bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-Associated and Extracellular Phospholipid Transfer Protein in Human Coronary Atherosclerosis
Authors: O’Brien Kevin D. , Vuletic Simona , McDonald Thomas O. , Wolfbauer Gertrud , Lewis Katherine , Tu An-Yue , Marcovina Santica , Wight Thomas N. , Chait Alan , Albers John J.
Published: July 2003

Background—

Phospholipid transfer protein (PLTP) plays an important role in HDL particle metabolism and may modulate hepatic secretion of apolipoprotein B–containing lipoproteins. However, whether PLTP might participate directly in human atherosclerotic lesion formation is unknown.

Methods and Results—

The cellular and extracellular distributions of PLTP were determined in normal and atherosclerotic human coronary lesions with a monoclonal antibody to human PLTP. Cell types (smooth muscle cells [SMCs] or macrophages), apolipoproteins (apoA-I, apoB, and apoE), and extracellular matrix proteoglycans (biglycan and versican) were identified on adjacent sections with monospecific antibodies. Minimal extracellular PLTP was detected in nonatherosclerotic coronary arteries, but extracellular and cellular PLTP immunostaining was widespread in atherosclerotic lesions. PLTP was detected in foam cell SMCs and in foam cell macrophages, which suggests that cellular cholesterol accumulation might increase PLTP expression in both cell types. This was confirmed by in vitro studies demonstrating that cholesterol loading of macrophages leads to 2- to 3-fold increases in PLTP steady-state mRNA levels, protein expression, and activity. PLTP also was detected in an extracellular distribution, colocalizing with apoA-I, apoB, apoE, and the vascular proteoglycan biglycan. In gel mobility shift assays, both active and inactive recombinant PLTP markedly increased HDL binding to biglycan, which suggests that PLTP may mediate lipoprotein binding to proteoglycans independent of its phospholipid transfer activity.

Conclusions—

PLTP is present in human atherosclerotic lesions, and its distribution suggests roles for PLTP in both cellular cholesterol metabolism and lipoprotein retention on extracellular matrix.
Racial Disparity in Cardiac Procedures and Mortality Among Long-Term Survivors of Cardiac Arrest
Authors: Groeneveld Peter W. , Heidenreich Paul A. , Garber Alan M.
Published: July 2003

Background—

It is unknown whether white and black Medicare beneficiaries have different rates of cardiac procedure utilization or long-term survival after cardiac arrest.

Methods and Results—

A total of 5948 elderly Medicare beneficiaries (5429 white and 519 black) were identified who survived to hospital discharge between 1990 and 1999 after admission for cardiac arrest. Demographic, socioeconomic, and clinical information about these patients was obtained from Medicare administrative files, the US census, and the American Hospital Association’s annual institutional survey. A Cox proportional hazard model that included demographic and clinical predictors indicated a hazard ratio for mortality of 1.30 (95% CI 1.09 to 1.55) for blacks aged 66 to 74 years compared with whites of the same age. The addition of cardiac procedures to this model lowered the hazard ratio for blacks to 1.23 (95% CI 1.03 to 1.46). In analyses stratified by race, implantable cardioverter-defibrillators (ICDs) had a mortality hazard ratio of 0.53 (95% CI 0.45 to 0.62) for white patients and 0.50 (95% CI 0.27 to 0.91) for black patients. Logistic regression models that compared procedure rates between races indicated odds ratios for blacks aged 66 to 74 years of 0.58 (95% CI 0.36 to 0.94) to receive an ICD and 0.50 (95% CI 0.34 to 0.75) to receive either revascularization or an ICD.

Conclusions—

There is racial disparity in long-term mortality among elderly cardiac arrest survivors. Both black and white patients benefited from ICD implantation, but blacks were less likely to undergo this potentially life-saving procedure. Lower rates of cardiac procedures may explain in part the lower survival rates among black patients.
Prognostic Impact of Vascular Leakage in Acute Kawasaki Disease
Authors: Terai Masaru , Honda Takafumi , Yasukawa Kumi , Higashi Kouji , Hamada Hiromichi , Kohno Yoichi
Published: July 2003

Background—

Increased microvascular permeability is an initial step of Kawasaki disease (KD). We reported that vascular endothelial growth factor (VEGF) might play a role in the vascular leakage of KD. In fatal KD, plasma leakage was extensively documented at VEGF-positive microvessels. Increases in vascular leakage cause hypoalbuminemia and noncardiogenic edema. However, the prognostic impact of vascular leakage in KD remains unclear.

Methods and Results—

We compared 76 patients who became afebrile within 5 days after starting intravenous gamma globulin (IVGG) (2 g/kg over 5 days) (IVGG-responsive) with 27 patients who did not respond (IVGG-resistant). Baseline levels of serum VEGF and albumin were similar between the groups. After IVGG, VEGF levels increased (
P
<0.0001) and albumin levels decreased (
P
<0.00001) in both groups. However, the IVGG-resistant group had higher VEGF levels (
P
=0.029) and severe hypoalbuminemia (
P
<0.00001) compared with the IVGG-responsive group. Coronary aneurysms were documented in 12 patients from the IVGG-resistant group but not in the IVGG-responsive group. Then IVGG-resistant patients were divided into 2 subgroups according to the presence (n=12) or absence (n=15) of coronary aneurysms. There was no difference between subgroups in age, sex, laboratory data including albumin, and retreated doses of IVGG. However, body weight gain after IVGG was documented in patients who subsequently developed coronary aneurysms (
P
=0.003) but not in those who did not (
P
=0.967).

Conclusions—

These results suggest that vascular leakage may be a key feature of KD pathophysiology. The present study may provide better insights into the pathogenesis and treatment of patients resistant to IVGG in acute KD.
Outcomes and Long-Term Survival for Patients Undergoing Mitral Valve Repair Versus Replacement
Authors: Thourani Vinod H. , Weintraub William S. , Guyton Robert A. , Jones Ellis L. , Williams Willis H. , Elkabbani Sharif , Craver Joseph M.
Published: July 2003

Background—

A paucity of literature is available on the effects of age and coronary artery bypass grafting (CABG) on the outcomes of patients undergoing mitral valve (MV) repair versus replacement.

