bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes Exacerbates Inflammatory Responses to Ischemia-Reperfusion
Authors: Panés Julián , Kurose Iwao , Rodriguez-Vaca M. Dolores , Anderson Donald C. , Miyasaka Masayuki , Tso Patrick , Granger D. Neil
Published: June 2012

Background
Diabetes is associated with an increased incidence of ischemic organ damage. The objectives of present study were to compare the leukocyte–endothelial cell adhesive interactions and albumin leakage response of mesenteric venules to ischemia-reperfusion between control rats, rats with streptozotocin-induced diabetes, and rats with hyperglycemia induced by glucose infusion and to define the molecular determinants of the leukocyte accumulation elicited by ischemia-reperfusion in diabetic rats.

Methods and Results
Under baseline conditions, lower venular shear rates and an increased number of rolling leukocytes were noted in diabetic rats, whereas the number of adherent and emigrated leukocytes did not differ from that in control rats. Spontaneous albumin leakage from mesenteric venules was markedly increased in diabetic rats but not in hyperglycemic nondiabetic rats. Ischemia-reperfusion elicited significantly larger increases in leukocyte adhesion and emigration and albumin leakage in diabetic rats. Acute elevation of glucose levels did not modify the microvascular responses to ischemia-reperfusion compared with control rats. Antibodies directed against CD11/CD18, intercellular adhesion molecule–1 (ICAM-1), or P-selectin but not
l
-selectin significantly decreased the number of adherent and emigrated leukocytes after ischemia-reperfusion in diabetic rats. However, none of the antibodies significantly attenuated the increased albumin leakage response to ischemia-reperfusion in diabetic rats.

Conclusions
Thes results indicate that diabetes mellitus is associated with exaggerated leukocyte–endothelial cell adhesion and albumin leakage responses to ischemia-reperfusion. The enhanced leukocyte accumulation in response to ischemia-reperfusion is mediated by CD11/CD18–ICAM-1 interactions (firm adhesion) and P-selectin (rolling). The exaggerated albumin leakage response to ischemia-reperfusion in diabetics is not mediated by the recruited inflammatory cells.
Regional Differences in Current Density and Rate-Dependent Properties of the Transient Outward Current in Subepicardial and Subendocardial Myocytes of Human Left Ventricle
Authors: Näbauer Michael , Beuckelmann Dirk J. , Überfuhr Peter , Steinbeck Gerhard
Published: June 2012

Background
Recordings of outward currents in human ventricular myocytes revealed the presence of a large calcium-insensitive transient outward current. This current has been suggested to contribute significantly to regional electrophysiological heterogeneity in myocardial cells and tissue of several animal species and to cause electrical gradients across the ventricular wall.

Methods and Results
The patch-clamp technique was used to record action potentials and outward currents in myocytes enzymatically isolated from thin subepicardial and subendocardial layers of human nonfailing and failing left ventricle. In all subepicardial cells studied, a calcium-insensitive transient outward current (I
to1
) could be recorded with large density (10.6±1.08 pA/pF at 40 mV), whereas current density of I
to1
in subendocardial cells was fourfold smaller (2.63±0.31 pA/pF,
P
<.0001, nonfailing myocardium). In failing hearts, the density of I
to1
was significantly smaller in subepicardial cells (7.81±0.53 pA/pF,
P
=.012) but not different in subendocardial myocytes (2.01±0.23 pA/pF,
P
=.25). Rate-dependent reduction of peak I
to1
at a 2-Hz depolarization rate was minimal in subepicardial cells (to 92.3±1.9%), whereas peak I
to1
in subendocardial myocytes was almost suppressed at 2 Hz (reduction to 13.2±2.1%,
P
<.0001). The different rate-dependent reduction of the transient outward current was due to a much slower time course of recovery from inactivation in subendocardial cells. Kinetic data, including action potentials recorded at 35°C, allow assessment of the role of the transient outward current for electrical activity and transmural voltage gradients in human left ventricle.

Conclusions
Marked regional differences in density and rate-dependent properties of the transient outward current exist in subendocardial and subepicardial layers in human left ventricular myocardium, causing transmural electrical gradients that are important for normal and pathological electrical behavior of the human heart. The difference in recovery rates of the transient outward current is a distinguishing feature between subepicardial and subendocardial myocytes.
Arrhythmogenic Action of Thrombin During Myocardial Reperfusion via Release of Inositol 1,4,5-Triphosphate
Authors: Jacobsen Alexander N. , Du Xiao-Jun , Lambert Kim A. , Dart Anthony M. , Woodcock Elizabeth A.
Published: June 2012

Background
Cardiac reperfusion initiates release of inositol 1,4,5-triphosphate [Ins(1,4,5)P
3
] and arrhythmogenesis via norepinephrine stimulation of α
1
-adrenergic receptors. The present study examines arrhythmogenic effects of thrombin-stimulated Ins(1,4,5)P
3
release under these conditions.

