diameter aortic mechanical prostheses is complicated by theoretical constraints relating to the hemodynamic relevance of Doppler-derived transprosthetic gradients. To establish the utility of Doppler echocardiography for evaluation of these valves, 20-mm Medtronic Hall and 19-mm St Jude prostheses were studied in vitro and in vivo.

Methods and Results
—Relations between the orifice transprosthetic gradient (equivalent to Doppler), the downstream gradient in the zone of recovered pressure (equivalent to catheter), and fluid mechanical energy losses were examined in vitro. Pressure-flow relations across the 2 prostheses were evaluated by Doppler echocardiography in vivo. For both types of prosthesis in vitro, the orifice was higher than the downstream gradient (
P
<0.001), and fluid mechanical energy losses were as strongly correlated with orifice as with downstream pressure gradients (
r
2
=0.99 for both). Orifice and downstream gradients were higher and fluid mechanical energy losses were larger for the St Jude than the Medtronic Hall valve (all
P
<0.001). Whereas estimated effective orifice areas for the 2 valves in vivo were not significantly different, model-independent dynamic analysis of pressure-flow relations revealed higher gradients for the St Jude than the Medtronic Hall valve at a given flow rate (
P
<0.05).

Conclusions
—Even in the presence of significant pressure recovery, the Doppler-derived gradient across small-diameter aortic mechanical prostheses does have hemodynamic relevance insofar as it reflects myocardial energy expenditure. Small differences in function between stenotic aortic mechanical prostheses, undetectable by conventional orifice area estimations, can be identified by dynamic Doppler echocardiographic analysis of pressure-flow relations.
Superoxide Production, Risk Factors, and Endothelium-Dependent Relaxations in Human Internal Mammary Arteries
Authors: Huraux Catherine , Makita Tetsuji , Kurz Sabine , Yamaguchi Koji , Szlam Fania , Tarpey Margaret M. , Wilcox Josiah N. , Harrison David G. , Levy Jerrold H.
Published: June 2012

Background
—In a variety of disease states, endothelium-dependent vasodilation is abnormal. Reduced nitric oxide (NO) production, increased destruction of NO by superoxide, diminished cellular levels of
l
-arginine or tetrahydrobiopterin, and alterations in membrane signaling have been implicated. We examined these potential mechanisms in human vessels.

Methods and Results
—Relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin, as well as superoxide production and NO synthase expression, were examined in vascular segments from patients with identified cardiovascular risk factors. Endothelium-dependent relaxations were also studied after incubation with
l
-arginine,
l
-sepiapterin, and liposome-entrapped superoxide dismutase (SOD) and after organoid culture with
cis
-vaccenic acid. Relaxations to acetylcholine and to a lesser extent the calcium ionophore A23187 were highly variable and correlated with the number of risk factors present among the subjects studied. Treatment of vessels with
l
-arginine,
l
-sepiapterin, liposome-entrapped SOD, or
cis
-vaccenic acid did not augment endothelium-dependent relaxations. Hypercholesterolemia was the only risk factor associated with high levels of superoxide; however, there was no correlation between superoxide production and the response to either endothelium-dependent vasodilator used.

Conclusions
—In human internal mammary arteries, depressed endothelium-dependent relaxations could not be attributed to increases in vascular superoxide production, deficiencies in either
l
-arginine or tetrahydrobiopterin, or reduced membrane fluidity. Variability in signaling mechanisms may contribute to the differences in responses to acetylcholine and the calcium ionophore A23187.
Genome-Wide Linkage Analyses of Systolic Blood Pressure Using Highly Discordant Siblings
Authors: Krushkal Julia , Ferrell Robert , Mockrin Stephen C. , Turner Stephen T. , Sing Charles F. , Boerwinkle Eric
Published: June 2012

Background
—Elevated blood pressure is a risk factor for cardiovascular, cerebrovascular, and renal diseases. Complex mechanisms of blood pressure regulation pose a challenge to identifying genetic factors that influence interindividual blood pressure variation in the population at large.

Methods and Results
—We performed a genome-wide linkage analysis of systolic blood pressure in humans using an efficient, highly discordant, full-sibling design. We identified 4 regions of the human genome that show statistical significant linkage to genes that influence interindividual systolic blood pressure variation (2p22.1 to 2p21, 5q33.3 to 5q34, 6q23.1 to 6q24.1, and 15q25.1 to 15q26.1). These regions contain a number of candidate genes that are involved in physiological mechanisms of blood pressure regulation.

Conclusions
—These results provide both novel information about genome regions in humans that influence interindividual blood pressure variation and a basis for identifying the contributing genes. Identification of the functional mutations in these genes may uncover novel mechanisms for blood pressure regulation and suggest new therapies and prevention strategies.
Cellular Effects of β-Particle Delivery on Vascular Smooth Muscle Cells and Endothelial Cells
Authors: Fareh Jeannette , Martel Rémi , Kermani Pouneh , Leclerc Guy
Published: June 2012

Background
—Although endovascular radiotherapy inhibits neointimal hyperplasia, the exact cellular alterations induced by β irradiation remain to be elucidated.

Methods and Results
—We investigated in vitro the ability of
32
P-labeled oligonucleotides to alter (1) proliferation of human and porcine vascular smooth muscle cells (VSMCs) and human coronary artery endothelial cells (ECs), (2) cell cycle progression, (3) cell viability and apoptosis, (4) cell migration, and (5) cell phenotype and morphological features. β radiation significantly reduced proliferation of VSMCs (ED
50
1.10 Gy) and ECs (ED
50
2.15 Gy) in a dose-dependent manner. Exposure to β emission interfered with cell cycle progression, with induction of G
0
/G
1
arrest in VSMCs, without evidence of cell viability alteration, apoptosis, or ultrastructural changes. This strategy also proved to efficiently inhibit VSMC migration by 80% and induce contractile phenotype appearance, as shown by the predominance of α-actin immunostaining in β-irradiated cells compared with control cells.

Conclusions
—
32
P-labeled oligonucleotide was highly effective in inhibiting proliferation of both VSMCs and ECs in a dose-dependent fashion, with ECs showing a higher resistance to these effects. β irradiation–induced G
1
arrest was not associated with cytotoxicity and apoptosis, thus demonstrating a potent cytostatic effect of β-based therapy. This effect, coupled to that on VSMC migration inhibition and the appearance of a contractile phenotype, reinforced the potential of ionizing radiation to prevent neointima formation after angioplasty.