bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial Blood Flow, Glucose Uptake, and Recruitment of Inotropic Reserve in Chronic Left Ventricular Ischemic Dysfunction
Authors: Gerber Bernhard L. , Vanoverschelde Jean-Louis J. , Bol Anne , Michel Christian , Labar Daniel , Wijns William , Melin Jacques A.
Published: June 2012

Background
Previous work has documented that dysfunctional noninfarcted collateral-dependent myocardium, a condition typical of myocardial hibernation, exhibited almost normal resting perfusion. The present study was designed to test whether these observations could be extended to unselected patients with chronic dysfunction and a previous infarction.

Methods and Results
Dynamic positron emission tomographic imaging with [
13
N]ammonia and [
18
F]fluorodeoxy-glucose (FDG) to assess myocardial perfusion and glucose uptake was performed in 39 patients with chronic anterior wall dysfunction undergoing coronary revascularization. Left ventricular function was evaluated by echocardiography before (at rest and during low-dose dobutamine infusion) and 5 months after revascularization. At follow-up, wall motion was improved in 24 patients and unchanged in 15 patients. Before revascularization, absolute myocardial blood flow was higher (84±27 versus 60±26 mL·min
−
1
·100 g
−
1
,
P
=.007) in reversibly compared with persistently dysfunctional segments. In segments with reversible dysfunction, values of myocardial blood flow were similar to those in the remote segments of the same patients or in anterior segments of normal volunteers. During glucose clamp, FDG uptake was higher (69±17% versus 49±18%,
P
<.01) but myocardial glucose uptake was not different (38±20 versus 29±19 μmol·min
−
1
·100 g
−
1
,
P
=NS) in reversibly compared with persistently dysfunctional segments. A flow-metabolism mismatch was present in 18 of 24 reversibly injured but absent in 10 of 15 persistently dysfunctional segments. With dobutamine, wall motion improved in 17 of 24 reversibly dysfunctional segments and did not change in 13 of 15 segments with persistent dysfunction.

Conclusions
This study indicates that chronic but reversible ischemic dysfunction is associated with almost normal resting myocardial perfusion, with maintained FDG uptake, and with recruitable inotropic reserve. These data support the contention that chronic hibernation is not the consequence of a permanent reduction of transmural myocardial perfusion at rest.
Prognostic Significance of Plasma Norepinephrine in Patients With Asymptomatic Left Ventricular Dysfunction
Authors: Benedict Claude R. , Shelton Brent , Johnstone David E. , Francis Gary , Greenberg Barry , Konstam Marvin , Probstfield Jeffrey L. , Yusuf Salim
Published: June 2012

Background
Elevated plasma neurohormonal levels are associated with increased mortality rates in patients with symptomatic heart failure. A previous Studies of Left Ventricular Dysfunction (SOLVD) trial suggested that neurohumoral activation precedes the development of symptoms as demonstrated by increased neurohormonal levels in patients with asymptomatic left ventricular dysfunction. However, the significance of this early neurohumoral activation is unclear. The goals of this study were to determine the prognostic significance of the plasma concentrations of plasma norepinephrine (PNE) and atrial natriuretic peptide (ANP) and the renin activity (PRA) in patients with asymptomatic left ventricular dysfunction.

Methods and Results
PNE and PRA were measured before randomization in 514 patients with left ventricular ejection fractions ≤35% who did not require treatment for congestive heart failure and were enrolled in the SOLVD Prevention Trial. Plasma ANP levels were measured in a subset of 241 patients owing to study design. Using the Cox proportional hazards model that included left ventricular ejection fraction, New York Heart Association functional class, age, sex, treatment assignment to placebo or enalapril, and cause of heart failure, we examined whether these neurohormones predicted all-cause mortality, cardiovascular mortality, hospitalization for heart failure, development of heart failure, or development of ischemic events (myocardial infarction or unstable angina). PNE was the strongest predictor of clinical events in this patient population. PNE levels above the median of 393 pg/mL were associated with a relative risk of 2.59 (
P
=.002) for all-cause mortality, 2.55 (
P
=.003) for cardiovascular mortality, 2.55 (
P
=.005) for hospitalization for heart failure, 1.88 (
P
=.002) for development of heart failure, 1.92 (
P
=.001) for ischemic events, and 2.59 (
P
=.005) for myocardial infarction. PNE remained the most powerful predictor for all-cause mortality and ischemic events when the analysis included only the patients with histories of ischemic left ventricular dysfunction. The increases in other neurohormonal levels were not useful in predicting the subsequent development of clinical events.

Conclusions
Increased PNE levels in patients with asymptomatic left ventricular dysfunction appear to predict all-cause and cardiovascular mortalities and development of clinical events related to the onset of heart failure or acute ischemic syndromes. Thus, measurement of PNE may be a possible early marker for assessment of disease progression in patients with left ventricular dysfunction, and modulating the release or effect of PNE may lead to improved prognosis and/or a reduction in morbidity.
Influence of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor Gene Polymorphisms on Aortic Stiffness in Normotensive and Hypertensive Patients
Authors: Benetos Athanase , Gautier Sylvie , Ricard Sylvain , Topouchian Jirar , Asmar Roland , Poirier Odette , Larosa Emile , Guize Louis , Safar Michel , Soubrier Florent , Cambien Franc¸ois
Published: June 2012

Background
Clinical and experimental studies have demonstrated a major role of the renin-angiotensin system in the functional and structural changes of the large arteries in hypertension. Because genetic studies may help us to understand the mechanisms underlying the involvement of this system in arterial regulation, the present study was designed to assess the contribution of polymorphisms of the ACE insertion/deletion (I/D) and angiotensin II type 1 receptor (AGTR
1
A
1166
C) genes on aortic stiffness regulation.

