bluuebunny/crossref_metadata_2025 huggingface dataset:
Collagenase Plaque Digestion for Facilitating Guide Wire Crossing in Chronic Total Occlusions
Authors: Strauss Bradley H. , Goldman Lorne , Qiang Beiping , Nili Nafiseh , Segev Amit , Butany Jagdish , Sparkes John D. , Jackson Zane S. , Eskandarian Mohammad R. , Virmani Renu
Published: August 2003

Background—

Chronic total occlusions (CTOs) are associated with significant angina, impaired left ventricular function, and worse long-term outcomes. Percutaneous coronary interventions in CTO are unsuccessful in up to 50% of cases, primarily because of inability to cross the lesion with a guide wire. Collagen is the predominant component of the atherosclerotic plaque. The objective of this study was to determine the efficacy and toxicity of local delivery of a collagen-degrading enzyme to facilitate guide wire crossing in CTO.

Methods and Results—

Type IA collagenase (100 or 450 μg) or placebo was locally administered to 45 CTOs in a rabbit femoral artery model. Mean occlusion duration was 16±5 weeks. Attempts to cross the CTO (mean length, 28±9 mm) with conventional guide wires were assessed at 72 hours after treatment. An additional 3 arteries per group were assessed for collagenase effects at 24 hours after treatment. Successful guide wire crossings were significantly higher in collagenase-treated arteries (13 of 21, 62%) than in placebo-treated arteries (7 of 24, 29%) (
P
=0.028). No adverse effects on arterial structure were observed in collagenase-treated arteries. At 24 hours, collagenase-treated arteries demonstrated increased collagenase protein, gelatinase activity, and collagen fragments.

Conclusions—

Local delivery of collagenase can safely facilitate guide wire crossing of CTO. This novel approach could lead to higher percutaneous coronary intervention success rates in CTO.
Rosuvastatin Reduces Atherosclerosis Development Beyond and Independent of Its Plasma Cholesterol–Lowering Effect in APOE*3-Leiden Transgenic Mice
Authors: Kleemann Robert , Princen Hans M.G. , Emeis Jef J. , Jukema J. Wouter , Fontijn Ruud D. , Horrevoets Anton J.G. , Kooistra Teake , Havekes Louis M.
Published: August 2003

Background—

Statins can exert anti-inflammatory antiatherosclerotic effects through an anti-inflammatory action, independent of lowering cholesterol. We addressed the question whether the anti-inflammatory activities of statins can reduce atherosclerosis beyond the reduction achieved by cholesterol lowering per se.

Methods and Results—

Two groups of 20 female APOE*3-Leiden mice received either a high-cholesterol diet (HC) or a high-cholesterol diet supplemented with 0.005% (wt/wt) rosuvastatin (HC+R). The HC diet alone resulted in a plasma cholesterol concentration of 18.9±1.4 mmol/L, and administration of rosuvastatin lowered plasma cholesterol to 14.1±0.7 mmol/L. In a separate low-cholesterol (LC) control group, the dietary cholesterol intake was reduced, which resulted in plasma cholesterol levels that were comparable to the HC+R group (13.4±0.8 mmol/L). Atherosclerosis in the aortic root area was quantified after 24 weeks. As compared with the HC group, the LC group had a 62% (
P
<0.001) reduction in cross-sectional lesion area. When compared with the LC group, the HC+R group showed a further decrease in cross-sectional lesion area (80%,
P
<0.001), size of individual lesions (63%,
P
<0.05), lesion number (58%,
P
<0.001), monocyte adherence (24%,
P
<0.05), and macrophage-containing area (60%,
P
<0.001). Furthermore, rosuvastatin specifically suppressed the expression of the inflammation parameters MCP-1 and TNF-α in the vessel wall and lowered plasma concentrations of serum amyloid A and fibrinogen, independent of its cholesterol-lowering effect.

Conclusions—

Rosuvastatin reduces atherosclerosis beyond and independent of the reduction achieved by cholesterol lowering alone. This additional beneficial effect of rosuvastatin may be explained, at least partly, by its anti-inflammatory activity.
Heterogeneous Ventricular Repolarization Provides a Substrate for Arrhythmias in a German Shepherd Model of Spontaneous Arrhythmic Death
Authors: Obreztchikova Maria N. , Sosunov Eugene A. , Anyukhovsky Evgeny P. , Moïse N. Sydney , Robinson Richard B. , Rosen Michael R.
Published: August 2003

Background—

German shepherd dogs with inherited arrhythmias and sudden death appear to be a model for catecholamine-dependent ventricular tachycardias in human subjects. We tested the hypothesis that heterogeneity of left ventricular repolarization creates an arrhythmogenic substrate for pause-dependent ventricular tachycardia in these animals.

Methods and Results—

We used microelectrode techniques to record action potentials (AP) from midmyocardial sections of anteroseptal, anterobasal, and posterobasal left ventricular (LV) wall of unafflicted and afflicted dogs. There were no differences in AP duration to 90% repolarization (APD) among LV regions in unafflicted dogs. In contrast, in afflicted dogs, there was significant heterogeneity, with the longest APD in anterobasal and shortest in anteroseptal regions. Isoproterenol did not affect repolarization in unafflicted dogs, whereas in afflicted dogs, it shortened APD anterobasally and prolonged APD anteroseptally. We studied the repolarizing currents,
I
Kr
and
I
Ks
, in single anteroseptal and anterobasal LV myocytes with the use of a whole-cell voltage clamp. There were no differences in
I
Kr
and
I
Ks
between anteroseptal and anterobasal regions in unafflicted dogs, whereas in afflicted dogs,
I
Kr
was smaller anterobasally (
P
<0.05). Isoproterenol produced a more prominent leftward shift in
I
Ks
voltage-dependent activation in anterobasal regions of afflicted than unafflicted dogs.