Methods and Results
[
3
H]Ins(1,4,5)P
3
release was measured in [
3
H]inositol-labeled rat hearts by high-performance liquid chromatography. Arrhythmia studies were performed in buffer-perfused rat hearts. Two-minute reperfusion after 20 minutes of global ischemia increased [
3
H]Ins(1,4,5)P
3
from 1123±77 to 2238±44 cpm/mg tissue. No increase was observed in catecholamine-depleted hearts (755±89 cpm/mg). The addition of thrombin (5 IU/mL) or thrombin receptor agonist peptide (TRAP
1-6
, 50 μmol/L) restored the reperfusion Ins(1,4,5)P
3
response (thrombin, 1518±68 cpm/mg and TRAP
1-6
, 1755±128 cpm/mg). Ins(1,4,5)P
3
release initiated by norepinephrine or thrombin was inhibited by gentamicin (150 μmol/L; 986±52 and 868±125 cpm/mg, respectively). The thrombin response was inhibited by the phospholipase C inhibitor U-73122 (5 μmol/L; 394±59 cpm/mg) but not by its inactive isomer U-73343. The norepinephrine response was not inhibited by U-73122 (2126±74 cpm/mg). Ventricular tachycardia and ventricular fibrillation were observed in intact hearts but not in hearts from catecholamine-depleted rats (ventricular fibrillation duration, 110±19 versus 0±0 seconds). The addition of thrombin or TRAP
1-6
increased arrhythmias in catecholamine-depleted hearts (112±32 and 89±28 seconds, respectively). Gentamicin and U-73122 but not U-73343 prevented thrombin-induced arrhythmias. Gentamicin inhibited norepinephrine-initiated arrhythmias, but U-73122 was ineffective.

Conclusions
This study demonstrates that the development of reperfusion arrhythmias under these conditions depends on the release of Ins(1,4,5)P
3
.
Smoking and Cardiac Events After Venous Coronary Bypass Surgery
Authors: Voors Adriaan A. , van Brussel Ben L. , Thijs Plokker H.W. , Ernst Sjef M.P.G. , Ernst Nicolette M. , Koomen Egbert M. , Tijssen Jan G.P. , Vermeulen Freddy E.E.
Published: June 2012

Background
The long-term clinical effects of smoking and smoking cessation after venous coronary bypass surgery have not been well established.

Methods and Results
Four hundred fifteen patients who underwent venous coronary bypass surgery between April 1976 and April 1977 were followed up prospectively for 15 years. Multivariate Cox survival analysis revealed that patients who smoked at the time of surgery had no elevated risks for clinical events compared with nonsmokers. However, smoking behavior at 1 and 5 years after surgery appeared to be an important predictor of clinical events during the subsequent follow-up period. Compared with patients who stopped smoking since surgery, smokers at 1 year after surgery had more than twice the risk for myocardial infarction and reoperation. Patients who were still smoking at 5 years after surgery had even more elevated risks for myocardial infarction and reoperation and a significantly increased risk for angina pectoris compared with patients who stopped smoking since surgery and patients who never smoked. Patients who started to smoke again within 5 years after surgery had increased risks for reoperation and angina pectoris. No differences in outcome were found between patients who stopped smoking since surgery and nonsmokers.

Conclusions
Our results show that smoking cessation after coronary bypass surgery may have important beneficial effects on clinical events during long-term follow-up.
Restricted Usage of T-Cell Receptor Vα-Vβ Genes in Infiltrating Cells in Aortic Tissue of Patients With Takayasu’s Arteritis
Authors: Seko Yoshinori , Sato Osamu , Takagi Atsuhiko , Tada Yusuke , Matsuo Hiroshi , Yagita Hideo , Okumura Ko , Yazaki Yoshio
Published: June 2012

Background
Infiltration by perforin-secreting killer lymphocytes, such as T cells and natural killer cells, has been shown to be involved in the pathogenesis of vascular cell damage in Takayasu’s arteritis.

Methods and Results
To investigate the immunological mechanisms involved, especially the nature of T-cell infiltration in Takayasu’s arteritis as well as atherosclerosis, we analyzed the expression of T-cell receptor (TCR) Vα and Vβ genes in infiltrating cells in the aortic tissue of patients with Takayasu’s arteritis and atherosclerotic aortic aneurysm by polymerase chain reaction (PCR). We also analyzed the expression of cytokine genes by PCR. We found that the repertoires of TCR Vα as well as Vβ gene transcripts in Takayasu’s arteritis were restricted. The infiltrating cells expressing Vα2, Vα16, Vα17, Vβ7, and Vβ13.1 were found in 3 of 4 patients. In contrast, TCR Vα-Vβ repertoires in atherosclerotic aortic aneurysm were polyclonal. There was no significant difference in the pattern of cytokine gene expression between the two diseases.

Conclusions
The restricted usage of TCR Vα as well as Vβ genes by infiltrating T cells in Takayasu’s arteritis may indicate that a specific antigen in the aortic tissue was targeted. Our findings provide the evidence that distinct immunological mechanisms are involved in the pathogenesis of Takayasu’s arteritis and atherosclerotic aortic aneurysm.
LDL-Apheresis Atherosclerosis Regression Study (LAARS)
Authors: Kroon Abraham A. , Aengevaeren Wim R.M. , van der Werf Tjeerd , Uijen Gerard J.H. , Reiber Johan H.C. , Bruschke Albert V.G. , Stalenhoef Anton F.H.
Published: June 2012

Background
Intensive lipid lowering may retard the progression of coronary atherosclerosis. LDL-apheresis has the potential to decrease LDL cholesterol to very low levels. To assess the effect of more aggressive lipid lowering with LDL-apheresis, we set up a randomized study in men with hypercholesterolemia and severe coronary atherosclerosis.