Methods and Results
This study included 311 untreated hypertensive and 128 normotensive subjects. Aortic stiffness was evaluated by measurement of the carotid-femoral pulse-wave velocity (PWV). In normotensive subjects, the two polymorphisms did not influence any of the studied parameters. In hypertensive subjects, there was a decreasing trend of mean PWV with the number of ACE D alleles, but this association became significant only after adjustment for blood pressure (
P
<.05). Conversely, the AGTR
1
A
1166
C polymorphism was independently associated with aortic stiffness. Mean values of PWV were 11.6±2.7 m/s in AGTR
1
AA homozygotes, 13.3±3.3 m/s in AC heterozygotes, and 15.3±4.3 m/s in CC homozygotes (
P
<.0001 and
P
<.00001 after adjustment for age and mean blood pressure, respectively). The percentage of variance of PWV explained by AGTR
1
A
1166
C polymorphism (11.6%) was much larger than that of ACE I/D polymorphism (1.7%).

Conclusions
These results suggest that in hypertensive but not normotensive subjects, the AGTR
1
and ACE geno-types are involved in the regulation of aortic rigidity. The presence of the AGTR
1
C allele is a strong independent determinant of aortic stiffness, whereas presence of the ACE I allele is weakly associated with increased stiffness.
Inhibition of Atherosclerosis Development in Cholesterol-Fed Human Apolipoprotein A-I–Transgenic Rabbits
Authors: Duverger Nicolas , Kruth Howard , Emmanuel Florence , Caillaud Jean-Michel , Viglietta Ce´line , Castro Graciela , Tailleux Anne , Fievet Catherine , Fruchart Jean Charles , Houdebine Louis Marie , Denefle Patrice
Published: June 2012

Background
Prospective epidemiological studies support the hypothesis that high levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I limit atherosclerosis development. However, more data from studies with animal models of atherosclerosis that resemble the human disease are required to demonstrate the effect of apo A-I in the inhibition of atherogenesis. The rabbit is a good animal model for human atherosclerosis.

Methods and Results
Human apo A-I–transgenic rabbits have been produced, and we have evaluated the effect of apo A-I on the development of atherosclerosis in transgenic rabbits fed a cholesterol-rich diet for 14 weeks. Plasma cholesterol levels of atherogenic apo B-containing lipoproteins were similar for transgenic and control rabbits (>1000 mg/dL), while plasma levels of HDL cholesterol in the transgenic group were always about twice that of the control group (68±11 versus 37±3 mg/dL at 14 weeks;
P
<.001). At the end of the experiment, the amount of aortic surface area covered by lesions as well as the amount of lipid accumulation in the aorta were significantly less in transgenic rabbits compared with the control group (15±12% versus 30±8%,
P
<.0027 for the surface area of the thoracic aorta; 116±31 versus 247±39 μmol/g aorta,
P
<.0068 for cholesterol content in total aorta).

Conclusions
Overexpression of human apo A-I in rabbits inhibits the development of atherosclerosis in this animal model that resembles, in many respects, human atherosclerosis.
Identification of Authentic Estrogen Receptor in Cultured Endothelial Cells
Authors: Venkov Christo D. , Rankin Alan B. , Vaughan Douglas E.
Published: June 2012

Background
Estrogen plays a major role in the delayed expression of coronary heart disease (CHD) in women, and recent data indicate that postmenopausal estrogen therapy reduces the incidence of CHD by >40%. The mechanism or mechanisms through which estrogen exerts this benefit are unknown, although effects on blood pressure, carbohydrate and lipid metabolism, and coagulation have been suggested. We hypothesized that at least part of the effect of estrogen in reducing the incidence of CHD is due to an effect on endothelial cell function.

Methods and Results
In the present study, we examined human aortic and umbilical vein endothelial cells and bovine aortic endothelial cells for the presence of estrogen receptors (ERs) through immunoblot and mRNA analyses. Electrophoretic mobility shift assays were also performed to determine the DNA-binding properties of the putative ERs. Nuclear extracts from all three endothelial cell types were found to contain a 67-kD protein that reacted with anti-ER monoclonal antibodies specific to different domains of the ERs. Each of these types of cells expresses proteins that bind specifically to consensus estrogen-responsive elements. Finally, Northern blots verified that endothelial cells express abundant amount of mRNA for the ER.

Conclusions
These data indicate that endothelial cells constitutively possess the potential for transcriptional regulation of target genes by estrogen. The evolutionary conservation of this receptor in bovine and human endothelial cells suggests a common mechanism for estrogen regulation of endothelial function.
Noninvasive Quantification of Regional Myocardial Metabolic Rate of Oxygen by
15
O
2
Inhalation and Positron Emission Tomography
Authors: Yamamoto Yusuke , de Silva Ranil , Rhodes Christopher G. , Iida Hidehiro , Lammertsma Adriaan A. , Jones Terry , Maseri Attilio
Published: June 2012

Background
The purpose of this study was to validate a novel method for noninvasive quantification of regional myocardial oxygen consumption (MMR
o
2
, mL·min
−1
·100 g
−1
) and oxygen extraction fraction (OEF) by use of positron emission tomography (PET) and inhalation of
15
O-labeled molecular oxygen gas (
15
O
2
).