Conclusions—

Spatial heterogeneity in expression and catecholamine responsiveness of
I
Kr
and
I
Ks
results in heterogeneous LV repolarization in afflicted German shepherd dogs, contributing importantly to the arrhythmogenic substrate.
Deficiency of Gelatinase A Suppresses Smooth Muscle Cell Invasion and Development of Experimental Intimal Hyperplasia
Authors: Kuzuya Masafumi , Kanda Shigeru , Sasaki Takeshi , Tamaya-Mori Norika , Cheng Xian Wu , Itoh Takeshi , Itohara Shigeyoshi , Iguchi Akihisa
Published: August 2003

Background—

Although it has been demonstrated that matrix metalloproteinases (MMPs) play an important role in the arterial remodeling in atherosclerosis and restenosis, it is not clear which MMP is involved in which process. To define the role of MMP-2 in arterial remodeling, we evaluated the influence of the targeted deletion of the MMP-2 gene on vascular remodeling after flow cessation in the murine carotid arteries.

Methods and Results—

The left common carotid arteries of wild-type and MMP-2–deficient mice were ligated just proximal to their bifurcations, and the animals were then processed for morphological and biochemical studies at specific time points. MMP-2 activity and mRNA levels increased in ligated carotid arteries of wild-type mice on the basis of observation by gelatin zymography and quantitative real-time RT-PCR. There was significantly less intimal hyperplasia in MMP-2–deficient mice at 2 and 4 weeks after ligation than there in wild-type mice. Arterial explants from the aorta of MMP-2–deficient mice showed that smooth muscle cell (SMC) migration was inhibited in comparison with wild-type mice. The chemoattractant-directed invasion through a reconstituted basement membrane barrier was significantly reduced in cultured SMCs derived from MMP-2–deficient mice, although no difference was observed in SMC migration across the filter or in proliferative response between the control and MMP-2–deficient mice.

Conclusions—

In a mouse carotid artery blood flow cessation model, MMP-2 contributes to intimal hyperplasia mainly through the SMC migration from the media into the intima by degrading and breaching the extracellular matrix proteins surrounding each cell and the internal elastic lamina.
Blockade of the Intermediate-Conductance Calcium-Activated Potassium Channel as a New Therapeutic Strategy for Restenosis
Authors: Köhler Ralf , Wulff Heike , Eichler Ines , Kneifel Marlene , Neumann Daniel , Knorr Andrea , Grgic Ivica , Kämpfe Doris , Si Han , Wibawa Judith , Real Robert , Borner Klaus , Brakemeier Susanne , Orzechowski Hans-Dieter , Reusch Hans-Peter , Paul Martin , Chandy K. George , Hoyer Joachim
Published: August 2003

Background—

Angioplasty stimulates proliferation and migration of vascular smooth muscle cells (VSMC), leading to neointimal thickening and vascular restenosis. In a rat model of balloon catheter injury (BCI), we investigated whether alterations in expression of Ca
2+
-activated K
+
channels (K
Ca
) contribute to intimal hyperplasia and vascular restenosis.

Methods and Results—

Function and expression of K
Ca
in mature medial and neointimal VSMC were characterized in situ by combined single-cell RT-PCR and patch-clamp analysis. Mature medial VSMC exclusively expressed large-conductance K
Ca
(BK
Ca
) channels. Two weeks after BCI, expression of BK
Ca
was significantly reduced in neointimal VSMC, whereas expression of intermediate-conductance K
Ca
(IKCa1) channels was upregulated. In the aortic VSMC cell line, A7r5 epidermal growth factor (EGF) induced IKCa1 upregulation and EGF-stimulated proliferation was suppressed by the selective IKCa1 blocker TRAM-34. Daily in vivo administration of TRAM-34 to rats significantly reduced intimal hyperplasia by ≈40% at 1, 2, and 6 weeks after BCI. Two weeks of treatment with the related compound clotrimazole was equally effective. Reduction of intimal hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content.

Conclusions—

The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.
Differentiation of Ischemic From Nonischemic Cardiomyopathy During Dobutamine Stress by Left Ventricular Long-Axis Function
Authors: Duncan Alison M. , Francis Darrel P. , Gibson Derek G. , Henein Michael Y.
Published: August 2003

Background—

Resting regional wall-motion abnormalities do not reliably distinguish ischemic from nonischemic cardiomyopathy. Dobutamine stress echocardiography with use of the wall-motion score index (WMSI) identifies coronary artery disease (CAD) in dilated cardiomyopathy (DCM), but the technique is subjective and further complicated by left bundle-branch block (LBBB). Long-axis motion is sensitive to ischemia and can be assessed quantitatively. We aimed to compare long-axis function with WMSI for detecting CAD in DCM with or without LBBB.

Methods and Results—

Seventy-three patients with DCM, 48 with CAD (16 with LBBB), and 25 without CAD (10 with LBBB) were studied. Long-axis M-mode, pulsed-wave tissue Doppler echograms (lateral, septal, and posterior walls), and WMSI were assessed at rest and at peak dobutamine stress. Failure to increase systolic amplitude (total amplitude minus postejection shortening) by 2 mm or early diastolic velocity by 1.1 cm/s was the best discriminator for CAD (systolic amplitude, sensitivity 85%, specificity 86%; lengthening velocity, 71% and 94%, respectively;
P
=NS). Both had greater predictive accuracy than did WMSI (sensitivity 67%, specificity 76%;
P
<0.001). The predictive accuracy of changes in septal long-axis function was similar to those of average long-axis function (systolic amplitude cutoff=1.5 mm, lengthening velocity cutoff=1.5 cm/s). However in LBBB, systolic amplitude proved to be the only significant discriminator for CAD, with sensitivity and specificity reaching 94% and 100%, respectively (
P
<0.01 versus early diastolic lengthening velocity).

Conclusions—

Quantified stress long-axis function identifies CAD in DCM with greater sensitivity and specificity than does standard WMSI, particularly in the presence of LBBB.
Long-Term Results of the Radial Artery Used for Myocardial Revascularization
Authors: Possati Gianfederico , Gaudino Mario , Prati Francesco , Alessandrini Francesco , Trani Carlo , Glieca Franco , Mazzari Mario A. , Luciani Nicola , Schiavoni Giovanni
Published: August 2003

Background—

No information is available on the long-term results of radial artery (RA) grafts used as coronary artery bypass conduits.