Methods and Results
For 2 years, 42 men were treated with either biweekly LDL-apheresis plus medication or medication alone. In both groups a dose of simvastatin of 40 mg per day was administered. Baseline (mean±SD) LDL cholesterol was 7.8±1.9 mmol·L
−1
and 7.9±2.3 mmol·L
−1
in the apheresis and medication groups, respectively. The mean reduction in LDL cholesterol was 63% (to 3.0 mmol·L
−1
) and 47% (to 4.1 mmol·L
−1
), respectively. Primary quantitative coronary angiographic end points were changes in average mean segment diameter and minimal obstruction diameter. No differences between the apheresis and medication groups were found in mean segment diameter (−0.01±0.16 mm versus 0.03±0.16 mm, respectively) or in minimal obstruction diameter (−0.01±0.13 mm versus 0.01±0.11 mm, respectively), expressed as means per patient. On the basis of coronary segment, mean percent stenosis of all lesions showed a tendency to decrease; only in the apheresis group more minor lesions disappeared in comparison to the medication group. On bicycle exercise tests, the time to 0.1 mV ST-segment depression increased significantly by 39% and the maximum level of ST depression decreased significantly by 0.07 mV in the apheresis group versus no changes in the medication group.

Conclusions
Two years of lipid lowering both with medication alone or LDL-apheresis with medication showed angiographic arrest of the progression of coronary artery disease. However, more aggressive treatment induced functional improvement, which may precede anatomic changes.
Echocardiographic Quantification of Regional Left Ventricular Wall Motion With Color Kinesis
Authors: Lang Roberto M. , Vignon Philippe , Weinert Lynn , Bednarz James , Korcarz Claudia , Sandelski RDMS Joanne , Koch Rick , Prater David , Mor-Avi Victor
Published: June 2012

Background
Color kinesis is a new technology for the echocardiographic assessment of left ventricular wall motion based on acoustic quantification. This technique automatically detects endocardial motion in real time by using integrated backscatter data to identify pixel transitions from blood to tissue during systole on a frame-by-frame basis. In this study, we evaluated the feasibility and accuracy of quantitative segmental analysis of color kinesis images to provide objective evaluation of regional systolic endocardial motion.

Methods and Results
Two-dimensional echocardiograms were obtained in the short-axis and apical four-chamber views in 20 normal subjects and 40 patients with regional wall motion abnormalities. End-systolic color overlays superimposed on the gray scale images were obtained with color kinesis to color encode left ventricular endocardial motion throughout systole on a frame-by-frame basis. These color-encoded images were divided into segments by use of custom software. In each segment, pixels of different colors were counted and displayed as stacked histograms reflecting the magnitude and timing of regional endocardial excursion. In normal subjects, histograms were found to be highly consistent and reproducible. The patterns of contraction obtained in normal subjects were used as a reference for the objective automated interpretation of regional wall motion abnormalities, defined as deviations from this pattern. The variability in the echocardiographic interpretation of wall motion between two experienced readers was similar to the diagnostic variability between the consensus of the two readers and the automated interpretation.

Conclusions
Color kinesis is a promising new tool that may be used clinically to improve the qualitative and quantitative evaluation of spatial and temporal aspects of global and regional wall motion. In this initial study, segmental analysis of color kinesis images provided accurate, automated, and quantitative diagnosis of regional wall motion abnormalities.
Cardiomyocyte Troponin T Immunoreactivity Is Modified by Cross-linking Resulting From Intracellular Calcium Overload
Authors: Gorza Luisa , Menabò Roberta , Vitadello Maurizio , Bergamini Carlo M. , Di Lisa Fabio
Published: June 2012

Background
During myocardial ischemia, the increase in cytosolic Ca
2+
promotes the activation of neutral proteases such as calpains. Since the troponin T subunit is a substrate for calpains, we investigated the effects of irreversible myocyte damage on troponin T immunoreactivity.

Methods and Results
Hearts from adult guinea pigs (n=32) were perfused under conditions of normoxia, ischemia, postischemic reperfusion, or Ca
2+
paradox. Hearts were frozen and processed for immunohistochemistry and Western blot with three anti–troponin T monoclonal antibodies. Two of these antibodies are unreactive on cryosections of freshly isolated and normoxic hearts and of hearts exposed to 30 minutes of no-flow ischemia. In contrast, reactivity is detected in rare myocytes after 60 minutes of ischemia, in a large population of myocytes after 60 minutes of ischemia followed by 30 minutes of reperfusion, and in every myocyte exposed to Ca
2+
paradox. In Western blots, samples from ischemia-reperfusion and Ca
2+
overloaded hearts show reactive polypeptides of about 240 to 260 kD and 65 to 66 kD in addition to troponin T. A similar pattern of immunoreactivity is observed with an anti–troponin I antibody. Histochemical troponin T immunoreactivity and reactivity on high-molecular-weight polypeptides are detectable in normal heart samples after preincubation with 10 mmol/L Ca
2+
or with transglutaminase, whereas they are not if either transglutaminase or calpain is inhibited.

Conclusions
The evolution of the ischemic injury is accompanied by changes in troponin T immunoreactivity as a consequence of the calcium-dependent activation of both calpain proteolysis and transglutaminase cross-linking.
Plasma Brain Natriuretic Peptide as an Indicator of Left Ventricular Systolic Function and Long-term Survival After Acute Myocardial Infarction
Authors: Omland Torbjørn , Aakvaag Asbjørn , Bonarjee Vernon V. S. , Caidahl Kenneth , Lie Rolv Terje , Nilsen Dennis W. T. , Sundsfjord Johan A. , Dickstein Kenneth
Published: June 2012

Background
Elevated plasma levels of atrial natriuretic peptide (ANP) and the N-terminal fragment of the ANP prohormone (N-ANP) are associated with decreased left ventricular function and decreased long-term survival after acute myocardial infarction (AMI). Previous data suggest that plasma brain natriuretic peptide (BNP) may increase proportionally more than plasma ANP after AMI and in chronic heart failure. The diagnostic and prognostic value of plasma BNP as an indicator of left ventricular dysfunction and long-term survival after AMI, relative to that of ANP and N-ANP, remain to be established.