Methods and Results
Twenty-four measurements were performed in eight closed-chest anesthetized greyhounds at baseline and during infusions of adenosine (100 to 200 μg·kg
−1
·min
−1
), isoproterenol (1 to 10 μg/min), and propranolol (5 mg bolus+0.2 to 1 mg/min) with morphine (5 mg slow infusion+0.2 to 0.5 mg/min) to obtain a wide range of oxidative metabolism. The PET imaging protocol consisted of
15
O
2
emission (OEF and MMR
o
2
), transmission, [
15
O]CO emission (blood pool), and [
15
O]CO
2
emission (myocardial blood flow: MBF
pet
, mL·min
−1
·g
−1
) scans. OEF was calculated from the PET data (OEF
pet
) by three different analytical techniques: steady-state, 5-minute, and 8-minute autoradiographic analyses. Reference measurements of MBF (MBF
ref
) and OEF (OEF
ref
) were obtained during
15
O
2
inhalation with radiolabeled microspheres and paired arterial and coronary sinus blood sampling, respectively. MMR
o
2
was calculated from the PET (MMR
o
2pet
) and the reference (MMR
o
2ref
) data as follows: MMR
o
2
=OEF×MBF×(O
2
content of arterial blood). OEF measured by the steady-state PET method was well correlated with the reference data over the range 0.16 to 0.73 (OEF
pet
=1.03 OEF
ref
−0.01,
r
=.97), as was MMR
o
2
over the range 2.4 to 27.5 mL·min
−1
·100 g
−1
(MMR
o
2pet
=0.98 MMR
o
2ref
+0.91,
r
=.94). OEF
pet
calculated by use of the 5-minute and 8-minute autoradiographic analyses were equally well correlated with the reference measurements (
r
=.95 and
r
=.97, respectively). There were no significant differences between values of MMR
o
2pet
calculated by use of the steady-state, 5-minute, and 8-minute autoradiographic analyses (
P
=NS by ANOVA). Regional values of MBF
pet
, OEF
pet
, and MMR
o
2pet
were homogeneously distributed and similar to the whole-heart values both at baseline and during the various pharmacological interventions.

Conclusions
Accurate quantification of OEF and MMR
o
2
is feasible with
15
O
2
inhalation and PET imaging using both the steady-state and autoradiographic analytical approaches. These studies suggest the applicability of this method for quantitative assessments of regional cardiac oxidative metabolism in clinical studies.
Para-Hisian Pacing
Authors: Hirao Kenzo , Otomo Kenichiro , Wang Xunzhang , Beckman Karen J. , McClelland James H. , Widman Lawrence , Gonzalez Mario D. , Arruda Mauricio , Nakagawa Hiroshi , Lazzara Ralph , Jackman Warren M.
Published: June 2012

Background
Differentiation between ventriculoatrial (VA) conduction over an accessory AV pathway (AP) and the AV node (AVN) may be difficult, especially in patients with a septal AP.

Methods and Results
A new pacing method, para-Hisian pacing, was tested in 149 patients with AP and 53 patients without AP who had AV nodal reentrant tachycardia (AVNRT). Ventricular pacing was performed adjacent to the His bundle and proximal right bundle branch (HB-RB), initially at high output to capture both RV and HB-RB. The output was then decreased to lose HB-RB capture. The change in timing and sequence of retrograde atrial activation between HB-RB capture and noncapture was examined. Loss of HB-RB capture without change in stimulus-atrial (S-A) interval or atrial activation sequence indicated exclusive retrograde AP conduction. An increase in S-A interval without change in His bundle-atrial interval or atrial activation sequence indicated exclusive retrograde AVN conduction. A change in atrial activation sequence indicated the presence of both retrograde AP and AVN conduction. Para-Hisian pacing correctly identified retrograde AP conduction in 132 of 147 AP patients, including all septal and right free wall APs. Retrograde AVN conduction masked AP conduction in 9 of 34 patients with a left free wall AP and 6 of 9 patients with the permanent form of junctional reciprocating tachycardia. Para-Hisian pacing correctly excluded AP conduction in all 53 patients with AVNRT.

Conclusions
Para-Hisian pacing reliably identifies retrograde conduction over septal and right free wall APs, but AVN conduction may mask APs located far from the pacing site or with a long retrograde conduction time.
Magnetic Resonance Images Lipid, Fibrous, Calcified, Hemorrhagic, and Thrombotic Components of Human Atherosclerosis In Vivo
Authors: Toussaint Jean-Franc¸ois , LaMuraglia Glenn M. , Southern James F. , Fuster Valentin , Kantor Howard L.
Published: June 2012

Background
Although MRI can discriminate the lipid core from the collagenous cap of atherosclerotic lesions in vitro with T2 contrast, it has not yet produced detailed in vivo images of these human plaque components.

Methods and Results
We imaged seven lesions from six patients who required surgical carotid endarterectomy and calculated T2 in vivo before surgery in various plaque regions. Using the same acquisition parameters, we repeated these measurements in vitro on the resected fragment and compared MR images with histology. T2 values calculated in vivo correlate with in vitro measurements for each plaque component; the in vitro discrimination we demonstrated previously with T2 contrast can therefore be performed similarly in vivo.

Conclusions
MRI is the first noninvasive imaging technique that allows the discrimination of lipid cores, fibrous caps, calcifications, normal media, and adventitia in human atheromatous plaques in vivo. This technique also characterizes intraplaque hemorrhage and acute thrombosis. This result may support further investigations that include MRI of plaque progression, stabilization, and rupture in human atherosclerosis.
Endothelial ICAM-1 Expression Associated With Inflammatory Cell Response in Human Ischemic Stroke
Authors: Lindsberg Perttu J. , Carpe´n Olli , Paetau Anders , Karjalainen-Lindsberg Marja-Liisa , Kaste Markku
Published: June 2012

Background
After focal brain ischemia, leukocytes adhere to the perturbed endothelium and are believed to aggravate reperfusion injury. Although ischemia-induced upregulation of endothelial adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and P-selectin, has been observed in experimental animals, the mechanism of cerebral leukocyte infiltration and thus therapeutic possibilities to reduce it in humans are uncertain.