Methods and Results—

In this report, we describe the long-term (105±9 months) angiographic results of a series of 90 consecutive patients in whom the RA was used as a coronary artery bypass conduit directly anastomosed to the ascending aorta. The long-term patency and perfect patency rates of the RA were 91.6% and 88%, respectively, versus 97.5% and 96.3% for internal thoracic artery grafts. The severity of stenosis of the target vessel clearly influenced long-term RA patency, whereas location of the target vessel and long-term use of calcium channel blockers did not influence angiographic results. Preserved endothelial function and absence of flow-limiting, fibrous, intimal hyperplasia were also documented.

Conclusions—

Ten years after surgery, RA grafts have excellent patency and perfect patency rates. Appropriate surgical technique and correct indication are the key factors for long-term RA patency.
Temporal Patterns in Long-Term Survival After Resuscitation From Out-of-Hospital Cardiac Arrest
Authors: Rea Thomas D. , Crouthamel Matthew , Eisenberg Mickey S. , Becker Linda J. , Lima Ann R.
Published: August 2003

Background—

During the past quarter century, advances in treatment of cardiovascular disease have occurred that might potentially benefit survivors of sudden cardiac arrest (SCA). Little is known, however, about the temporal patterns in long-term survival among persons resuscitated from SCA. We hypothesized that long-term survival would improve over time and that this temporal pattern would be most evident for cardiac causes of death.

Methods and Results—

The investigation was a retrospective cohort study of survival among persons who were discharged alive from the hospital after resuscitation from out-of-hospital SCA due to heart disease in King County, Wash, between May 1, 1976, and December 31, 2001 (n=2035). Calendar time was divided into four 5-year intervals: 1976 to 1980, 1981 to 1985, 1986 to 1990, and 1991 to 1995, and one 6-year interval, 1996 to 2001. Age-adjusted survival curves were constructed, and Cox proportional-hazards regression was used to compute hazard ratios (HRs) for the association between mortality and time period. During 11 201 person-years of follow-up, 1334 persons died. Compared with the initial time period, the HR for total mortality was 0.86 (95% confidence interval, 0.73 to 1.01) for 1981 to 1985, 0.82 (0.69 to 0.96) for 1986 to 1990, 0.66 (0.55 to 0.79) for 1991 to 1995, and 0.58 (0.47 to 0.71) for 1996 to 2001 (HR for trend=0.87 [0.84 to 0.91] for each successive time period). In analyses that assessed cardiac mortality, an even stronger temporal association was evident (HR for trend=0.79 [0.75 to 0.84]).

Conclusions—

Long-term survival after resuscitation from SCA improved steadily over time in this cohort. To continue this trend, future studies should identify circumstances in which proven treatments are underutilized as well as investigate new therapies that might benefit survivors of SCA.
Effects of Exercise and Respiration on Blood Flow in Total Cavopulmonary Connection
Authors: Hjortdal V.E. , Emmertsen K. , Stenbøg E. , Fründ T. , Schmidt M. Rahbek , Kromann O. , Sørensen K. , Pedersen E.M.
Published: August 2003

Background—

Little is known about blood flow and its relationship to respiration during exercise in patients with total cavopulmonary connection (TCPC).

Methods and Results—

We studied 11 patients 12.4±4.6 years (mean±SD) of age 5.9±2.8 years (mean±SD) after TCPC operation. Real-time MRI was used to measure blood flow in the superior vena cava (SVC), inferior vena cava (IVC), and ascending aorta under inspiration and expiration during supine lower-limb exercise (rest, 0.5 and 1.0 W/kg) on an ergometer bicycle. IVC and aortic flow increased from 1.60±0.52 and 2.99±0.83 L/min per m
2
at rest to 2.58±0.71 and 3.97±1.20 L/min per m
2
at 0.5 W/kg and to 3.25±1.23 and 4.62±1.49 L/min per m
2
at 1.0 W/kg (
P
≤0.05). SVC flow remained unchanged. Resting flow in the IVC was greater during inspiration (2.99±1.25 L/min per m
2
) than during expiration (0.83±0.44 L/min per m
2
) (inspiratory/mean flow ratio, 1.9±0.5), and retrograde flow was present during expiration (11±12% of mean flow). The predominance of inspiratory flow in IVC diminished with exercise to an inspiratory/mean flow ratio of 1.5±0.2 (
P
≤0.05) and 1.4±0.3 at 0.5 and 1.0 W/kg, respectively.

Conclusions—

In the TCPC, circulation IVC and aortic but not SVC flows increase with supine leg exercise. Inspiration facilitates IVC flow at rest but less so during exercise, when the peripheral pump seems to be more important.
Influence of Altitude Exposure on Coronary Flow Reserve
Authors: Wyss Christophe A. , Koepfli Pascal , Fretz Gregory , Seebauer Magdalena , Schirlo Christian , Kaufmann Philipp A.
Published: August 2003

Background—

Although no data exist on the effect of altitude exposure on coronary flow reserve (CFR), patients with coronary artery disease (CAD) are advised not to exceed moderate altitudes of ≈2500 m above sea level. We studied the influence of altitude on myocardial blood flow (MBF) in controls and CAD patients.

Methods and Results—

In 10 healthy controls and 8 patients with CAD, MBF was measured by positron emission tomography and
15
O-labeled water at rest, during adenosine stress, and after supine bicycle exercise. This protocol was repeated during inhalation of a hypoxic gas mixture corresponding to an altitude of 4500 m (controls) and 2500 m (CAD). Workload was targeted to comparable heart rate–blood pressure products at normoxia and hypoxia. Resting MBF increased significantly in controls at 4500 m (+24%,
P
<0.01) and in CAD patients at 2500 m (+24%,
P
<0.05). Altitude had no influence on adenosine-induced hyperemia and CFR. Exercise-induced hyperemia increased significantly in controls (+38%,
P
<0.01) at 4500 m (despite a reduction in workload, −28%,
P
<0.0001) but not in CAD patients at 2500 m (moderate decrease in workload, −11%,
P
<0.05). Exercise-induced reserve was preserved in controls (+10%,
P
=NS) but decreased in CAD patients (−18%,
P
<0.005).