Methods and Results
Venous blood samples for analysis of ANP, N-ANP, and BNP were obtained on day 3 after symptom onset from 131 patients with documented AMI. Left ventricular ejection fraction was determined by echocardiography in a subsample of 79 patients. Twenty-eight cardiovascular and 3 noncardiovascular deaths occurred during the follow-up period (median, 1293 days). All three peptides proved to be powerful predictors of cardiovascular mortality by univariate Cox proportional hazards regression analyses (ANP:
P
<.0001; N-ANP:
P
=.0002; BNP:
P
<.0001). In a multivariate model, plasma BNP (
P
=.021) but not ANP (
P
=.638) or N-ANP (
P
=.782) provided additional prognostic information beyond left ventricular ejection fraction. Logistic regression analysis showed that ANP (
P
=.003) and N-ANP (
P
=.027) but not BNP (
P
=.14) were significantly associated with a left ventricular ejection fraction ≤45%.

Conclusions
These results suggest that plasma BNP determination provides important, independent prognostic information after AMI. Although plasma ANP appears to be a better predictor of left ventricular dysfunction, plasma BNP may have greater potential to complement standard prognostic indicators used in risk stratification after AMI because of its strong, independent association with long-term survival, enhanced in vitro stability, and simplicity of analysis.
Relation of Hormone-Replacement Therapy to Measures of Plasma Fibrinolytic Activity
Authors: Shahar Eyal , Folsom Aaron R. , Salomaa Veikko V. , Stinson Valarie L. , McGovern Paul G. , Shimakawa Tomoko , Chambless Lloyd E. , Wu Kenneth K.
Published: June 2012

Background
The mechanisms by which replacement hormones may reduce the risk of coronary heart disease are not fully understood. Of specific interest is a potential effect of replacement hormones on plasma fibrinolytic activity, a putative determinant of thrombotic events.

Methods and Results
We investigated the relation of current use of replacement hormones to three measures of plasma fibrinolytic activity: tissue-type plasminogen activator (TPA) antigen, plasminogen activator inhibitor–1 (PAI-1) antigen, and
d
-dimer. The sample was composed of 288 women, free of clinical cardiovascular disease, who were selected for a case-control study of atherosclerosis: 142 women with ultrasonographic evidence of carotid intimal-medial thickening (cases) and 146 control subjects. Twenty percent (59 women) reported current use of replacement hormones. TPA antigen and PAI-1 antigen were highly correlated with each other (
r
=.67), whereas
d
-dimer correlated only weakly with TPA or PAI-1. Compared with nonusers, current users of replacement hormones had lower mean levels of TPA and PAI-1 antigens, suggesting enhanced fibrinolytic potential. In the entire sample, the multivariate-adjusted geometric mean values of TPA antigen were 6.3 and 7.3 ng/mL among current users and nonusers, respectively (
P
=.01); the corresponding values for PAI-1 antigen were 6.1 and 7.5 ng/mL (
P
=.13). These results were generally consistent for both atherosclerosis cases and their control subjects.
d
-dimer levels were lower in current hormone users than in nonusers, but the difference was not statistically significant (
P
>.15) in any of the analyses.

Conclusions
The use of replacement hormones appears to be associated with enhancement of endogenous fibrinolytic potential. Enhanced plasma fibrinolytic activity among hormone users may explain, in part, the inverse association between hormone replacement therapy and coronary heart disease.
Effects of Brain Natriuretic Peptide on Exercise Hemodynamics and Neurohormones in Isolated Diastolic Heart Failure
Authors: Clarkson Peter B.M. , Wheeldon Nigel M. , MacFadyen Robert J. , Pringle Stuart D. , MacDonald Thomas M.
Published: June 2012

Background
Experimental models suggest that brain natriuretic peptide (BNP) can modify left ventricular diastolic performance. The aim of this study was to evaluate the effects of BNP on resting and exercise hemodynamics and neurohormones in patients with isolated diastolic heart failure.

Methods and Results
Six patients with isolated diastolic heart failure were studied. After baseline hemodynamic measurements were obtained with use of thermistor-tipped pulmonary artery catheters, patients were randomized to receive infusion of BNP or placebo in a single-blind, crossover study. Hemodynamic and neurohormonal parameters were measured at rest after 30 minutes of infusion and during incremental supine bicycle exercise. BNP did not significantly affect resting hemodynamics but attenuated the rise in both pulmonary capillary wedge pressure (placebo, 23±2 mm Hg; BNP, 16±2 mm Hg;
P
<.01) and mean pulmonary artery pressure (placebo, 34±3 mm Hg; BNP, 29±3 mm Hg;
P
<.05) during exercise without affecting changes in heart rate, systemic blood pressure, or stroke volume. In response to BNP, there was significant suppression of plasma aldosterone concentration (placebo, 551±107 pmol/L; BNP, 381±56 pmol/L;
P
<.05).