Methods and Results
We counted the granulocytes, mononuclear phagocytes, and the percentages of cerebral microvessels expressing ICAM-1 by applying immunohistochemistry on brain sections showing a variable degree of neuronal damage from 11 human subjects who died 15 hours to 18 days after ischemic stroke and from normal control brains. In infarcted regions, granulocytes were detected as early as at 15 hours after injury (11.3 versus 0.5 cells/mm
2
in noninfarcted hemisphere); their amount exceeded 200 cells/mm
2
by 2.2 days but was back to normal level at 6.3 and 8.5 days. Acute infarctions (0.6 to 8.5 days) harbored significantly more ICAM-1–stained microvessels (up to 97% of microvessels at 1.8 days) than the noninfarcted hemisphere (
P
<.001), although the noninfarcted hemisphere (1.8 to 6.3 days) also showed higher ICAM-1 expression than controls. In the absence of ICAM-1 upregulation, macrophages (>200/mm
2
) were abundant in the core of neuronal damage at 17 and 18 days.

Conclusions
The striking upregulation of endothelial ICAM-1 expression, functioning in concert with chemotactic factors, may cause granulocyte infiltration during the first 3 days after stroke. This study may support the usage and timing of antibody infusions to block endothelial adhesion molecules in an attempt to reduce leukocyte-induced damage in stroke.
Cost-effectiveness of Routine Coronary Angiography After Acute Myocardial Infarction
Authors: Kuntz Karen M. , Tsevat Joel , Goldman Lee , Weinstein Milton C.
Published: June 2012

Background
Coronary angiography is indicated for many patients after acute myocardial infarction (AMI). There are a number of subgroups of AMI patients, however, for whom the indication for coronary angiography is not well established.

Methods and Results
We developed a decision-analytic model for AMI in representative patient subgroups based on relevant clinical characteristics. The model estimates quality-adjusted life expectancy and direct lifetime costs for two strategies: coronary angiography and treatment guided by its results versus initial medical therapy without angiography. Decision tree chance node probabilities were estimated with the use of pooled data from randomized clinical trials and other relevant literature, costs were estimated with the use of the Medicare Part A database, and quality of life adjustments were derived from a survey of 1051 patients who had had a recent AMI. In our analysis, incremental cost-effectiveness ratios for coronary angiography and treatment guided by its result, compared with initial medical therapy without angiography, ranged between $17 000 and >$1 million per quality-adjusted year of life gained. Patient subgroups with severe postinfarction angina or a strongly positive exercise tolerance test (ETT) typically had cost-effectiveness ratios of <$50 000 per quality-adjusted year of life gained. In addition, most patient subgroups with a prior AMI had cost-effectiveness ratios of <$50 000 per quality-adjusted year of life gained, even with a negative ETT result.

Conclusions
In many patient subgroups after AMI, the cost-effectiveness of routine coronary angiography and treatment guided by its results compares favorably with other treatment strategies for coronary heart disease.
Significance of Automated Stenosis Detection During Quantitative Angiography
Authors: Escaned Javier , Baptista Jose , Di Mario Carlo , Haase Ju¨rgen , Ozaki Yukio , Linker David T. , de Feyter Pim J. , Roelandt Jos R.T.C. , Serruys Patrick W.
Published: June 2012

Background
Automated stenosis analysis is a common feature of commercially available quantitative coronary angiography (QCA) systems, allowing automatic detection of the boundaries of the stenosis, interpolation of the expected dimensions of the coronary vessel at the point of obstruction, and angiographically derived estimation of atheromatous plaque size. However, the ultimate meaning of this type of analysis in terms of the degree of underlying atherosclerotic disease remains unclear. We investigated the relationship between stenosis analysis performed with QCA and the underlying degree of atherosclerotic disease judged by intracoronary ultrasound (ICUS) imaging.

Methods and Results
In 40 coronary stenoses, automated identification of the sites of maximal luminal obstruction and the start of the stenosis was performed with QCA by use of curvature analysis of the obtained diameter function. Plaque size at these locations also was estimated with ICUS, with an additional ICUS measurement immediately proximal to the start of the stenosis. Crescentlike distribution of plaque, indicating an atheroma-free arc of the arterial wall, was recorded. At the site of the obstruction, total vessel area measured with ICUS was 16.65±4.04 mm
2
, whereas an equivalent measurement obtained from QCA-interpolated reference dimensions was 7.48±3.30 mm
2
(
P
=.0001). Plaque area derived from QCA data was significantly less than that calculated from ICUS (6.32±3.21 and 13.29±4.22 mm
2
, respectively; mean difference, 6.92±4.43 mm
2
;
P
=.0001). At the start of the stenosis identified by automated analysis, ICUS plaque area was 9.38±3.17 mm
2
, and total vessel area was 18.77±5.19 mm
2
(50±11% total vessel area stenosis). The arterial wall presented a disease-free segment in 28 proximal locations (70%) but in only 5 sites (12%) corresponding to the start of the stenosis and none at the obstruction (
P
=.0001). At the site of obstruction, all vessels showed a complete absence of a disease-free segment, and the atheroma presented a cufflike or all-around distribution with a variable degree of eccentricity.