Conclusions—

At 2500 m altitude, there is a significant decrease in exercise-induced reserve in CAD patients, indicating that compensatory mechanisms might be exhausted even at moderate altitudes, whereas healthy controls have preserved reserve up to 4500 m. Thus, patients with CAD and impaired CFR should be cautious when performing physical exercise even at moderate altitude.
Inhibition of Clinical Benefits of Aspirin on First Myocardial Infarction by Nonsteroidal Antiinflammatory Drugs
Authors: Kurth Tobias , Glynn Robert J. , Walker Alexander M. , Chan K. Arnold , Buring Julie E. , Hennekens Charles H. , Gaziano J. Michael
Published: August 2003

Background—

There is clear evidence from numerous randomized trials and their meta-analyses that aspirin reduces risks of first myocardial infarction (MI). Recent data also suggest that other nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with this benefit of aspirin.

Methods and Results—

We performed subgroup analysis from a 5-year randomized, double-blind, placebo-controlled trial of 325 mg aspirin on alternate days among 22 071 apparently healthy US male physicians with prospective observational data on use of NSAIDs. A total of 378 MIs were confirmed, 139 in the aspirin group and 239 in the placebo group. Aspirin conferred a statistical extreme (
P
<0.00001) 44% reduction in risk of first MI. Among participants randomized to aspirin, use of NSAIDs on 1 to 59 d/y was not associated with MI (multivariable adjusted relative risk [RR], 1.21; 95% confidence interval [CI], 0.78 to 1.87), whereas the use of NSAIDs on ≥60 d/y was associated with MI (RR, 2.86; 95% CI, 1.25 to 6.56) compared with no use of NSAIDs. In the placebo group, the RRs for MI across the same categories of NSAID use were 1.14 (95% CI, 0.81 to 1.60) and 0.21 (95% CI, 0.03 to 1.48).

Conclusions—

These data suggest that regular but not intermittent use of NSAIDs inhibits the clinical benefits of aspirin. Chance, bias, and confounding remain plausible alternative explanations, despite the prospective design and adjustment for covariates. Nonetheless, we believe the most plausible interpretation of the data to be that regular but not intermittent use of NSAIDs inhibits the clinical benefit of aspirin on first MI.
Novel Passive Implantable Atrial Defibrillator Using Transcutaneous Radiofrequency Energy Transmission Successfully Cardioverts Atrial Fibrillation
Authors: Manoharan Ganesh , Evans Noel , Kidwai Bakthiar , Allen Desmond , Anderson John , Adgey Jennifer
Published: August 2003

Background—

Conventional methods for cardioversion of atrial fibrillation (AF) to sinus rhythm have numerous difficulties. A novel method for cardioversion using the passive implantable atrial defibrillator (PIAD) was tested in acute animal models. This device does not have a battery or a capacitor to store energy and is activated by transferring RF energy across the skin from an external transmitter to the subcutaneously implanted defibrillator. On activation, a novel monophasic shock waveform with 5% tilt is delivered to the heart via 2 intracardiac defibrillation leads.

Methods and Results—

Cardioversion attempts with the device were assessed in 2 phases: a feasibility and efficacy study and randomized comparison against standard waveforms. Defibrillation leads were placed transvenously into the distal coronary sinus and the right atrial appendage. These were connected to the subcutaneously implanted PIAD. Sustained AF was induced by rapid atrial pacing. The transmitter coil was placed on the skin overlying the defibrillator, and defibrillation synchronized to the R wave was attempted. The method was found to be efficacious at very low voltage and energy, with 100% cardioversion success observed for 10-ms 100-V shocks (mean energy, 1.54±0.02 J). The PIAD waveform had a higher cardioversion success rate than a truncated, 70% tilt monophasic exponential pulse (100 V, 100% versus 78.0±7.57%;
P
=0.001). There were no postshock complications.

Conclusions—

Considering these animal results, this method is promising for cardioverting AF in symptomatic patients.
Cerebral Venous Thrombosis in Children
Authors: Heller Christine , Heinecke Achim , Junker Ralf , Knöfler Ralf , Kosch Andrea , Kurnik Karin , Schobess Rosemarie , von Eckardstein Arnold , Sträter Ronald , Zieger Barbara , Nowak-Göttl Ulrike ,   the Childhood Stroke Study Group
Published: August 2003

Background—

The present study was performed to assess the association of prothrombotic risk factors and underlying conditions (infections, vascular trauma, immobilization, malignancies, autoimmune diseases, renal diseases, metabolic disorders, obesity, birth asphyxia, cardiac malformations, and use of prothrombotic drugs) with cerebral venous thrombosis (CVT) in children.

Methods and Results—

From 1995 to 2002, 149 pediatric patients aged newborn to <18 years (median 6 years) with CVT were consecutively enrolled. In patients and in 149 age- and gender-matched children with similar underlying clinical conditions but without CVT, the factor V G1691A mutation, the factor II G20210A variant, lipoprotein(a) [Lp(a)], protein C, protein S, antithrombin, and antiphospholipid antibodies, as well as associated clinical conditions, were investigated. Eighty-four (56.4%) of the patients had at least 1 prothrombotic risk factor compared with 31 control children (20.8%;
P
<0.0001). In addition, 105 (70.5%) of 149 patients with CVT presented with an underlying predisposing condition. On univariate analysis, factor V, protein C, protein S, and elevated Lp(a) were found to be significantly associated with CVT. However, in multivariate analysis, only the combination of a prothrombotic risk factor with an underlying condition (OR 3.9, 95% CI 1.8 to 8.6), increased Lp(a) (OR 4.1, 95% CI 2.0 to 8.7), and protein C deficiency (OR 11.1, 95% CI 1.2 to 104.4) had independent associations with CVT in the children investigated.