Conclusions
BNP infusion causes beneficial hemodynamic and neurohormonal effects during exercise in patients with isolated diastolic heart failure.
Electrophysiological Effects of Catheter Ablation of Inferior Vena Cava–Tricuspid Annulus Isthmus in Common Atrial Flutter
Authors: Cauchemez Bruno , Haissaguerre Michel , Fischer Bruno , Thomas Olivier , Clementy Jacques , Coumel Philippe
Published: June 2012

Background
The electrophysiological mechanisms for successful catheter ablation of atrial flutter (AFl) targeting the inferior vena cava–tricuspid annulus (IVC-TA) isthmus have not been determined.

Methods and Results
Twenty patients with common AFl were studied. All had inducible common AFl, and 8 of them had both common and reverse AFl. Right atrial (RA) activation sequences were investigated during pacing from sites proximal (low lateral RA) and distal (proximal coronary sinus) to the IVC-TA isthmus both during entrainment of common or reverse AFl and during pacing in sinus rhythm. This was repeated after ablation. During pacing in sinus rhythm from the low lateral RA, the septum was activated by caudocranial and craniocaudal wave fronts. Similarly, during pacing from the proximal coronary sinus, the lateral RA was activated by two wave fronts. Catheter ablation of the IVC-TA isthmus induced dramatic changes in mapping due to the loss of caudocranial wave front in all but 1 patient. The septum and the lateral RA were activated by a single craniocaudal front as during entrainment of reverse or common AFl, respectively. After a follow-up of 8±2 months, common or reverse AFl occurred in 4 patients. Two had no or only unidirectional changes in the isthmus conduction induced by ablation. The other 2 had a late recovery of conduction.

Conclusions
The present study provides evidence that the mechanism of successful AFl ablation targeting the IVC-TA isthmus is local bidirectional conduction block. This change can be used as a new and complementary electrophysiological end point for the procedure. AFl recurrences are associated with failure to achieve a permanent block.
Adventitial Remodeling After Coronary Arterial Injury
Authors: Shi Yi , Pieniek Marc , Fard Ali , O’Brien James , Mannion John D. , Zalewski Andrew
Published: June 2012

Background
Intraluminal thrombus formation and medial smooth muscle (SM) cell proliferation are recognized responses of the arterial system to injury. In contrast to these well-characterized processes during vascular repair, changes involving the adventitia have been largely neglected in previous studies. Hence, the goal of this investigation was to assess the response of the adventitia to coronary arterial injury.

Methods and Results
Adventitial changes in porcine coronary arteries subjected to medial injury were characterized by immunohistochemistry, histochemistry, and microscopic morphometry. The rapid development of a hypercellular response in the adventitia was evident 3 days after balloon-induced medial injury. Cell proliferation, as assessed by proliferating cell nuclear antigen immunostaining, reached the maximum level in the adventitia at 3 days, whereas at 14 and 28 days, the number of replicating cells reverted toward the baseline. The proliferating activity in the adventitia exceeded that seen in the media at all times after injury. To further define the changes in the phenotype of adventitial cells, the expression of three cytoskeletal proteins (vimentin, α-SM actin, and desmin) was characterized. Fibroblasts in normal adventitia expressed vimentin but no α-SM actin or desmin. After injury, these cells acquired characteristics of myofibroblasts expressing α-SM actin, which peaked at 7 and 14 days. Desmin expression was patchy in the adventitia, as opposed to its homogeneous distribution in medial SM cells. The modulation of fibroblast phenotype was transient, inasmuch as α-SM actin immunostaining declined at 28 days after injury, when dense, collagen-rich scar was evident within the adventitia. The above-described changes involving hypercellularity of the adventitia, myofibroblast formation, and fibrosis were associated with a significant focal adventitial thickening at 3, 7, 14, and 28 days after injury (
P
<.01 versus uninjured coronary arteries).

Conclusions
This study demonstrates the involvement of the adventitia in the vascular repair process after medial injury. The hypercellularity of the adventitial layer, proliferation of fibroblasts, and modulation of their phenotype to myofibroblasts are associated with the development of the thickened adventitia. It is postulated that these phenomena affect vascular remodeling and may provide an important insight into the mechanisms of vascular disorders.
Reduction in Thrombotic Events With Heparin-Coated Palmaz-Schatz Stents in Normal Porcine Coronary Arteries
Authors: Hårdhammar Peter A. , van Beusekom Heleen M.M. , Emanuelsson Håkan U. , Hofma Sjoerd H. , Albertsson Per A. , Verdouw Pieter D. , Boersma Eric , Serruys Patrick W. , van der Giessen Willem J.
Published: June 2012

Background
The use of stents improves the result after balloon coronary angioplasty. Thrombogenicity of stents is, however, a concern. In the present study, we compared stents with an antithrombotic coating with regular stents.

Methods and Results
Regular stents were placed in coronary arteries of pigs receiving no aspirin (group 1; n=8) or aspirin over 4 weeks (group 2, n=10) or 12 weeks (group 3, n=9). Stents coated with heparin (antithrombin III uptake, 5 pmol/stent) were placed in 7 pigs that did not receive aspirin (group 4). The other animals received aspirin and coated stents with a heparin activity of 12 pmol antithrombin III/stent (group 5, n=10) or 20 pmol/stent (group 6, n=10; group 7, n=10). Quantitative arteriography was performed at implantation and after 4 (groups 1, 2, and 4 through 6) or 12 weeks (groups 3 and 7). In an additional 5 animals, five regular and five coated stents (20 pmol/stent) were placed and explanted after 5 days for examination of the early responses to the implants. Thrombotic occlusion of the regular stent occurred in 9 of 27 in groups 1 through 3. However, in 0 of 30 of the animals receiving high-activity heparin-coated stents (groups 5 through 7), thrombotic stent occlusion was observed (
P
<.001). Histological analysis at 4 weeks showed that the neointima in group 6 was thicker compared with its control group 2 (259±104 and 117±36 μm,
P
<.01), but at 12 weeks the thickness was similar (152±61 and 198±49 μm, respectively). Comparison at 5 days suggested delayed endothelialization of the coating.