Methods and Results—

A matched study was performed using prospectively collected data from the Emory cardiovascular database from 1984 to 1997 comparing 625 MV repair patients with 625 MV replacement patients. Mean age was significantly higher in the replacement group (56±14 versus 55±14 years). Preoperative demographics and postoperative outcomes were similar between groups. Length of stay (LOS) was significantly less in the repair group (9.5±9.4 versus 12.3±13.1 days). In-hospital mortality was significantly less in the repair group (4.3% versus 6.9%), and overall 10-year survival was significantly higher in the repair group (62% versus 46%). Ten-year survival of patients <60 years of age was significantly higher in repair patients (81% versus 55%) but similar in patients ≥60 years of age (33% versus 36%, respectively). Ten-year survival of MV repair without CABG was significantly higher compared with MV replacement patients (74% versus 51%) but similar to patients with concomitant CABG (28% versus 34%, respectively). Independent predictors of long-term mortality included increasing age, urgent/emergent status, female sex, diabetes mellitus, increasing weight, heart failure, decreasing ejection fraction, concomitant CABG, and MV replacement.

Conclusions—

Mitral valve repair has reduced LOS and improved in-hospital and 10-year survival. However, in the present series, MV repair does not provide significant long-term survival benefit over MV replacement in patients older than 60 years of age or those requiring concomitant CABG.
Low-Gradient Aortic Stenosis
Authors: Monin Jean-Luc , Quéré Jean-Paul , Monchi Mehran , Petit Hélène , Baleynaud Serge , Chauvel Christophe , Pop Camélia , Ohlmann Patrick , Lelguen Claude , Dehant Patrick , Tribouilloy Christophe , Guéret Pascal
Published: July 2003

Background—

The prognostic value of dobutamine stress hemodynamic data in the setting of low-gradient aortic stenosis has been addressed in small, single-center studies. Larger studies are needed to define the criteria for selecting the patients who will benefit from valve replacement.

Methods and Results—

Six centers prospectively enrolled 136 patients with aortic stenosis (96 men; median age, 72 years [range, 65 to 77 years]; median aortic valve area, 0.7 cm
2
[range, 0.6 to 0.8]; mean transaortic gradient, 29 mm Hg [range, 23 to 34 mm Hg]; cardiac index, 2.11 L · min
−1
· m
−2
[range, 1.75 to 2.55 L · min
−1
· m
−2
]). Left ventricular contractile reserve on the dobutamine stress Doppler study was present in 92 patients (group I) and absent in 44 patients (group II). Operative mortality was 5% (3 of 64 patients) in group I compared with 32% (10 of 31 patients) in group II (
P
=0.0002). Predictors for operative mortality were the lack of contractile reserve (odds ratio, 10.9; 95% confidence interval [CI], 2.6 to 43.4;
P
=0.001) and a mean transaortic gradient ≤20 mm Hg (odds ratio, 4.7; 95% CI, 1.1 to 21.0;
P
=0.04). Predictors for long-term survival were valve replacement (hazard ratio, 0.30; 95% CI, 0.17 to 0.53;
P
=0.001) and left ventricular contractile reserve (hazard ratio, 0.40; 95% CI, 0.23 to 0.69;
P
=0.001).

Conclusions—

In the setting of low-gradient aortic stenosis, surgery seems beneficial for most of the patients with left ventricular contractile reserve. In contrast, the postoperative outcome of patients without reserve is compromised by a high operative mortality. Thus, dobutamine stress Doppler hemodynamics may be factored into the risk-benefit analysis for each patient.
C-Reactive Protein and Lesion Morphology in Patients With Acute Myocardial Infarction
Authors: Sano Toshihiko , Tanaka Atsushi , Namba Masashi , Nishibori Yoshiharu , Nishida Yukio , Kawarabayashi Takahiko , Fukuda Daiju , Shimada Kenei , Yoshikawa Junichi
Published: July 2003

Background—

Elevated serum C-reactive protein (CRP) is of clinical significance in the management of acute coronary syndromes, but there have been few in vivo studies detailing the relation between lesion morphology and elevated CRP in the setting of acute myocardial infarction (AMI). In this study, we investigated the relation between lesion morphology as seen under preintervention intravascular ultrasound (IVUS) and CRP in the acute phase of AMI.

Methods and Results—

Our patient population comprised 90 consecutive patients with AMI who underwent preintervention IVUS within 6 hours of the onset of symptoms. Patients were divided into an elevated CRP group (≥3 mg/L) or a normal CRP group on the basis of serum CRP levels. There were no differences in patient characteristics or angiographic findings. We observed significantly more plaque rupture in the elevated CRP group than in the normal CRP group (70% versus 43%,
P
=0.01). A multivariate logistic regression model revealed that the presence of ruptured plaque alone correlated with elevation of serum CRP (
P
=0.02; odds ratio, 3.35; 95% CI, 1.22 to 9.18).

Conclusions—

Elevated CRP may be related to the presence of ruptured plaque. Our results suggest that in the setting of AMI, elevated CRP levels may reflect the inflammatory activity of a ruptured plaque.
Prognostic Value of QT Interval Parameters for Mortality Risk Stratification in Chagas’ Disease
Authors: Salles Gil , Xavier Sergio , Sousa Andrea , Hasslocher-Moreno Alejandro , Cardoso Claudia
Published: July 2003

Background—

QT interval parameters are potential prognostic markers of arrhythmogenicity risk and cardiovascular mortality and have never been evaluated in Chagas’ disease.