Conclusions—

CVT in children is a multifactorial disease that, in the majority of cases, results from a combination of prothrombotic risk factors and/or underlying clinical condition.
Benefits and Risks of Abciximab Use in Primary Angioplasty for Acute Myocardial Infarction
Authors: Tcheng James E. , Kandzari David E. , Grines Cindy L. , Cox David A. , Effron Mark B. , Garcia Eulogio , Griffin John J. , Guagliumi Giulio , Stuckey Thomas , Turco Mark , Fahy Martin , Lansky Alexandra J. , Mehran Roxana , Stone Gregg W.
Published: August 2003

Background—

Trials of platelet glycoprotein IIb/IIIa inhibitors as adjuncts to primary percutaneous coronary intervention for acute myocardial infarction (MI) have shown improved early clinical and angiographic outcomes with treatment. However, variations in trial designs, modest sample sizes, and limited long-term follow-up have precluded these studies from being definitive.

Methods and Results—

As a prespecified secondary analysis of the CADILLAC trial, we compared early and late outcomes by abciximab assignment among 2082 patients randomized in an open-label, 2×2 factorial-design trial of primary stenting versus angioplasty and abciximab treatment (n=1052) versus no abciximab treatment (n=1030). Baseline characteristics were balanced between groups. Abciximab treatment was associated with a significant reduction in the composite end point of death, MI, ischemia-driven target-vessel revascularization (TVR), or disabling stroke at 30 days (4.6% versus 7.0%; relative risk, 0.65; 95% CI, 0.46 to 0.93;
P
=0.01). Subacute thrombosis also was significantly reduced with abciximab treatment. At 12 months, however, rates of the composite end point did not differ significantly (18.4% for controls versus 16.9% for abciximab-treated patients; relative risk, 0.92; 95% CI, 0.76 to 1.10;
P
=0.29), reflecting a decrease in the relative difference in TVR rates (ie, no effect of abciximab on reducing restenosis). In an angiographic substudy (n=656), myocardial salvage, restenosis, and infarct-artery reocclusion at 7 months were unaffected by abciximab treatment. There was no significant interaction between stenting and abciximab treatment.

Conclusions—

Adjunctive abciximab treatment during primary percutaneous coronary intervention significantly enhanced 30-day event-free survival, predominantly by reducing ischemia-driven TVR. Abciximab treatment did not affect the composite end point at 1 year, reflecting a lack of effect on restenosis.
Phase I Drug and Light Dose-Escalation Trial of Motexafin Lutetium and Far Red Light Activation (Phototherapy) in Subjects With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention and Stent Deployment
Authors: Kereiakes Dean J. , Szyniszewski Arthur M. , Wahr Dennis , Herrmann Howard C. , Simon Daniel I. , Rogers Campbell , Kramer Paul , Shear Wendy , Yeung Alan C. , Shunk Kendrick A. , Chou Tony M. , Popma Jeffrey , Fitzgerald Peter , Carroll Tanya E. , Forer David , Adelman Daniel C.
Published: August 2003

Background—

Motexafin lutetium (MLu; Antrin) is a photosensitizer that is taken up by atherosclerotic plaque and concentrated within macrophages and vascular smooth muscle cells. After photoactivation with far red light, MLu facilitates production of cytotoxic oxygen radicals that mediate apoptosis. We assessed the safety and tolerability of phototherapy (PT) with MLu in patients undergoing percutaneous coronary intervention with stent deployment.

Methods and Results—

An open-label, phase I, drug and light dose-escalation clinical trial of MLu PT enrolled 80 patients undergoing de novo coronary stent deployment. MLu was administered to 79 patients by intravenous infusion 18 to 24 hours before procedure, and photoactivation was performed after balloon predilatation and before stent deployment. Clinical evaluation, serial quantitative angiography, and intravascular ultrasound were performed periprocedurally and at 6 months follow-up. MLu PT was well tolerated without serious dose-limiting toxicities, and side effects (paresthesia and rash) were minor. No adverse angiographic outcomes were attributed to phototherapy.

Conclusions—

This study demonstrates that coronary MLu PT seems safe, and the maximum well-tolerated MLu dose and range of tolerated light doses were identified. These data can be used in phase II efficacy trials of MLu PT for the treatment of coronary atherosclerosis or vulnerable plaque.
Rapid Left-to-Right Shunt Quantification in Children by Phase-Contrast Magnetic Resonance Imaging Combined With Sensitivity Encoding (SENSE)
Authors: Beerbaum Philipp , Körperich Hermann , Gieseke Jürgen , Barth Peter , Peuster Matthias , Meyer Hans
Published: August 2003

Background—

Parallel imaging by sensitivity encoding (SENSE) may considerably reduce scan time in MRI. For rapid flow quantification in children with congenital heart disease, we evaluated phase-contrast MRI (PC-MRI) techniques combined with SENSE.

Methods and Results—

In 22 pediatric patients (mean age, 7.2±6.2 years) with cardiac left-to-right shunt, blood flow rate in the pulmonary artery (Q
p
) and ascending aorta (Q
s
) and flow ratio Q
p
/Q
s
were determined by PC-MRI with SENSE reduction-factor 2 and 3 (SF-2 and SF-3). Additionally, we used PC-MRI with higher spatial in-plane resolution (1.6×2.1 versus 2.3×3.1 mm) with and without SF-3. Results were compared with a recently validated standard PC-MRI protocol and tested in vitro using a pulsatile flow phantom. Reduction of signal averages from 2 to 1 and application of SENSE accelerated flow measurements by a factor of 3.5 (5.2) using PC-MRI with SF-2 (SF-3) compared with standard PC-MRI. For blood flow rate through the pulmonary artery and aorta, as well as for the Q
p
/Q
s
ratio we found negligible differences of ±3%, lower limits of agreement (mean±2 SD) of −7% to −18%, and upper limits of agreement (mean±2 SD) of +3 to +24%, demonstrating good agreement with standard PC-MRI. Mean Q
p
/Q
s
ratio by standard PC-MRI was 1.69±0.45 (range, 1.27 to 2.79). Interobserver variability was low, and high accuracy was confirmed in vitro for all protocols.