Conclusions
At the site of maximal obstruction, QCA underestimated plaque size as measured with ICUS. Atherosclerotic disease was consistently present at the start of the stenosis and was used as a reference site by automated stenosis analysis. At the start of the stenosis, ICUS demonstrated a mean 50±11% total vessel area stenosis, with a characteristic loss of disease-free arcs of arterial wall present in proximal locations. Thus, the site identified by automated stenosis analysis as the start of the stenosis does not represent a disease-free site but rather the place where compensatory vessel enlargement fails to preserve luminal dimensions, a phenomenon that seems related to the observed loss of a remnant arc of normal arterial wall.
Identification of Active Tissue Factor in Human Coronary Atheroma
Authors: Marmur Jonathan D. , Thiruvikraman Singanallore V. , Fyfe Billie S. , Guha Arabinda , Sharma Samin K. , Ambrose John A. , Fallon John T. , Nemerson Yale , Taubman Mark B.
Published: June 2012

Background
Recent observations suggest that thrombosis in vivo is initiated via the tissue factor (TF) pathway. The TF activity of human coronary atheroma has not been reported.

Methods and Results
Directional coronary atherectomy (DCA) specimens from 63 lesions were analyzed with the use of a quantitative TF-specific activity assay. The median content of TF was 10 ng/g plaque (95% CI, 6 to 13 ng/g; range, 0 to 47 ng/g). After homogenization of the specimens, TF activity was detected in 28 of 31 lesions (90%). With a polyclonal anti-human TF antibody, the use of immunohistochemistry detected TF antigen in 43 of 50 lesions (86%); TF antigen was expressed in cellular and acellular areas of the plaque. Histologically defined thrombus was present in 19 of the 43 lesions with detectable TF antigen and in none of the 7 lesions without detectable TF antigen (19 of 43 versus 0 of 7;
P
<.02). TF antigen was undetectable with immunohistochemistry in 4 of 13 restenotic lesions (31%) and in 3 of 37 de novo lesions (8%) (
P
<.05).

Conclusions
TF contributes to the procoagulant activity of most atherosclerotic lesions treated with DCA. The association of immunohistochemically detectable TF with plaque thrombus suggests that TF plays a role in coronary thrombosis. Diminished TF expression in restenotic lesions may in part account for the lower complication rate that has been associated with DCA of restenotic versus de novo lesions. Inhibition of TF may represent a therapeutic goal for the prevention of thrombotic complications associated with percutaneous coronary interventions.
One-Year Results From the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) Trial
Authors: Califf Robert M. , White Harvey D. , Van de Werf Frans , Sadowski Zygmunt , Armstrong Paul W. , Vahanian Alec , Simoons Maarten L. , Simes R. John , Lee Kerry L. , Topol Eric J.
Published: June 2012

Background
In the randomized Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries (GUSTO-I) trial, 41 021 patients received one of four thrombolytic regimens. Patients treated with accelerated tissue plasminogen activator (TPA) had a lower 30-day mortality rate (6.3%) than those treated with the other regimens (7.3%, combined streptokinase groups).

Methods and Results
Each patient who was alive at 30 days was sent a return postcard to ascertain vital status at 1 year. If the postcard was not returned, the patient (or an alternate specified at randomization) was contacted by telephone. A locator service was used in the United States for patients who could not be located by these methods. Final follow-up was 96% worldwide. One-year mortality rates remained in favor of accelerated TPA (9.1%) over streptokinase with subcutaneous heparin (10.1%,
P
=.011) and streptokinase with intravenous heparin (10.1%,
P
=.009). Combination therapy had an intermediate 1-year mortality (9.9%); this outcome was statistically indistinguishable from that with streptokinase (
P
=.47) but was marginally different from that with accelerated TPA (
P
=.05).

Conclusions
The 1-year results demonstrated a saving of 10 lives per 1000 patients treated with accelerated TPA versus streptokinase and subcutaneous or intravenous heparin. Combination thrombolytic therapy had an intermediate benefit but offered no advantage over accelerated TPA treatment alone.
Patterns and Mechanisms of In-Stent Restenosis
Authors: Hoffmann Rainer , Mintz Gary S. , Dussaillant Gaston R. , Popma Jeffrey J. , Pichard Augusto D. , Satler Lowell F. , Kent Kenneth M. , Griffin Jennifer , Leon Martin B.
Published: June 2012

Background
Studies have suggested that restenosis within Palmaz-Schatz stents results from neointimal hyperplasia or chronic stent recoil and occurs more frequently at the articulation.

Methods and Results
Serial intravascular ultrasound (IVUS) was performed after intervention and at follow-up in 142 stents in 115 lesions. IVUS measurements (external elastic membrane [EEM], stent, and lumen cross-sectional areas [CSAs] and diameters) were performed, and plaque CSA (EEM lumen in reference segments and stent lumen in stented segments), late lumen loss (Δlumen), remodeling (ΔEEM in reference segments and Δstent in stented segments), and tissue growth (Δplaque) were calculated. After intervention, the lumen tended to be smallest at the articulation because of tissue prolapse. At follow-up, tissue growth was uniformly distributed throughout the stent; the tendency for greater neointimal tissue accumulation at the central articulation reached statistical significance only when normalized for the smaller postintervention lumen CSA. In stented segments, late lumen area loss correlated strongly with tissue growth but only weakly with remodeling. Stents affected adjacent vessel segments; remodeling progressively increased and tissue growth progressively decreased at distances from the edge of the stent. These findings were similar in native arteries and saphenous vein grafts and in lesions treated with one or two stents. There was no difference in the postintervention or follow-up lumen (at the junction of the two stents) when overlapped were compared with nonoverlapped stents.