Methods and Results—

Outpatients (738) in the chronic phase of Chagas’ disease were enrolled in a long-term follow-up study. Maximal heart rate-corrected QT (QTc) and T-wave peak-to-end (TpTe) intervals and QRS, QT, JT, QTapex, and TpTe dispersions and variation coefficients were measured manually and calculated from 12-lead ECGs obtained on admission. Clinical, radiological, and 2-dimensional echocardiographic data were also recorded. Primary end points were all-cause, Chagas’ disease-related, and sudden cardiac mortalities. During a follow-up of 58±39 months, 62 patients died, 54 of Chagas’ disease-related causes and 40 suddenly. Multivariate Cox survival analysis revealed that the QT-interval dispersion (QTd) (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.63;
P
<0.001, for 10-ms increments) and left ventricular (LV) end-systolic dimension (hazard ratio, 1.36; 95% confidence interval, 1.21 to 1.53;
P
<0.001, for 5-mm increments) were the strongest independent predictors for all end points. The maximum QTc interval (QTcmax) could substitute for QTd with a worse predictive performance. Other predictors were heart rate, presence of pathological Q waves, frequent premature ventricular contractions (PVCs), and isolated left anterior fascicular block (LAFB) on the ECGs. Kaplan-Meier survival curves demonstrated that a QTd ≥65 ms or a QTcmax ≥465 ms
1/2
discriminated the 2 groups with significantly different prognoses.

Conclusions—

Electrocardiographic QTd and echocardiographic LV end-systolic dimension were the most important mortality predictors in patients with Chagas’ disease. Heart rate, the presence on ECG of pathological Q waves, frequent PVCs, and isolated LAFB refined the mortality risk stratification.
Mechanical Prevention of Distal Embolization During Primary Angioplasty
Authors: Limbruno Ugo , Micheli Andrea , De Carlo Marco , Amoroso Giovanni , Rossini Roberta , Palagi Caterina , Di Bello Vitantonio , Petronio Anna Sonia , Fontanini Gabriella , Mariani Mario
Published: July 2003

Background—

Effective myocardial reperfusion after primary percutaneous coronary intervention (PCI) may be limited by distal embolization. We tested the safety, feasibility, and efficacy of the FilterWire-Ex (FW), a distal embolic protection device, as an adjunct to primary PCI.

Methods and Results—

Fifty-three consecutive patients undergoing primary PCI with FW protection were compared with a matched control group treated by primary PCI alone. Successful FW positioning was obtained in 47 patients (89%) without complications. Histological analysis of the content of the last 13 filters showed multiple embolic debris in all cases. FW use was associated with lower postinterventional corrected TIMI frame count (22±14 versus 31±19;
P
=0.005) and higher occurrence of grade 3 myocardial blush (66% versus 36%;
P
=0.006) and early ST-segment elevation resolution (80% versus 54%;
P=
0.006). At multivariate analysis, FW use was the only independent predictor of early ST-segment elevation resolution and of grade 3 myocardial blush. FW patients showed lower peak creatine kinase-MB release (236±172 versus 333±219 ng/mL;
P
=0.013) and greater improvement at 30 days in left ventricular wall motion score index (−0.30±0.19 versus −0.18±0.26;
P=
0.008) and ejection fraction (+7±4% versus +4±7%;
P
=0.012).

Conclusions—

FW use during primary PCI is feasible and safe. Distal embolization prevention appears to exert a beneficial effect on markers of myocardial reperfusion and on left ventricular function improvement at 30 days.
Reentrant Circuits in the Canine Atrioventricular Node During Atrial and Ventricular Echoes
Authors: Loh Peter , Ho Siew Yen , Kawara Tokuhiro , Hauer Richard N.W. , Janse Michiel J. , Breithardt Günter , de Bakker Jacques M.T.
Published: July 2003

Background—

The anatomic-electrophysiological correlation of AV nodal reentry is unclear. To localize reentrant circuits during atrial and ventricular echoes and to characterize sites of slow conduction and block, we correlated histology with electrophysiology of the AV node.

Methods and Results—

In 10 isolated dog hearts, extracellular electrical activity was recorded in Koch’s triangle at 208 or 247 sites (interelectrode distance, 0.5 and 0.3 mm) after removal of 0.7 to 1.5 mm of overlying atrial tissue. Resection did not affect refractory periods. Five hearts were subjected to histology. Complete atrial echoes were induced in 1 heart, incomplete atrial echoes in 5 hearts. Unidirectional conduction block occurred at the atrial–transitional cell junction in the superior area. Zones of slow conduction arose at the atrial–transitional or the transitional–compact node junction in the inferior area. Complete reentrant circuits of ventricular echoes were obtained in 5 hearts. Unidirectional conduction block occurred at the compact node–transitional cell junction in the superior area. Localized zones of slow conduction arose at the junctions between the different types of tissue in the inferior area.

Conclusions—

In the dog heart, tissue architecture and functional dissociation between the inferior and the superior region of the AV node enable dual physiology and reentry. Slow conduction and functional conduction block occur at the junctions between the different types of tissue in the AV nodal area. Atrial echoes were enabled by conduction block at the atrial-transitional cell junction, whereas during ventricular echoes conduction block occurred at the compact node-transitional cell junction.
Ultrasound Imaging of Acute Cardiac Transplant Rejection With Microbubbles Targeted to Intercellular Adhesion Molecule-1
Authors: Weller Gregory E.R. , Lu Erxiong , Csikari Melissa M. , Klibanov Alexander L. , Fischer David , Wagner William R. , Villanueva Flordeliza S.
Published: July 2003

Background—

Noninvasive techniques for detecting acute cardiac transplant rejection are limited. We hypothesized that ultrasound contrast microbubbles targeted to the endothelial cell (EC) inflammatory marker intercellular adhesion molecule-1 (ICAM-1) would selectively bind to rejecting versus nonrejecting myocardium and that myocardial contrast echocardiography can therefore detect acute rejection.