Conclusions—

PC-MRI for flow quantitation may be combined with SENSE to achieve a substantive reduction of scanning time. In children with left-to-right shunt, Q
p
/Q
s
quantification is possible by PC-MRI+SF-3 in <60 seconds. Use of higher in-plane resolution did not improve measurement results.
Randomized Comparison of Percutaneous Transluminal Coronary Angioplasty and Medical Therapy in Stable Survivors of Acute Myocardial Infarction With Single Vessel Disease
Authors: Zeymer Uwe , Uebis Rainer , Vogt Albrecht , Glunz Hans-Georg , Vöhringer Hans-Friedrich , Harmjanz Dietrich , Neuhaus Karl-Ludwig
Published: August 2003

Background—

Percutaneous transluminal coronary angioplasty of the infarct-related artery in stable survivors of acute myocardial infarction is often performed, even in patients without any symptoms or residual ischemia. Despite the lack of randomized studies, it is widely believed that this intervention will improve the clinical outcome of these patients.

Methods and Results—

Three hundred patients with single vessel disease of the infarct vessel and no or minor angina pectoris in the subacute phase (1 to 6 weeks) after an acute myocardial infarction were randomized to angioplasty (n=149) or medical therapy (n=151). Primary end point was the survival free of reinfarction, (re)intervention, coronary artery bypass surgery, or readmission for severe angina pectoris at 1 year. The event-free survival at 1 year was 82% in the medical group and 90% in the angioplasty group (
P
=0.06). This difference was mainly driven by the difference in the need for (re)interventions (20 versus 8,
P
=0.03). At long-term follow-up (mean, 56 months), survival was 89% and 96% (
P
=0.02). Survival free of reinfarction, (re)intervention, or coronary artery bypass surgery was 66% and 80% in the medically and interventionally treated patients, respectively (
P
=0.05). The use of nitrates was significantly lower in the angioplasty group, both at 1 year (38% versus 67%,
P
=0.001) and at long-term follow-up (36% versus 55%,
P
=0.006).

Conclusions—

Percutaneous revascularization of the infarct-related coronary artery in stable patients with single vessel disease improves clinical outcome at long-term follow-up and reduces the use of nitrates. The results of our study should be reproduced in a confirmatory study with a larger sample size before percutaneous coronary intervention in this low-risk patient subgroup, after myocardial infarction can be recommended as routine treatment in clinical practice.
Risk Stratification After Acute Myocardial Infarction by Heart Rate Turbulence
Authors: Barthel Petra , Schneider Raphael , Bauer Axel , Ulm Kurt , Schmitt Claus , Schömig Albert , Schmidt Georg
Published: August 2003

Background—

Retrospective postinfarction studies revealed that decreased heart rate turbulence (HRT) indicates increased risk for subsequent death. This is the first prospective study to validate HRT in a large cohort of the reperfusion era.

Methods and Results—

One thousand four hundred fifty-five survivors of an acute myocardial infarction (age <76 years) in sinus rhythm were enrolled. HRT onset (TO) and slope (TS) were calculated from Holter records. Patients were classified into the following HRT categories: category 0 if both TO and TS were normal, category 1 if either TO or TS was abnormal, or category 2 if both TO and TS were abnormal. The primary end point was all-cause mortality. During a follow-up of 22 months, 70 patients died. Multivariately, HRT category 2 was the strongest predictor of death (hazard ratio, 5.9; 95% CI, 2.9 to 12.2), followed by left ventricular ejection fraction (LVEF) ≤30% (4.5; 2.6 to 7.8), diabetes mellitus (2.5; 1.6 to 4.1), age ≥65 years (2.4; 1.5 to 3.9), and HRT category 1 (2.4; 1.2 to 4.9). LVEF ≤30% had a sensitivity of 27% at a positive predictive accuracy level of 23%. The combined criteria of LVEF ≤30%, HRT category 2 or LVEF >30%, age ≥65 years, diabetes mellitus, and HRT category 2 had a sensitivity of 24% at a positive predictive accuracy level of 37%. The combined criteria of LVEF ≤30% or LVEF >30%, age ≥65 years, diabetes mellitus, and HRT category 1 or 2 had a sensitivity of 44% at a positive predictive accuracy level of 23%.

Conclusions—

HRT is a strong predictor of subsequent death in postinfarction patients of the reperfusion era.
Direct Imaging of Exercise-Induced Myocardial Ischemia With Fluorine-18–Labeled Deoxyglucose and Tc-99m-Sestamibi in Coronary Artery Disease
Authors: He Zuo-Xiang , Shi Rong-Fang , Wu Yong-Jian , Tian Yue-Qin , Liu Xiu-Jie , Wang Shi-Wen , Shen Rui , Qin Xue-Wen , Gao Run-Lin , Narula Jagat , Jain Diwakar
Published: August 2003

Background—

Scintigraphic myocardial perfusion imaging is the most widely used noninvasive modality for the detection of coronary artery disease (CAD). A technique for direct imaging of exercise-induced myocardial ischemia is highly desirable and preferable over perfusion imaging but is presently unavailable. We evaluated the feasibility and diagnostic accuracy of direct imaging of exercise-induced myocardial ischemia with fluorine-18-2-deoxyglucose (
18
FDG).

Methods and Results—

Twenty-six patients with known or suspected CAD and no prior myocardial infarction underwent simultaneous myocardial perfusion and ischemia imaging after the intravenous injection of Tc-99m-sestamibi (
99m
Tc-sestamibi) and
18
FDG at peak exercise. Rest perfusion imaging was carried out separately. All patients underwent coronary angiography. Exercise
18
FDG myocardial images were compared with exercise-rest
99m
Tc-sestamibi images and coronary angiography. Of 22 patients with ≥50% narrowing of ≥1 coronary arteries, 18 had perfusion abnormalities (sensitivity 82%) whereas 20 had abnormal myocardial
18
FDG uptake (sensitivity 91%,
P
=NS). Perfusion abnormalities were seen in myocardial segments corresponding to 25 vascular territories of a total of 51 vessels with ≥50% luminal narrowing in 22 patients (sensitivity 49%), whereas increased
18
FDG uptake was seen in 34 vascular territories (sensitivity 67%,
P
=0.008).
18
FDG images were of high quality and easy to interpret but required simultaneous perfusion images for localizing abnormal myocardial
18
FDG uptake.