Conclusions
Late lumen loss and in-stent restenosis were the result of neointimal tissue proliferation, which tended to be uniformly distributed over the length of the stent.
Enhanced Cellular Proliferation in Intact Stenotic Lesions Derived From Human Arteriovenous Fistulas and Peripheral Bypass Grafts
Authors: Hofstra Leo , Tordoir Jan H.M. , Kitslaar Peter J.E.H.M. , Hoeks Arnold P.G. , Daemen Mat J.A.P.
Published: June 2012

Background
Vascular interventions are often complicated by the development of intimal thickening, leading to stenosis. Cellular proliferation is a key event in stenosis formation in animals, but the role of cell proliferation in intimal thickening in humans is still unclear. Furthermore, the relation between proliferation in human stenotic lesions and flow parameters has not been established.

Methods and Results
We studied the proliferation patterns of 35 anatomically intact human stenotic lesions derived from either peripheral bypasses (normal flow) or hemodialysis AV fistulas (high flow) with the use of Ki-67, a cell proliferation marker. Local flow parameters were assessed with ultrasound. Proliferation patterns were similar in AV fistula and bypass stenoses. In the intima, proliferation was highest in the area just below the endothelium (AV fistulas, 3.6%; bypasses, 3.5%;
P
=NS). In adjacent nonstenotic vessel segments that were used as controls, proliferation rate in the intima was 0.3%. Double-labeling studies revealed that subendothelial-intimal proliferation consisted mainly (90%) of vascular smooth muscle cells, whereas proliferation in the other layers of the vessel wall also consisted of endothelial cells and macrophages. Blood flow velocity was negatively correlated with subendothelial-intimal proliferation (
r
=−.61,
P
<.05). The endothelial cell coverage of the lumen was positively correlated with proliferation (
r
=.85,
P
<.01).

Conclusions
These data suggest enhanced cellular proliferation in human stenotic tissue derived from AV fistulas and peripheral bypass grafts. Furthermore, high proliferation rates seem to be associated with endothelial cell coverage of the lumen and low local flow velocities.
Natural Course of Moderate Cardiac Allograft Rejection (International Society for Heart Transplantation Grade 2) Early and Late After Transplantation
Authors: Rocca Hans P. Brunner-La , Su¨tsch Gabor , Schneider Jakob , Follath Ferenc , Kiowski Wolfgang
Published: June 2012

Background
The significance of International Society for Heart Transplantation (ISHT) grade 2 cardiac allograft rejection has been questioned, and the medical community is not in complete agreement as to its clinical management. We therefore retrospectively analyzed the follow-up of all available endomyocardial biopsy samples obtained from 161 transplant patients since introduction of the ISHT nomenclature at our institution.

Methods and Results
Of 2868 biopsies performed 3 days to 8.9 years after transplantation, 420 biopsies had no follow-up or were preceded by intensified immunosuppression and were excluded from analysis. Of the remaining 2448 biopsies, 374 (15.3%) were repeat biopsies performed 7 to 10 days after prior ISHT 2 rejection without change of treatment. Of these, 70 (18.7%) had progressed to ≥ISHT 3A, whereas 82 (21.9%) remained unchanged and 222 (59.4%) resolved. In contrast, follow-up of 2074 biopsies with lower-grade rejection showed graft rejection classified as ≥ISHT 3A in 153 (7.4%), ISHT 2 in 240 (11.6%), and ≤ISHT 1B in 1681 (81.1%) biopsy samples (
P
<.0001). In univariate analysis, the odds ratio (OR) of graft rejection ≥ISHT 3A after ISHT 2 rejection was 2.89. Other univariate predictors of rejection ≥ISHT 3A were time after transplantation (OR=0.96 per month,
P
<.0001), blood group type B (OR=1.62,
P
<.005), “Quilty” lesion on previous biopsy (OR=1.70,
P
<.005), number of HLA mismatches (OR=1.27 per mismatch,
P
<.005), female sex (OR=1.55,
P
<.05), and serum creatinine level (OR=0.93 per 10 μmol/L,
P
<.005). Young age of recipients was a risk factor during long-term (≥2 years) follow-up (
P
<.002), and lower cyclosporine level was a risk factor during the first month after transplantation (
P
<.01). In multivariate logistic regression analysis, ISHT 2 rejection on previous biopsy remained the strongest predictor of rejection ≥ISHT 3A (OR=2.40,
P
<.0001).

Conclusions
Several factors independently increase the risk of rejection classified as ≥ISHT 3A. The strongest predictor of a grade of ≥ISHT 3A was ISHT 2 rejection on the previous biopsy obtained 7 to 10 days earlier. Therefore, ISHT 2 graft rejection is of clinical significance, and short-term follow-up appears to be warranted even late after transplantation.
Restoration of Endothelium-Dependent Vasodilation After Reperfusion Injury by Tetrahydrobiopterin
Authors: Tiefenbacher Christiane P. , Chilian William M. , Mitchell Michael , DeFily David V.
Published: June 2012

Background
A deficit in the endothelial production of nitric oxide (NO) is associated with the sequelae of reperfusion injury. Because endothelial NO synthesis depends on the cofactor tetrahydrobiopterin (BH4), we hypothesized that depletion of this cofactor underlies the reduction of endothelium-dependent dilation in reperfusion injury.