Methods and Results—

Lipid-based microbubbles were conjugated to anti-rat ICAM-1 (MB
ICAM
) or isotype control antibody (MB
Control
). In vitro MB
ICAM
adhesion to cultured rat ECs, as assessed in a parallel plate flow apparatus, was greater to inflammatory versus normal ECs (11±3 versus 3±2 microbubbles/EC,
P
<0.005). In vivo abdominal heterotopic heart transplantation was performed in rats (rejection group: Brown Norway to Lewis strain; control group: Lewis to Lewis or Brown Norway to Brown Norway). Triggered myocardial contrast echocardiography was performed during intravenous MB
ICAM
or MB
Control
(2.5×10
6
) injection on postoperative day 5. Myocardial videointensity from adhered MB
ICAM
was significantly higher in rejecting (n=8) versus control (n=7) rats (10±4 versus 1±4 U,
P
=0.01). Postmortem histology showed normal myocardium in control rats, whereas allograft myocardium demonstrated grade III to IV rejection and strong immunohistochemical ICAM-1 staining.

Conclusions—

Preferential adherence of ICAM-1-targeted microbubbles to rejecting versus nonrejecting rat cardiac transplant myocardium can be detected ultrasonically. Targeted microbubbles may thus offer a noninvasive ultrasound imaging technique for the detection of acute cardiac transplant rejection and other processes characterized by endothelial dysfunction.
Plasma Concentration of C-Reactive Protein and the Calculated Framingham Coronary Heart Disease Risk Score
Authors: Albert Michelle A. , Glynn Robert J. , Ridker Paul M
Published: July 2003

Background—

Although C-reactive protein (CRP) predicts vascular risk, few data are available evaluating the relation between CRP and the Framingham Coronary Heart Disease Risk Score (FCRS).

Methods and Results—

CRP levels were compared with calculated 10-year FCRS in a cross-sectional survey of 1666 individuals free of cardiovascular disease. Among men and women not using hormone replacement therapy (HRT), CRP levels were significantly related to 10-year Framingham Coronary Heart Disease Risk categories [total cholesterol (TC) score for men and women:
r
=0.29 and
r
=0.22, respectively; LDL cholesterol score for men and women:
r
=0.29 and
r
=0.22, respectively, all probability values <0.01]. However, CRP levels correlated minimally with individual components of the FCRS, which included age (
r
men
=0.17,
r
women
=−0.003), TC (
r
men
=−0.02,
r
women
=−0.006), HDL-C (
r
men
=0.13), LDL-C (
r
men
=−0.0002,
r
women
=0.012), blood pressure (
r
men
=0.18,
r
women
=0.22), diabetes (
r
men
=0.10,
r
women
=0.07), and smoking (
r
men
=0.16,
r
women
=0.14) status. For women taking HRT, no significant relation was observed between CRP and the FCRS, although the power to detect effects in this subgroup is limited.

Conclusions—

Our data demonstrate that CRP levels significantly correlate with calculated 10-year Framingham Coronary Heart Disease Risk in men and women not taking HRT but correlate minimally with most individual components of the FCRS. These data provide additional support for continued evaluation of CRP as a potential adjunct in the global prediction of cardiovascular risk.
Proarrhythmic Effect of Pacemaker Stimulation in Patients With Implanted Cardioverter-Defibrillators
Authors: Himmrich Ewald , Przibille Oliver , Zellerhoff Christian , Liebrich Andreas , Rosocha Stefan , Andreas Klaus , Nebeling Dirk , Omogbehin Babatunde , Meyer Jürgen
Published: July 2003

Background—

We sought to determine the potential of right ventricular VVI backup pacing to induce ventricular tachyarrhythmias in patients with implanted cardioverter-defibrillators.

Methods and Results—

All consecutive patients presenting exclusively with pacemaker-induced tachycardias (PITs) were included in a prospective study using a crossover protocol. Patients were randomized to either group 1 (augmentation of the baseline frequency of the pacemaker to 60 bpm) or group 2 (pacemaker turned off) and were followed up for 1 year and then crossed over to the other programming, looking for reoccurrence of PIT. Of 150 consecutive patients, 39 (26%) had PIT, 13 of them exclusively (8.6%). Forty of 1063 analyzed tachyarrhythmias of all the patients were PIT (3%). Before inclusion in the study, the patients had 2.7±0.9 PITs in 11±6.5 months with their pacemakers programmed empirically at 42.3 bpm. During the study phase, no PIT occurred while the pacemaker was turned off, whereas programming to 60 bpm led to the recurrence of PIT in 5 of 6 patients (1.4±0.6 per patient). At the end of the study, 9 patients underwent a prolonged follow-up with their pacemakers turned off, resulting in spontaneous episodes of ventricular tachycardia/fibrillation in 5 patients, but PITs were no longer observed.

Conclusions—

This crossover protocol proves the potential proarrhythmic effect of pacemaker stimulation in implantable cardioverter-defibrillator patients. Resulting PITs led to clinical symptoms and antitachycardia therapy by the implantable cardioverter-defibrillator. Thus, in patients presenting with PIT but without a pacemaker indication, the pacemaker feature should be turned off, or, alternatively, the longest possible escape interval should be programmed.
Preoperative Thallium Scanning, Selective Coronary Revascularization, and Long-Term Survival After Major Vascular Surgery
Authors: Landesberg Giora , Mosseri Morris , Wolf Yehuda G. , Bocher Moshe , Basevitch Alon , Rudis Ehud , Izhar Uzi , Anner Haim , Weissman Charles , Berlatzky Yacov
Published: July 2003

Background—

Ischemia on thallium scanning is a strong predictor of long-term mortality in CAD patients. Whether coronary revascularization (CR) in patients with significant ischemia on preoperative thallium scanning (PTS) improves long-term survival after major vascular surgery has not been determined.