Conclusions
High-activity heparin coating of stents eliminates subacute thrombosis in porcine coronary arteries.
Inhibition of Neointimal Proliferation With Low-Dose Irradiation From a β-Particle–Emitting Stent
Authors: Laird John R. , Carter Andrew J. , Kufs William M. , Hoopes Timothy G. , Farb Andrew , Nott Sepideh H. , Fischell Robert E. , Fischell David R. , Virmani Renu , Fischell Tim A.
Published: June 2012

Background
Restenosis after successful percutaneous transluminal coronary angioplasty is the major factor limiting the long-term effectiveness of this procedure. Neointimal proliferation in response to arterial injury is an important contributor to restenosis. The use of radiation for the treatment of malignant and benign proliferative conditions has been well established. External beam irradiation and endovascular irradiation by use of an after-loading technique have been shown to inhibit neointimal proliferation in experimental models of restenosis. The objective of this study was to investigate whether low-dose irradiation from a β-particle–emitting stent would inhibit neointimal proliferation after placement in porcine iliac arteries.

Methods and Results
Fourteen titanium-mesh stents were implanted in the iliac arteries of nine NIH miniature swine. There were seven β-particle–emitting radioisotope stents (
32
P, activity level 0.14 μCi) and seven control stents (
31
P, nonradioactive). Treatment effect was assessed by angiography and histomorphological examination of the stented iliac segments 28 days after implantation. There was a significant reduction in neointimal area (1.76±0.37 mm
2
versus 2.81±1.22 mm
2
,
P
=.05) and percent area stenosis (24.6±2.9% versus 36.0±10.7%,
P
=.02) within the β-particle–emitting stents compared with the control stents. Neointimal thickness, which was assessed at each wire site, was also significantly less within the treatment stents (0.26±0.04 mm versus 0.38±0.10 mm,
P
=.012). Scanning electron microscopy was performed on sections from four stents. This demonstrated endothelialization of both the treatment and control stents. There was no excess inflammatory reaction or fibrosis in the media, adventitia, or perivascular space of vessels treated with the β-particle–emitting stent compared with control vessels. At 28 days, there was no difference in smooth muscle cell proliferation as measured by the proliferating cell nuclear antigen index.

Conclusions
A local, continuous source of low-dose endovascular irradiation via a β-particle–emitting stent inhibits neointimal formation in porcine arteries. This low dose of local irradiation did not prevent endothelialization of the stents. This novel technique offers promise for the prevention of restenosis and warrants further investigation.
Effect of Coronary Artery Diameter in Patients Undergoing Coronary Bypass Surgery
Authors: O’Connor Nancy J. , Morton Jeremy R. , Birkmeyer John D. , Olmstead Elaine M. , O’Connor Gerald T.
Published: June 2012

Background
Coronary artery diameter is known to be inversely associated with perioperative mortality related to coronary artery bypass grafting (CABG). This association is believed to be responsible for increased risk among women and smaller people. However, the associations between sex, body size, and coronary size have not been carefully examined because direct information about coronary size is rarely available. Also, whether sex has an independent effect on vessel size is largely unknown.

Methods and Results
Height, weight, sex, age, status at hospital discharge, and luminal diameter of the midleft anterior descending coronary artery (mid-LAD) were recorded prospectively in 1325 patients undergoing CABG. Small vessel size was associated with substantially increased risk of in-hospital mortality (15.8% for 1.0-mm vessels, 4.6% for 1.5- to 2.0-mm vessels, and 1.5% for 2.5- to 3.5-mm vessels,
P
[trend]
<.001). Vessel size was strongly related to both sex and measures of body size. In multiple linear regression analysis, vessel size was positively correlated with body surface area (
P
[trend]
<.01), body mass index (
P
[trend]
=.004), height (
P
[trend]
=.001), and weight (
P
[trend]
=.001). After controlling for differences in age and body size, sex remained an important predictor of coronary size. Within each quartile of each body-size measure, mid-LAD diameter in men was greater than that in women (mean difference [range], 0.14 to 0.23 mm).

Conclusions
Small mid-LAD diameter is associated with substantially increased risk of in-hospital mortality with CABG. Although body size is correlated with mid-LAD diameter, women have smaller coronary arteries than men after controlling for differences in body size. These findings further support the hypothesis that smaller coronary arteries explain higher perioperative mortality with CABG in women and smaller people.
Effects of Diuretic Therapy on the Development of Tolerance to Nitroglycerin and Exercise Capacity in Patients With Chronic Stable Angina
Authors: Parker John D. , Parker Andrea B. , Farrell Bernice , Parker John O.
Published: June 2012

Background
Therapy with diuretics has been reported to prevent the development of nitrate tolerance. Importantly, diuretics may have independent antianginal effects through their effects on intravascular volume. The present investigation was designed to determine whether diuretic therapy could prevent the development of tolerance to continuous transdermal nitroglycerin. The study was also designed to examine whether diuretic therapy has an independent antianginal effect.