Conclusions—

Exercise-induced myocardial ischemia can be imaged directly with
18
FDG. Combined exercise
18
FDG-
99m
Tc-sestamibi imaging provides a better assessment of exercise-induced myocardial ischemia compared with exercise-rest perfusion imaging. Direct ischemia imaging eliminates some of the limitations of presently used myocardial perfusion imaging. Large-scale clinical studies are warranted.
Sustained Reduction of Aldosterone in Response to the Angiotensin Receptor Blocker Valsartan in Patients With Chronic Heart Failure
Authors: Cohn Jay N. , Anand Inder S. , Latini Roberto , Masson Serge , Chiang Yann-Tong , Glazer Robert
Published: August 2003

Background—

Aldosterone has been implicated in the progression of heart failure. The Valsartan Heart Failure Trial (Val-HeFT) provided the first opportunity to examine the long-term effects of an angiotensin receptor blocker on plasma aldosterone levels in patients with NYHA class II through IV heart failure.

Methods and Results—

Plasma aldosterone was measured by radioimmunoassay in core laboratories at baseline and during follow-up in patients assigned to valsartan at a target dose of 160 mg twice daily or placebo. In the placebo group, aldosterone (baseline, 150±160 pg/mL, mean±SD; n=2025) increased at 4, 12, and 24 months. In the valsartan group, aldosterone (baseline, 137±124 pg/mL, mean±SD; n=2023) decreased at 4 months and remained suppressed for up to 2 years. At end point (last measurement in each patient), mean aldosterone increased by 17.8±3.0 pg/mL (SEM) (11.9%) in the placebo group and decreased by 23.8±3.0 pg/mL (SEM) (−17.4%) in the valsartan group (
P
<0.00001). The effect of valsartan was similar in all subgroups, including those receiving neither ACE inhibitors (ACE-I) nor β-blockers (BB) at baseline and those receiving concomitant ACE-I or BB. In contrast, outcome effects varied in the 4 subgroups, with a statistically significant reduction in the combined mortality/morbidity end point in those receiving neither neurohormonal inhibitor and an adverse trend in those treated with both drugs.

Conclusions—

Valsartan added to background therapy for heart failure produces sustained reduction in plasma aldosterone, consistent with the observed significant reduction in the combined mortality/morbidity end point. A similar reduction in all subgroups based on ACE-I or BB therapy, despite differing clinical outcomes in these subgroups, suggests that aldosterone plasma levels may not be a critical marker of the progression of heart failure.
Glucose-Induced TGF-β1 and TGF-β Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-α
Authors: Lindschau Carsten , Quass Petra , Menne Jan , Güler Faikah , Fiebeler Anette , Leitges Michael , Luft Friedrich C. , Haller Hermann
Published: August 2003

Sclerosis and increased matrix expression in diabetes are mediated by glucose-induced transforming growth factor (TGF)-β1 expression. The intracellular effects of high glucose occur at least in part by way of protein kinase C (PKC). We previously described a role for PKC-α in glucose-induced permeability. We now investigated the hypothesis that glucose-induced expression of TGF-β1 and its receptors (TGF-β-R1 and -R2) are mediated by activation of this PKC isoform. TGF-β1 and TGF-β-R expressions were determined in vascular smooth muscle cells (VSMCs) by immunocytochemistry and Western blotting. PKC isoforms were assessed by confocal microscopy. PKC isoforms were inhibited with antisense oligodeoxynucleotides. PKC-α was upregulated by overexpression or microinjection. High glucose (20 mmol/L) increased VSMC TGF-β1 and TGF-β-R1 expression but not TGF-β-R2 expression. PKC inhibitors and specific PKC-α downregulation by antisense treatment prevented this effect, whereas antisense treatment against PKC-β, -ε, and -ζ had no influence. PKC-α overexpression increased TGF-β1 and TGF-β-R1 expression but not TGF-β-R2 expression. PKC-α microinjection into individual VSMCs also increased TGF-β1 and TGF-β-R immunofluorescence. Last, VSMCs from PKC-α-deficient mice did not respond to high glucose compared with VSMCs from wild-type mice. We propose that high glucose-induced TGF-β1 and TGF-β-R1 expression is mediated by PKC-α. Our findings suggest an autocrine feedback mechanism and a possible role for PKC-α in diabetic vascular disease.
5,6-Epoxyeicosatrienoic Acid Mediates the Enhanced Renal Vasodilation to Arachidonic Acid in the SHR
Authors: Pomposiello Silvia I. , Quilley John , Carroll Mairead A. , Falck John R. , McGiff John C.
Published: August 2003