Methods and Results—

The perioperative data, including PTS and subsequent CR in patients with moderate to severe reversible ischemia on PTS, and long-term survival of 502 consecutive patients who underwent 578 major vascular procedures were analyzed retrospectively. Patients with PTS who ultimately did not undergo the planned vascular operation were also studied. Cox regression and propensity score analyses were used to analyze survival. A total of 407 patients (81.1%) had PTS: 221 (54.3%) had no or mild defects (group I); 50 (12.3%) had moderate-severe fixed defects (group II); 62 (15.2%) had moderate-severe reversible ischemia yet did not undergo CR (group III); and 74 (18.2%) had moderate-severe reversible ischemia and subsequent CR by CABG (36) or PTCA (38; group IV). Patients who sustained major complications as a result of the preoperative cardiac workup were included in group IV. By multivariate analysis, age, type of vascular surgery, presence of diabetes, previous myocardial infarction, and moderate-severe ischemia on PTS independently predicted mortality (
P
=0.001, 0.009, 0.039, 0.006, and 0.029, respectively), and preoperative CR predicted improved survival (OR 0.52,
P
=0.018). Group IV had better survival than group III even when subdivided according to normal and reduced left ventricular function (OR 0.40 and 0.41,
P
=0.035 and 0.021, respectively).

Conclusions—

Long-term survival after major vascular surgery is significantly improved if patients with moderate-severe ischemia on PTS undergo selective CR.
Spatial Distribution of Phase Singularities in Ventricular Fibrillation
Authors: Valderrábano Miguel , Chen Peng-Sheng , Lin Shien-Fong
Published: July 2003

Background—

Multiple excitation wavelets are present during ventricular fibrillation (VF). The underlying wavelet organization of VF is unclear. Phase singularities (PSs)—locations of ambiguous activation state—underlie reentry and wavelet splitting and represent the sources of VF. Understanding the mechanisms of PS formation might be important in the development of effective therapies for sudden death.

Methods and Results—

We performed voltage, phase, and PS mapping in fibrillating ventricles, applying an automated PS detection algorithm to optically recorded fibrillation signals. PS clustering was noted along epicardial vessels, ridges of endocardial trabeculae, and papillary muscle insertions. Microscopically, these locations correlated with areas of apposition of fibers with different angulations and intramural vessels. A total of 83.2% of PSs were formed at and meandered about these anatomic structures, which acted as stabilizers: PSs colocalizing at anatomic substrates had longer life spans than nonanatomic PS (82.46±60.8 versus 40.5±31.9 ms,
P
<0.01). The RV endocardium had a higher PS incidence than the epicardium (42.3±9.2 versus 23.5±11.6 PS/s,
P
<0.01). Autocorrelation showed that irregular behavior was spatially restricted to anatomic heterogeneities compared with other areas, which had nearly periodic behaviors. Simple spatial PS distributions underlay complex and variable activation patterns attributable to variable PS behaviors, life spans, and inter-PS interactions.

Conclusions—

PSs occur in a nonrandom spatial distribution and colocalize with normal anatomic heterogeneities. Varying PS behaviors and life spans but stable PS spatial distributions cause ever-changing activation patterns that characterize VF.
Enhanced Umbilical Blood Flow During Acute Hypoxemia After Chronic Umbilical Cord Compression
Authors: Gardner David S. , Giussani Dino A.
Published: July 2003

Background—

The continuing incidence of intrapartum morbidity may be partly due to antenatal compromise, which influences the fetal defense to labor and delivery. We have shown that antenatal exposure of the ovine fetus to partial compression of the umbilical cord suppresses femoral vasoconstriction during subsequent acute hypoxemia through elevated nitric oxide (NO) activity. This study investigated whether elevated NO activity in cord-compressed fetuses enhanced the vasodilator response to hypoxemia in circulations in which blood flow is known to increase during acute hypoxemia, such as the umbilical vascular bed.

Methods and Results—

Fifteen fetal sheep were chronically instrumented between 117 and 120 days of gestation with vascular catheters and an umbilical flow probe. In 8 of these fetuses, umbilical blood flow was reduced by 30% for 3 days between 125 and 128 days. The remaining 7 fetuses acted as sham-operated controls. Between 2 and 7 days after umbilical cord/sham compression, fetuses were exposed to 2 episodes of acute hypoxemia, on separate days, during infusion with either saline or treatment with a combination of
N
G
-nitro-
l
-arginine methyl ester and sodium nitroprusside. The data show that umbilical cord compression significantly enhances the umbilical hyperemia through NO-dependent mechanisms during a subsequent episode of acute hypoxemia.

Conclusions—

Increased fetal NO activity after chronic cord compression has opposing effects in circulations that either constrict or dilate during subsequent acute hypoxemia. The data imply that antenatal compromise switches the fetal strategy to withstand episodes of subsequent acute hypoxemia of the type that may occur during labor and delivery from a reliance on vasoconstrictor mechanisms to those promoting NO-dependent vasodilation.
Imaging Tumor Angiogenesis With Contrast Ultrasound and Microbubbles Targeted to α
v
β
3
Authors: Ellegala Dilantha B. , Leong-Poi Howard , Carpenter Joan E. , Klibanov Alexander L. , Kaul Sanjiv , Shaffrey Mark E. , Sklenar Jiri , Lindner Jonathan R.
Published: July 2003

Background—

Angiogenesis is a critical determinant of tumor growth and metastasis. We hypothesized that contrast-enhanced ultrasound (CEU) with microbubbles targeted to α
v
-integrins expressed on the neovascular endothelium could be used to image angiogenesis.