Methods and Results
Twelve patients with chronic stable angina were studied in a randomized, double-blind, crossover trial. Patients received diuretic (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each double-blind treatment period, patients underwent treadmill exercise testing on three separate occasions. The first exercise testing was performed after 7 to 10 days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently, exercise testing was repeated on the first day of active transdermal nitroglycerin therapy and following 7 to 10 days of continuous transdermal nitroglycerin application. Therapy with a diuretic was associated with an increase in exercise capacity but had no effect on nitroglycerin tolerance. During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an increase in treadmill walking time to the development of moderate angina compared with placebo (371±26 versus 288±16 seconds, diuretic versus placebo,
P
<.01). Similar results were obtained during both acute and sustained nitroglycerin therapy.

Conclusions
The results of this study demonstrate that therapy with a diuretic has no effect on the development of tolerance to continuous transdermal nitroglycerin. Interestingly, diuretic therapy itself has important antianginal effects and improves exercise capacity in patients with stable angina.
Role of Activation of Protein Kinase C in the Infarct SizeLimiting Effect of Ischemic Preconditioning Through Activation of Ecto-5′-nucleotidase
Authors: Kitakaze Masafumi , Node Koichi , Minamino Tetsuo , Komamura Kazuo , Funaya Hiroharu , Shinozaki Yoshiro , Chujo Mitsuaki , Mori Hidezo , Inoue Michitoshi , Hori Masatsugu , Kamada Takenobu
Published: June 2012

Background
We have reported previously that ischemic preconditioning limits infarct size by increasing ecto-5′-nucleotidase activity. Since we have also reported that protein kinase C activation increases ecto-5′-nucleotidase activity in rat cardiomyocytes, we tested whether activation of protein kinase C during ischemic preconditioning contributes to the infarct size–limiting effect through augmentation of ecto-5′-nucleotidase activity in the canine heart.

Methods and Results
The coronary artery was occluded four times for 5 minutes with alternating 5-minute periods of reperfusion (ischemic preconditioning). Then the coronary artery was occluded for 90 minutes followed by 6 hours of reperfusion. Infarct size, normalized by the risk area, in the ischemic preconditioning group was smaller than in the control group (42.6±3.6% in the control group versus 7.9±1.8% in the ischemic preconditioning group,
P
<.001). Myocardial ecto-5′-nucleotidase activity was increased after the ischemic preconditioning procedure but the increase in ecto-5′-nucleotidase was attenuated by inhibitors of protein kinase C (polymyxin B and GF109203X). Both polymyxin B and GF109203X blunted the infarct size–limiting effect of ischemic preconditioning (infarct size 33.1±6.9% and 35.1±6.4%, respectively). The infarct size–limiting effect was also blunted by an inhibitor of ecto-5′-nucleotidase. Transient administration of methoxamine mimicked the increase in ecto-5′-nucleotidase activity and the infarct size–limiting effect, both of which were abolished by inhibitors of protein kinase C.

Conclusions
We conclude that activation of ecto-5′-nucleotidase and protein kinase C contributes to the infarct size–limiting effect of ischemic preconditioning.
Assessment of Flow Events at the Ductus VenosusInferior Vena Cava Junction and at the Foramen Ovale in Fetal Sheep by Use of Multimodal Ultrasound
Authors: Schmidt Klaus G. , Silverman Norman H. , Rudolph Abraham M.
Published: June 2012

Background
Previous techniques for the study of the fetal circulation did not permit assessment of phasic events associated with the cardiac cycle. We used multimodal ultrasound techniques to examine flow events that occur in the major veins and across the foramen ovale in the circulation of the fetal lamb.

Methods and Results
We studied eight fetal lambs instrumented with catheters in the superior and inferior venae cavae and a peripheral umbilical vein and performed ultrasound studies that included M-mode and two-dimensional imaging, pulsed and Doppler color flow ultrasound, and contrast echocardiography to evaluate flow in the ductus venosus, in both venae cavae, and through the foramen ovale. Two blood streams of different flow velocities were identified within the cephalic portion of the inferior vena cava. The stream that originated from the narrowed ductus venosus had a higher velocity than that from the caudal inferior vena cava (mean velocity, 57±13 versus 16±3 cm/s;
P
<.0002). Facilitated by the eustachian valve and the septum primum, the ductus venosus stream preferentially passed through the foramen ovale to the left atrium. This flow occurred during most of the cardiac cycle, except for 19.6±2.3% of the cycle when the foramen ovale was closed during atrial contraction. Superior vena cava flow passed almost exclusively into the right atrium and tricuspid valve; a small amount that was refluxed from the right atrium into the inferior vena cava subsequently passed through the foramen into the left atrium.

Conclusions
Visualization of fetal circulatory streaming at the venous sites by ultrasound techniques aids in understanding the function of the fetal circulation and may be helpful in detecting the human fetus that is hemodynamically compromised.
TIMI Frame Count
Authors: Gibson C. Michael , Cannon Christopher P. , Daley William L. , Dodge J. Theodore , Alexander Barbara , Marble Susan J. , McCabe Carolyn H. , Raymond Lori , Fortin Terry , Poole W. Kenneth , Braunwald Eugene
Published: June 2012

Background
Although the Thrombolysis in Myocardial Infarction (TIMI) flow grade is a valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature.