We have shown a cytochrome P450–dependent renal vasodilator effect of arachidonic acid in response to inhibition of cyclooxygenase and elevation of perfusion pressure, which was enhanced in the spontaneously hypertensive rat (SHR) and linked to increased production of and/or responsiveness to epoxyeicosatrienoic acids (EETs). In the SHR, vasodilation elicited by low doses of arachidonic acid was attenuated by the nitric oxide synthase inhibitor
N
w
-nitro-
l
-arginine (50 μmol/L), whereas the responses to high doses were unaffected. Inhibition of epoxygenases with miconazole (0.3 μmol/L) in the presence of
N
w
-nitro-
l
-arginine greatly reduced the renal vasodilator response to all doses of arachidonic acid. Tetraethylammonium (10 mmol/L), a nonselective K
+
channel blocker, abolished the nitric oxide–independent renal vasodilator effect of arachidonic acid as well as the vasodilator effect of 5,6-EET, confirming that EET-dependent vasodilation involves activation of K
+
channels. Under conditions of elevated perfusion pressure (200 mm Hg) and cyclooxygenase inhibition, 5,6-EET, 8, 9-EET, and 11,12-EET caused renal vasodilatation in both SHR and Wistar-Kyoto rats (WKY), whereas 14,15-EET produced vasoconstriction. 5,6-EET was the most potent renal vasodilator of the EET regioisomers in the SHR by a factor of 4 or more. In the SHR, 5,6-EET- and 11,12-EET–induced renal vasodilatation was >2-fold greater than that registered in WKY. Thus, the augmented vasodilator responses to arachidonic acid in the SHR is through activation of K
+
channels, and 5,6-EET is the most likely mediator.
Comprehensive Congenic Coverage Revealing Multiple Blood Pressure Quantitative Trait Loci on Dahl Rat Chromosome 10
Authors: Palijan Ana , Lambert Raphaelle , Dutil Julie , Sivo Zsuzsa , Deng Alan Y.
Published: August 2003

Chromosome mapping based on congenic strains can restrict quantitative trait loci (QTLs) for blood pressure (BP) into small intervals that are otherwise indistinguishable in linkage analysis. Also, congenic strains can be created to test a candidate gene to be a BP QTL. Taking full advantage of these features, we produced 10 congenic strains by replacing various segments of chromosome (Chr) 10 of the Dahl salt-sensitive (DSS) rat with those of the Lewis (LEW) rat. These strains were made to systematically cover an entire section of Chr 10. Three of the strains were designed to narrow the intervals that harbor previously mapped QTL1 and QTL2. Two of the strains were designed for the express purpose of testing the QTL candidacy of loci for inducible nitric oxide synthase (
Nos2
) and angiotensin-converting enzyme (
Ace
) genes. BPs of these strains were measured by telemetry and compared with those of the DSS rat. Consequently, QTL1 and QTL2 were narrowed to segments of 53.5 and 100.4 centiRays, respectively. A new QTL, QTL3, was found between QTL1 and QTL2. Both
Nos2
and
Ace
have been disqualified as QTLs in the DSS and LEW comparison. Therefore, there are no obvious candidate genes in the segments that harbor these 3 QTLs, which represent genes previously not thought to be involved in BP regulation. These QTLs will likely have an influence on studies of human hypertension because of their homology with the human CHR 17 region in which QTLs for BP have been found.
Cardiovascular Responses Evoked by Leptin Acting on Neurons in the Ventromedial and Dorsomedial Hypothalamus
Authors: Marsh Ainsley J. , Fontes Marco A.P. , Killinger Suzanne , Pawlak Dorota B. , Polson Jaimie W. , Dampney Roger A.L.
Published: August 2003

Leptin, a circulating hormone produced by adipose tissue, is believed to act on the hypothalamus to increase sympathetic vasomotor activity, in addition to its well-known effects on appetite and energy expenditure. In this study, we determined the cardiovascular effects of direct application of leptin to specific cell groups within the hypothalamus that are known to be activated by circulating leptin. In rats anesthetized with urethane, microinjections of leptin (16 ng in 20 nL solution) were made into the ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and paraventricular nucleus. Compared with vehicle solution, microinjections of leptin into the ventromedial hypothalamic nucleus evoked significant increases in arterial pressure and renal sympathetic nerve activity, but not heart rate. In contrast, microinjections of leptin into the dorsomedial hypothalamic nucleus evoked significant increases in arterial pressure and heart rate but not renal sympathetic nerve activity, whereas microinjections of leptin into the paraventricular nucleus had no significant effect on any of the measured cardiovascular variables. These results indicate that the ventromedial and dorsomedial hypothalamic regions might be important sites at which leptin activation leads to increases in sympathetic vasomotor activity and heart rate, as occurs in obesity-related hypertension.
Hypertensive Retinal Vessel Wall Signs in a General Older Population
Authors: Wang Jie Jin , Mitchell Paul , Leung Harry , Rochtchina Elena , Wong Tien Yin , Klein Ronald
Published: August 2003

To describe cross-sectional relations between hypertension and retinal vessel wall signs in an older white population. These signs were defined from fundus photographs in 3654 Blue Mountains Eye Study participants ≥49 years of age. Focal arteriolar narrowing and arteriovenous nicking were graded through the use of standard protocol. Photographs were digitized to measure retinal vessel diameters. Average arteriolar diameter, summarized as central retinal arteriolar equivalent and arteriole-to-venule ratio, were used as indexes of generalized arteriolar narrowing. Blood pressure was measured with the use of a mercury sphygmomanometer. Hypertension was defined through the use of antihypertensive medications, systolic blood pressure ≥160 mm Hg, or diastolic blood pressure ≥95 mm Hg. Hypertension was categorized as controlled (using medication, normal blood pressure), uncontrolled (using medication, high blood pressure), or untreated (not using medication). Hypertensive subjects had higher prevalence of all retinal microvascular signs. After adjusting for age, gender, body mass index, and smoking, persons with controlled (18.2%), uncontrolled (13.8%), or untreated hypertension (13.8%) were significantly more likely than normotensive subjects (54.2%) to have (a) lower central retinal arteriolar equivalent: adjusted odds ratios 1.5, (95% CI, 1.1 to 1.9), 2.1 (1.6 to 2.7), and 2.1 (1.6 to 2.7), respectively, and lower arteriole-to-venule ratio: 1.3 (1.0 to 1.6), 1.4 (1.1 to 1.8), and 1.7 (1.3 to 2.2), respectively; (b) focal arteriolar narrowing: 1.3 (0.9 to 1.9), 2.2 (1.5 to 3.2), and 2.5 (1.8 to 3.6), respectively; and (c) arteriovenous nicking: 1.3 (0.9 to 1.8), 2.3 (1.6 to 3.2), and 1.9 (1.3 to 2.7), respectively. Our findings demonstrate a strong relation between presence and severity of hypertension and retinal microvascular structural changes.