Methods and Results—

Malignant gliomas were produced in 14 athymic rats by intracerebral implantation of U87MG human glioma cells. On day 14 or day 28 after implantation, CEU was performed with microbubbles targeted to α
v
β
3
by surface conjugation of echistatin. CEU perfusion imaging with nontargeted microbubbles was used to derive tumor microvascular blood volume and blood velocity. Vascular α
v
-integrin expression was assessed by immunohistochemistry, and microbubble adhesion was characterized by confocal microscopy. Mean tumor size increased markedly from 14 to 28 days (2±1 versus 35±14 mm
2
,
P
<0.001). Tumor blood volume increased by ≈35% from day 14 to day 28, whereas microvascular blood velocity decreased, especially at the central portions of the tumors. On confocal microscopy, α
v
β
3
-targeted but not control microbubbles were retained preferentially within the tumor microcirculation. CEU signal from α
v
β
3
-targeted microbubbles in tumors increased significantly from 14 to 28 days (1.7±0.4 versus 3.3±1.0 relative units,
P
<0.05). CEU signal from α
v
β
3
-targeted microbubbles was greatest at the periphery of tumors, where α
v
-integrin expression was most prominent, and correlated well with tumor microvascular blood volume (
r
=0.86).

Conclusions—

CEU with microbubbles targeted to α
v
β
3
can noninvasively detect early tumor angiogenesis. This technique, when coupled with changes in blood volume and velocity, may provide insights into the biology of tumor angiogenesis and be used for diagnostic applications.
Altered Atrial Electrical Restitution and Heterogeneous Sympathetic Hyperinnervation in Hearts With Chronic Left Ventricular Myocardial Infarction
Authors: Miyauchi Yasushi , Zhou Shengmei , Okuyama Yuji , Miyauchi Mizuho , Hayashi Hideki , Hamabe Akira , Fishbein Michael C. , Mandel William J. , Chen Lan S. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: July 2003

Background—

The substrates for the increased incidence of atrial fibrillation (AF) in hearts with chronic left ventricular myocardial infarction (MI) remain poorly defined. We hypothesized that chronic MI is associated with atrial electrical and neural remodeling that enhances AF vulnerability.

Methods and Results—

We created MI in 8 dogs by permanent occlusion of the left anterior descending (LAD) coronary artery. Seven dogs (3 with thoracotomy) that had no LAD occlusion served as controls. Eight weeks after surgery, the incidence and duration of pacing-induced AF in the open chest anesthetized state were significantly (
P
<0.05) higher in the MI than in control dogs. Multisite biatrial monophasic action potential (MAP) recordings showed increased heterogeneity of MAP duration (MAPD) and MAPD restitution slope. AF in the MI groups was preceded by significantly higher MAPD (
P
<0.01) and MAP amplitude (
P
<0.05) alternans in both atria compared with controls. Epicardial mapping using 1792 bipolar electrodes (1-mm spatial resolution) showed multisite wavebreaks of the paced wavefronts leading to AF in MI but not in control dogs. Multiple wavelets in MI dogs were associated with significantly higher incidence and longer duration of AF compared with control. The density of biatrial tyrosine hydroxylase (TH) and growth-associated protein43 (GAP43) nerves were 5- to 8-fold higher and were more heterogeneous in MI compared with control dogs.

Conclusions—

Chronic ventricular MI with no atrial involvement causes heterogeneous alteration of atrial electrical restitution and atrial sympathetic hyperinnervation that might provide important substrates for the observed increased AF vulnerability.
Endothelial Progenitor Cells Are Decreased in Blood of Cardiac Allograft Patients With Vasculopathy and Endothelial Cells of Noncardiac Origin Are Enriched in Transplant Atherosclerosis
Authors: Simper David , Wang Shaohua , Deb Arjun , Holmes David , McGregor Christopher , Frantz Robert , Kushwaha Sudhir S. , Caplice Noel M.
Published: July 2003

Background—

Recent studies in animals suggest that circulating recipient endothelial precursors may participate in the biology of transplant vasculopathy. It is currently unknown whether a similar interaction between recipient endothelial cells and the vessel wall occurs in human subjects undergoing allogeneic cardiac transplantation.

Methods and Results—

Circulating endothelial cells and endothelial progenitor cells (EPCs) were quantified in 15 cardiac transplantation subjects with and without angiographic evidence of vasculopathy. In a separate series of experiments, the origin (donor or recipient) of transplant plaque endothelial cells was assessed in subjects who had undergone a gender-mismatched cardiac transplantation and had histological evidence of severe vasculopathy at the time of heart explantation. Circulating EPC outgrowth colonies in peripheral blood were significantly reduced in subjects with transplant vasculopathy compared with those without angiographic evidence of disease (EPC colony-forming units [CFU
EPC
]: 4.5±1.9 versus 15.1±3.7,
P
<0.05). There was no significant difference in circulating endothelial cell numbers as defined by day 4 culture acetylated LDL/lectin assay in either of these patient groups. In a separate group of 5 subjects who underwent gender-mismatched cardiac transplantation, there was a significant seeding of recipient endothelial cells (range: 1% to 24% of all luminal endothelial cells) in large-vessel lumen and adventitial microvessel lumen of arteriopathic vessels. No opposite-sex chimeric cells were observed in control gender-matched transplantation scenarios.

Conclusions—

These data suggest that the human cardiac transplant arteriopathy is associated with reduction in circulating endothelial precursors and with seeding of recipient-derived endothelial cells at the site of plaque development.
Phosphorylation of the
I
Ks
Channel Complex Inhibits Drug Block
Authors: Yang Tao , Kanki Hideaki , Roden Dan M.
Published: July 2003

Background—

I
Ks
, an important repolarizing current in heart, is an antiarrhythmic drug target and is markedly increased by activation of protein kinase A (PKA; eg, by β-adrenergic stimulation). Because β-adrenergic stimulation is a frequent trigger of arrhythmias, we hypothesized that PKA stimulation inhibits drug block.