Methods and Results
After occlusion of the left anterior descending coronary artery of a pig for 60 minutes followed by 90 minutes of reperfusion (ischemia/reperfusion), hearts were removed and the arterioles were isolated, cannulated, pressurized, and placed on an inverted microscope stage. Dose responses to the endothelium-independent dilator sodium nitroprusside and the endothelium-dependent dilators serotonin, A23187, and substance P were obtained under control conditions, after incubation with sepiapterin (intracellularly converted to BH4) or synthetic BH4 6-methyltetrahydropterin (MH4), and again after their washout. After ischemia/reperfusion, sodium nitroprusside maximally dilated arterioles (99±3%), whereas relaxation to serotonin, A23187, and substance P was significantly reduced (19±9%, 44±9%, and 54±8%, respectively). During incubation with sepiapterin (1 μmol/L) or MH4 (10 μmol/L), endothelium-dependent dilation was significantly enhanced (
P
<.05), whereas the response to sodium nitroprusside was unaltered. After washout, the vasodilatory responses were not significantly different from the initial ischemia/reperfusion responses. Sepiapterin and MH4 did not affect vasodilatory responses in vessels obtained from nonischemic control hearts. As after ischemia/reperfusion, incubation of control vessels with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, decreased endothelium-dependent vasodilation, which was restored in the presence of sepiapterin or MH4.

Conclusions
These data indicate that exogenous administration of sepiapterin or MH4 restores the response to endothelium-dependent vasodilators in pig coronary arterioles after ischemia/reperfusion. We therefore conclude that ischemia/reperfusion alters the availability or production of BH4, which contributes to blunted endothelial nitroxidergic vasodilation.
Significance of Mild Transient Release of Creatine Kinase–MB Fraction After Percutaneous Coronary Interventions
Authors: Abdelmeguid Alaa E. , Topol Eric J. , Whitlow Patrick L. , Sapp Shelly K. , Ellis Stephen G.
Published: June 2012

Background
The clinical significance of minor elevations in creatine kinase–myocardial band isoenzyme (CK-MB) after coronary interventions has not been systematically evaluated.

Methods and Results
We examined 4484 patients who underwent successful percutaneous transluminal coronary angioplasty or directional coronary atherectomy and whose peak CK levels did not exceed twice the upper limit of laboratory normal. Group 1 (3776 patients) had no CK or MB elevation after the procedure (ie, CK ≤180 IU/L, with MB fraction ≤4%). Group 2 (450 patients) had a peak CK level between 100 and 180 IU/L, with MB fraction >4%, and group 3 (258 patients) had a peak CK level between 181 and 360 IU/L, with MB fraction >4%. The strongest correlate of postprocedure CK-MB elevation was the performance of directional coronary atherectomy (odds ratio, 4.1;
P
<.0001), followed by the development of ≥1 in-lab minor procedural complication (odds ratio, 2.6;
P
<.0001). Clinical follow-up was available in 4461 patients (99.5%), with a mean duration of 36±22 months. Survival analysis, adjusted with Cox proportional hazards regression model, showed that the groups with elevated CK-MB had a significantly higher incidence of cardiac death (risk ratio, 1.3;
P
=.04) and myocardial infarction (risk ratio, 1.3;
P
=.03). Major ischemic complications (death, myocardial infarction, and coronary revascularization) occurred more frequently in the groups with increased CK-MB (groups 1 versus 2 versus 3, 37.3% versus 43.3% versus 48.9%;
P
=.01).

Conclusions
This study shows that minor elevations of CK-MB after successful coronary interventions identify a population with a worse long-term prognosis compared with patients with no enzyme elevations and appear to have an adverse effect on long-term prognosis. Future studies of percutaneous coronary revascularization should include routine measurements of biochemical cardiac markers as important predictors of long-term prognosis.
Fish Oils and Low-Molecular-Weight Heparin for the Reduction of Restenosis After Percutaneous Transluminal Coronary Angioplasty
Authors: Cairns John A. , Gill John , Morton Brian , Roberts Robin , Gent Michael , Hirsh Jack , Holder Douglas , Finnie Keith , Marquis Jean Franc¸ois , Naqvi Salim , Cohen Eric
Published: June 2012

Background
Percutaneous transluminal coronary angioplasty (PTCA) is complicated by restenosis within 6 months in >40% of patients. Theoretical, animal experimental, and human epidemiological and clinical trial findings have suggested that fish oils (n-3) might reduce restenosis. Low-molecular-weight heparin (LMWH) has reduced cellular proliferation and restenosis in several experimental systems.

Methods and Results
We randomized 814 patients to fish oils (5.4 g n-3 fatty acids) or placebo a median of 6 days before PTCA and continued for 18 weeks. At the time of sheath removal, 653 patients with at least one successfully dilated lesion were randomized to LMWH (30 mg SC BID) or control for 6 weeks in a 2×2 factorial design. Follow-up with quantitative coronary angiography (QCA; target, 18 weeks) was interpretable on 96% of these patients. Restenosis rates per patient were for n-3, 46.5%; placebo, 44.7%; LMWH, 45.8%; and control, 45.4%. Restenosis rates per lesion were for n-3, 39.7%; placebo, 38.7%; LMWH, 38%; and control, 40.4%. At follow-up QCA, mean minimal lumen diameters were (mm) for n-3, 1.12; placebo, 1.10; LMWH, 1.12; and control, 1.10. Fifteen percent of patients permanently discontinued n-3/placebo before study completion, and 21% of patients discontinued LMWH early. There were no significant differences in the occurrences of ischemic events. Bleeding was more common with LMWH, usually was mild, and led to early discontinuation of study medication in only 0.9% of patients. Gastrointestinal side effects were more common in patients receiving n-3 than placebo.