Methods and Results
In normal patients and patients with acute myocardial infarction (MI) (TIMI 4), the number of cineframes needed for dye to reach standardized distal landmarks was counted to objectively assess an index of coronary blood flow as a continuous variable. The TIMI frame-counting method was reproducible (mean absolute difference between two injections, 4.7±3.9 frames, n=85). In 78 consecutive normal arteries, the left anterior descending coronary artery (LAD) TIMI frame count (36.2±2.6 frames) was 1.7 times longer than the mean of the right coronary artery (20.4±3.0) and circumflex counts (22.2±4.1,
P
<.001 for either versus LAD). Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC). The mean CTFC in culprit arteries 90 minutes after thrombolytic administration followed a continuous unimodal distribution (there were not subpopulations of slow and fast flow) with a mean value of 39.2±20.0 frames, which improved to 31.7±12.9 frames by 18 to 36 hours (
P
<.001). No correlation existed between improvements in CTFCs and changes in minimum lumen diameter (
r
=−.05,
P
=.59). The mean 90-minute CTFC among nonculprit arteries (25.5±9.8) was significantly higher (flow was slower) compared with arteries with normal flow in the absence of acute MI (21.0±3.1,
P
<.001) but improved to that of normal arteries by 1 day after thrombolysis (21.7±7.1,
P
=NS).

Conclusions
The CTFC is a simple, reproducible, objective, and quantitative index of coronary flow that allows standardization of TIMI flow grades and facilitates comparisons of angiographic end points between trials. Disordered resistance vessel function may account in part for reductions in flow in the early hours after thrombolysis.
Role of Angiographically Identifiable Thrombus on Long-term Luminal Renarrowing After Coronary Angioplasty
Authors: Violaris Andonis G. , Melkert Rein , Herrman Jean-Paul R. , Serruys Patrick W.
Published: June 2012

Background
Experimental studies suggest that mural thrombus may be involved in postangioplasty restenosis. The aim of our study was to examine the role of angiographically identifiable thrombus in the clinical situation.

Methods and Results
The study population comprised 2950 patients (3583 lesions). The presence of angiographically identifiable thrombus either before or after the procedure was defined as the presence of a generalized haziness or filling defect within the arterial lumen. Restenosis was assessed by both a categorical (>50% diameter stenosis at follow-up) and a continuous approach (absolute and relative losses). The study population included 160 lesions with and 3423 lesions without angiographically identifiable thrombus. The categorical restenosis rate was significantly higher in lesions containing angiographically identifiable thrombus: 43.1% versus 34.4%,
P
<.01; relative risk, 1.449; CI, 1.051 to 1.997. The absolute and relative losses were also higher in lesions containing angiographically identifiable thrombus (absolute loss, 0.43±0.66 versus 0.32±0.52; relative loss, 0.16±0.26 versus 0.13±0.21; both
P
<.05). The higher restenosis in these lesions was due primarily to an increased incidence of occlusion at follow-up angiography in this group: 13.8% versus 5.7%,
P
<.001. When lesions that went on to occlude by the time of follow-up angiography were excluded from the analysis, the restenosis rate between the two groups was similar by both the categorical (34.1% versus 30.4%,
P
=NS; relative risk, 1.183; CI, 0.824 to 1.696) and continuous (absolute loss, 0.23±0.46 versus 0.24±0.42,
P
=NS; relative loss, 0.09±0.17 versus 0.09±0.16,
P
=NS) approaches.

Conclusions
Our results indicate that the presence of angiographically identifiable thrombus at the time of the angioplasty procedure is associated with higher restenosis. The mechanism by which this occurs is through vessel occlusion at follow-up angiography. Measures aimed at improving outcome in this group of patients should be focused in this direction.
Ultrafast Computed Tomography as a Diagnostic Modality in the Detection of Coronary Artery Disease
Authors: Budoff Matthew J. , Georgiou Demetrios , Brody Alan , Agatston Arthur S. , Kennedy John , Wolfkiel Christopher , Stanford William , Shields Paul , Lewis Roger J. , Janowitz Warren R. , Rich Stuart , Brundage Bruce H.
Published: June 2012

Background
Ultrafast computed tomography (CT), by acquiring images of the proximal coronary arteries, detects coronary calcifications and has been demonstrated to be highly sensitive for the detection of coronary artery disease in many small studies. The aim of this study was to determine the relationship between ultrafast CT scanning and coronary angiography in a large number of symptomatic patients.

Methods and Results
The study population consisted of 710 patients from six participating centers. A multivariate logistic regression model was used to evaluate the individual contributions of age, number of calcified vessels, and the calcium score for the probability of angiographically significant disease. Of the 710 patients enrolled, 427 patients had significant angiographic disease, and coronary calcification was detected in 404, yielding a sensitivity of 95%. Of the 23 patients without calcifications, 19 (83%) had single-vessel disease at angiography. Of the 283 patients without angiographically significant disease, 124 had negative ultrafast CT coronary studies, for a specificity of 44%. An increasing number of vessels with calcification present on ultrafast CT was found to increase specificity for the presence of obstructive coronary artery disease in at least one vessel (
P
<.0001). As the log of the calcium score increases, the probability of multivessel obstructive disease increases (
P
<.0001).

Conclusions
Ultrafast CT scanning is a noninvasive, non–exercise-dependent test with an excellent sensitivity for the detection of coronary artery disease. The presence of calcifications in multiple vessels and in younger populations correlates with higher specificities for obstructive disease, making ultrafast CT coronary scanning a very useful diagnostic test.