Methods and Results—

CHO cells were transfected with KCNQ1 cDNA (encoding the pore-forming subunit) with or without the ancillary subunit KCNE1. IC
50
for quinidine block of basal
I
Ks
was 5.8±1.2 μmol/L, versus 19.9±3.2 μmol/L (
P
<0.01) for PKA-stimulated current. A similar >3-fold shift was apparent in the absence of KCNE1 and with the
I
Ks
-specific blocker chromanol 293B. The first current recorded after channels were held at rest and exposed to the drug was reduced ≈40%, and further depolarizations increased the block with a time constant (τ) of 181±27 seconds. By contrast, PKA-stimulated channels displayed a <5% first-pulse block and much slower block development (τ=405±85 seconds). Alanine substitution at 3 potential PKA target sites (S27, S468, and T470) generated an
I
Ks
that did not increase with PKA stimulation; this mutant retained wild-type drug sensitivity that was unaffected by PKA.

Conclusions—

Activation of this key intracellular signaling pathway blunts drug block. The onset of block and the data with the PKA-resistant mutant support the concept that phosphorylation of the KCNQ1 subunit directly modulates drug access to a binding site on the channel. These data identify a novel mechanism for modulation of drug-channel interactions that may be especially important during β-adrenergic stimulation.
Association Between Supine Hypertension and Orthostatic Hypotension in Autonomic Failure
Authors: Goldstein David S. , Pechnik Sandra , Holmes Courtney , Eldadah Basil , Sharabi Yehonatan
Published: July 2003

Supine hypertension occurs commonly in primary chronic autonomic failure. This study explored whether supine hypertension in this setting is associated with orthostatic hypotension (OH), and if so, what mechanisms might underlie this association. Supine and upright blood pressures, hemodynamic responses to the Valsalva maneuver, baroreflex-cardiovagal gain, and plasma norepinephrine (NE) levels were measured in pure autonomic failure (PAF), multiple-system atrophy (MSA) with or without OH, and Parkinson’s disease (PD) with or without OH. Controls included age-matched, healthy volunteers and patients with essential hypertension or those referred for dysautonomia. Baroreflex-cardiovagal gain was calculated from the relation between the interbeat interval and systolic pressure during the Valsalva maneuver. PAF, MSA with OH, and PD with OH all featured supine hypertension, which was equivalent in severity to that in essential hypertension, regardless of fludrocortisone treatment. Among patients with PD or MSA, those with OH had higher mean arterial pressure during supine rest (109±3 mm Hg) than did those lacking OH (96±3 mm Hg,
P
=0.002). Baroreflex-cardiovagal gain and orthostatic increments in plasma NE levels were markedly decreased in all 3 groups with OH. Among patients with PD or MSA, those with OH had much lower mean baroreflex-cardiovagal gain (0.74±0.10 ms/mm Hg) than did those lacking OH (3.13±0.72 ms/mm Hg,
P
=0.0002). In PAF, supine hypertension is linked to both OH and low baroreflex-cardiovagal gain. The finding of lower plasma NE levels in patients with than without supine hypertension suggests involvement of pressor mechanisms independent of the sympathetic nervous system.
Angiotensin I Conversion to Angiotensin II Stimulates Cortical Collecting Duct Sodium Transport
Authors: Komlosi Peter , Fuson Amanda L. , Fintha Attila , Peti-Peterdi János , Rosivall Laszlo , Warnock David G. , Bell Phillip Darwin
Published: July 2003

Angiotensin (Ang) II directly stimulates epithelial sodium channel activity in the rabbit cortical collecting duct. Because Ang I and converting enzyme analogues might be present in the distal nephron, this raises the possibility of intraluminal generation of Ang II. Conversion of Ang I to Ang II was monitored by Ang II–dependent changes in intracellular sodium concentration as a reflection of sodium transport across the apical membrane. This involved imaging-based fluorescence microscopy with sodium-binding benzofuran isophthalate in isolated, perfused, cortical collecting-duct segments from rabbit kidney. Principal and intercalated cells were differentiated by rhodamine-conjugated peanut lectin. Control principal cell intracellular sodium concentration, during perfusion with 25 mmol/L NaCl and zero sodium in the bath plus monensin (10
−5
mol/L) averaged 5.8±0.14 mmol/L (n=156). The increase in intracellular sodium concentration, when luminal NaCl was increased from 25 to 150 mmol/L, was elevated by 3.5-fold in the presence of intraluminal Ang I (10
−6
mol/L). Also, the effects of Ang I on sodium transport were not significantly different from the effects of Ang II (10
−9
mol/L). Ang I was used in micromolar concentrations to ensure that there was sufficient substrate available for conversion to Ang II. Inhibition of the angiotensin-converting enzyme with captopril reduced the stimulatory effect of Ang I. These results suggest that intraluminal conversion of Ang I to Ang II can occur in the cortical collecting duct, resulting in enhanced apical sodium entry.
Alterations of Circadian Expressions of Clock Genes in Dahl Salt-Sensitive Rats Fed a High-Salt Diet
Authors: Mohri Takao , Emoto Noriaki , Nonaka Hidemi , Fukuya Hiroyuki , Yagita Kazuhiro , Okamura Hitoshi , Yokoyama Mitsuhiro
Published: July 2003