Conclusions
There is no evidence for a clinically important reduction of PTCA restenosis in this trial by either n-3 or LMWH. Evaluation of the results for n-3 in the context of previously published data on the reduction of PTCA restenosis indicates that n-3 is not efficacious and that further trials are unwarranted.
Effect of Atrial Fibrillation on Atrial Refractoriness in Humans
Authors: Daoud Emile G. , Bogun Frank , Goyal Rajiva , Harvey Mark , Man K. Ching , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
The acute effect of atrial fibrillation (AF) on the atrial effective refractory period (ERP) in humans is unknown.

Methods and Results
In 20 patients without structural heart disease, the atrial ERP was measured before and after pacing-induced AF at drive cycle lengths of 350 and 500 ms. Immediately after spontaneous AF conversion, the post-AF ERP was measured. The pre-AF ERPs at 350 and 500 ms were 206±23 and 216±17 ms, respectively. The time to spontaneous conversion of AF was 7.3±1.9 minutes. The first post-AF ERPs at drive cycle lengths of 350 and 500 ms were 175±30 ms (
P
<.0001 versus pre-AF) and 191±30 ms (
P
<.0001 versus pre-AF), respectively. The post-AF ERP returned to the pre-AF ERP value after a mean of 8.4±0.3 minutes. In 15 patients, during the determination of the post-AF ERP, secondary episodes of AF lasting 1±1.5 minutes were reinduced 6±3 times per patient. There was a significant inverse logarithmic relationship between the time to reinduction of AF and the duration of secondary episodes of AF (
P
<.0001,
r
=.5).

Conclusions
In humans, several minutes of induced AF is sufficient to shorten the ERP for up to ≈8 minutes. The temporal recovery of the ERP is reflected in progressively shorter episodes of reinduced AF. These data imply that AF transiently shortens the atrial wavelength and suggest a mechanism by which AF may perpetuate itself.
Efficacy and Safety of Repeated Intravenous Doses of Ibutilide for Rapid Conversion of Atrial Flutter or Fibrillation
Authors: Stambler Bruce S. , Wood Mark A. , Ellenbogen Kenneth A. , Perry Kimberly T. , Wakefield Linda K. , VanderLugt James T.
Published: June 2012

Background
Currently available antiarrhythmic drugs have limited efficacy for acute termination of atrial fibrillation and flutter, especially if the arrhythmia is not of recent onset. The purpose of this multicenter study was to determine the efficacy and safety of repeated doses of intravenous ibutilide, a class III antiarrhythmic drug, in terminating atrial fibrillation or flutter.

Methods and Results
Two hundred sixty-six patients with sustained atrial fibrillation (n=133) or flutter (n=133), with an arrhythmia duration of 3 hours to 45 days, were randomized to receive up to two 10-minute infusions, separated by 10 minutes, of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo. The conversion rate was 47% after ibutilide and 2% after placebo (
P
<.0001). The two ibutilide dosing regimens did not differ in conversion efficacy (44% versus 49%). Efficacy was higher in atrial flutter than fibrillation (63% versus 31%,
P
<.0001). In atrial fibrillation but not flutter, conversion rates were higher in patients with a shorter arrhythmia duration or a normal left atrial size. Arrhythmia termination occurred a mean of 27 minutes after start of the infusion. Of 180 ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular tachycardia during or soon after the infusion. The arrhythmia required cardioversion in 3 patients (1.7%) and was nonsustained in 12 patients (6.7%).

Conclusions
Intravenous ibutilide given in repeated doses is effective in rapidly terminating atrial fibrillation and flutter and under monitored conditions is an alternative to current cardioversion options.
Antithrombotic Assessment of the Effects of Combination Therapy With the Anticoagulants Efegatran and Heparin and the Glycoprotein IIb-IIIa Platelet Receptor Antagonist 7E3 in a Canine Model of Coronary Artery Thrombosis
Authors: Shetler Timothy J. , Crowe V. Gail , Bailey Blanche D. , Jackson Charles V.
Published: June 2012

Background
There is a paucity of data regarding the antithrombotic pharmacology of the drug-drug interactions between the newer anticoagulant and antiplatelet agents. In this investigation, we have studied the antithrombotic effects of combinations of minimum effective doses of the glycoprotein IIb-IIIa receptor antagonist 7E3 [murine F(ab′)
2
] with both heparin and the novel tripeptide arginal antithrombin efegatran (
LY294468
) in a canine model of coronary artery thrombosis.

Methods and Results
Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. The groups studied were efegatran (0.25 mg · kg
−1
·h
−1
), heparin (80 U/kg, single injection, plus 30 U · kg
−1
·h
−1
), 7E3 (0.4 mg/kg, single injection), 7E3+efegatran, and 7E3+heparin. The combination of 7E3+efegatran was found to maintain better vessel patency (
P
<.05) at the end of the experiment (4 of 5 vessels) than all other groups (0 of 5, 0 of 4, 1 of 6, 2 of 7, and 1 of 6 for the vehicle-, heparin-, 7E3-, efegatran-, and 7E3+heparin–treated groups, respectively). Bleeding times were increased (
P
<.05) in both the 7E3+heparin group (fourfold) and the 7E3+efegatran group (threefold). 7E3 alone and both combination treatments produced significant reductions in ADP, arachidonic acid, and thrombin-induced platelet aggregation, whereas efegatran and heparin abolished only thrombin-induced aggregation.

Conclusions
The present investigation demonstrates that combination therapy with minimum effective doses of 7E3+efegatran provided enhanced antithrombotic efficacy compared with 7E3+heparin in this model of thrombosis.