In mammals, behavioral and physiologic processes display 24-hour rhythms that are regulated by a circadian system consisting of central and peripheral oscillators. Because various cardiovascular functions show diurnal variations and abnormal patterns of circadian blood pressure variation carry a high risk of cardiovascular complications, we investigated whether the expression of clock genes is altered in an animal model of hypertension. In Dahl salt-sensitive rats fed a high-salt (4% NaCl) diet for 6 weeks (DS-H), radiotelemetry monitoring showed increased amplitude of circadian variations in blood pressure. The ratio of heart weight to body weight and the ratio of kidney weight to body weight were higher in DS-H. Echocardiographic data showed that the wall thickness of the left ventricle was greater in DS-H. Northern blot analysis and single cosinor analysis revealed that the amplitudes of circadian expression changes of the clock genes (
mPer2
,
Bmal1
, and
dbp
) in the heart, liver, and kidney were significantly decreased in DS-H rats compared with a normal-salt-diet group, except for
Bmal1
in the liver. The circadian expression changes of plasminogen activator inhibitor-1, a clock-regulated gene, were attenuated in the hearts of DS-H. The present results demonstrate that DS-H show altered circadian expression of peripheral clock genes. Detailed analyses of the relation between circadian expression of clock genes and blood pressure regulation might reveal a role for chronologic therapy of cardiovascular disease.
Cooperation Between Insulin and Leptin in the Modulation of Vascular Tone
Authors: Vecchione Carmine , Aretini Alessandra , Maffei Angelo , Marino Gennaro , Selvetella Giulio , Poulet Roberta , Trimarco Valentina , Frati Giacomo , Lembo Giuseppe
Published: July 2003

High levels of insulin and leptin have been reported in human hypertension, suggesting a role for these metabolic hormones in blood pressure homeostasis. These hormones interact on intermediate metabolism, but nothing is known about their interaction at the vascular level. Our data demonstrate that insulin (0.6 nmol/L) is able to enhance vasodilation induced by leptin (10
−11
to 10
−6
mol/L; percentage change in maximal vasodilation, 39±3% vs 26±2%; n=6,
P
<0.03) but not by acetylcholine. Moreover, we demonstrate by 4,5-diaminofluorescein (DAF)-2 that insulin potentiates leptin-induced nitric oxide (NO) release. Finally, Western blotting studies show that insulin enhances the leptin-induced phosphorylation of Akt in Ser
473
and Thr
308
and of endothelial NO synthase in Ser
1177
. In conclusion, our data demonstrate that insulin and leptin cooperate in the modulation of vascular tone through enhancement of endothelial NO release. This phenomenon could have a major impact on the regulation of the cardiovascular system, principally in those clinical conditions characterized by endothelial NO dysfunction and metabolic disorders, such as arterial hypertension.
Aorta of ApoE-Deficient Mice Responds to Atherogenic Stimuli by a Prelesional Increase and Subsequent Decrease in the Expression of Antioxidant Enzymes
Authors: ’t Hoen Peter A.C. , Van der Lans Christian A.C. , Van Eck Miranda , Bijsterbosch Martin K. , Van Berkel Theo J.C. , Twisk Jaap
Published: July 2003

Oxidative stress has been implicated in the development of atherosclerotic lesions. We evaluated the relationship between extent of atherosclerotic lesion formation and vascular expression of pro- and antioxidant enzymes in apoE-deficient mice. On normal chow, these mice showed elevated serum cholesterol levels (7.5- to 9.5-fold), and age-dependent, spontaneous development of all stages of atherosclerotic lesions, starting at the age of 12 weeks. RNA was extracted from the aortic arch and descending aorta, and mRNA expression of pro- and antioxidant enzymes was measured with real-time PCR. Local infiltration of monocytes/macrophages, reflected by increased vascular expression of CD68 mRNA (>10-fold), indicated that the arch was more susceptible than the descending aorta. The expression of catalase-1 and various isoforms of superoxide dismutase, glutathione peroxidase, and glutathione
S
-transferase alpha was significantly increased in the aortic arch, but not in the descending aorta, in the period preceding lesion formation (age 6 to 12 weeks). These expression levels were 1.5 to 5 times higher than in age-matched wild-type animals. Remarkably, there was an inverse relationship between extent of lesion formation and the mRNA levels of antioxidant enzymes, most of which started to decline after 12 weeks, as lesions developed. In contrast, inducible nitric oxide synthase expression increased 4-fold in the aortic arch over the course of the disease. Our results suggest that the arterial wall responds to increased serum levels of atherogenic lipoproteins by stimulating expression of antioxidant enzymes. The observed co-ordinate decline in expression of many of these protective systems may greatly accelerate the development of atherosclerosis.
Engineering the Response to Vascular Injury
Authors: Goukassian David A. , Kishore Raj , Krasinski Kevin , Dolan Christine , Luedemann Corinne , Yoon Young-sup , Kearney Marianne , Hanley Allison , Ma Hong , Asahara Takayuki , Isner Jeffrey M. , Losordo Douglas W.
Published: July 2003

Tumor necrosis factor-α (TNF-α) is expressed locally in the vessel wall after angioplasty and induces growth arrest and apoptosis in endothelial cells (ECs), thereby delaying reendothelialization. Prior studies have shown that direct antagonism of TNF-α, using a systemically administered soluble receptor, can enhance endothelial recovery and reduce neointimal thickening. These studies have also shown that downregulation of the transcription factor E2F1 was a key mechanism of TNF’s effect on ECs. We now show that Ad-E2F1 overexpression at sites of balloon injury accelerates functional endothelial recovery, consistent with the prior in vitro findings. Moreover these studies also reveal divergent effects of TNF-α and overexpression of E2F1 on ECs versus VSMCs. TNF-α exposure of VSMCs had no affect on proliferation or apoptosis, in contrast to the effect seen in ECs. In Ad-E2F1-transduced VSMCs, however, TNF-α-induced marked apoptosis in contrast to the survival effect seen in ECs. Finally, these studies suggest that differential activation of NF-κB may play a key role in mediating these opposing effects. Nuclear translocation and transcriptional activity of NF-κB was markedly attenuated in Ad-E2F1-transduced VSMCs, whereas it remained active in similarly treated ECs when the cells were exposed to TNF-α. These studies reveal that overexpression of Ad-E2F1 primes VSMCs to TNF-α-induced apoptosis. Furthermore, E2F1 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF-κB activation. The divergent responses of VSMCs and ECs to E2F1 overexpression provide unique therapeutic possibilities: simultaneously targeting the cell cycle of two different cell types, within same tissue microenvironment resulting in opposite and biologically complimentary effects.