bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Training Alters the Pathogenesis of Pacing-Induced Heart Failure Through Endothelium-Mediated Mechanisms in Awake Dogs
Authors: Wang Jie , Yi Geng-Hua , Knecht Mathias , Cai Bo-lin , Poposkis Sulli , Packer Milton , Burkhoff Daniel
Published: June 2012

Background
Beneficial effects of exercise training on cardiovascular function in chronic heart failure (CHF) have been suggested previously, but the underlying mechanisms are unknown. We tested whether daily exercise training improves systemic hemodynamics and preserves endothelium-mediated vasodilator function during development of heart failure.

Methods and Results
Fifteen dogs were surgically instrumented for hemodynamic measurements. One group of dogs underwent 4 weeks of cardiac pacing (210 bpm for 3 weeks and 240 bpm during week 4), and another group underwent pacing plus daily exercise training (4.4±0.3 km/h, 2 h/d). Pacing-alone dogs developed CHF characterized by typical hemodynamic abnormalities, blunted endothelium-mediated vasodilator function in coronary and femoral circulations, and decreased gene expression of endothelial constitutive nitric oxide synthase (ECNOS, normalized to GAPDH expression; normal, 1.15±0.31 versus CHF, 0.29±0.08,
P
<.05). Exercise training preserved normal hemodynamics at rest, endothelium-mediated vasodilator function, and gene expression of ECNOS (0.72±0.16 versus normal,
P
=NS). Inhibition of NO synthesis (nitro-
l
-arginine) in exercise-trained dogs abolished the preserved endothelium-mediated vasodilation of epicardial coronary arteries and elevated left ventricular end-diastolic pressure (7.7±0.3 to 19±3.4 mm Hg,
P
<.05), suggesting that the preservation of resting hemodynamics was in large part due to preserved endothelial function concealing the underlying CHF state.

Conclusions
Long-term exercise training altered the natural history of heart failure due to rapid cardiac pacing. One of the underlying mechanisms is through the preservation of endothelial vasodilator function.
Heart Rate Adjustment of Exercise-Induced ST-Segment Depression Identifies Men Who Benefit From a Risk Factor Reduction Program
Authors: Okin Peter M. , Prineas Ronald J. , Grandits Greg , Rautaharju Pentti M. , Cohen Jerome D. , Crow Richard S. , Kligfield Paul
Published: June 2012

Background
Whether subjects identified as being at increased risk of coronary heart disease (CHD) death by heart rate adjustment of exercise-induced ST-segment depression will benefit from therapy aimed at reducing risk factors has not been examined.

Methods and Results
Exercise ECGs were performed in 11 880 men from the Usual Care (UC) and Special Intervention (SI) groups of the Multiple Risk Factor Intervention Trial. UC men were referred to customary sources of care in the community; SI men received counseling on smoking cessation and dietary reduction of cholesterol, and stepped-care therapy for hypertension. An abnormal ST-segment response to exercise was defined according to standard criteria as ≥100 μV of additional horizontal or downsloping ST-segment depression and by an ST-segment/heart rate (ST/HR) index >1.60 μV/bpm. After 7 years of follow-up, CHD mortality was significantly lower in SI than UC men with an abnormal ST/HR index (2.4%, 19/786 versus 5.3%, 39/729,
P
=.005) but was comparable in SI and UC men with a normal ST/HR index (1.6%, 84/5154 versus 1.3%, 70/5211,
P
=NS). Risk reduction in SI men with an abnormal ST/HR index was independent of age and other cardiac risk factors. In contrast, there was no significant difference in CHD death rate between the smaller groups of SI and UC men with an abnormal test by standard criteria (3.6%, 7/192 versus 2.7%, 5/186,
P
=NS).

Conclusions
An abnormal ST/HR index identifies men in whom therapy aimed at reducing CHD risk factors reduces the risk of CHD death by 61%. These findings support the application of heart rate adjustment of ST depression for screening of asymptomatic subjects at increased risk of CHD to identify those who will benefit most from risk factor–reduction programs.
\E Induction of Meandering Functional Reentrant Wave Front in Isolated Human Atrial Tissues
Authors: Ikeda Takanori , Czer Lawrence , Trento Alfredo , Hwang Chun , Ong James J. C. , Hough Dustan , Fishbein Michael C. , Mandel William J. , Karagueuzian Hrayr S. , Chen Peng-Sheng
Published: June 2012

Background
The purpose of this study was to test the hypothesis that a single meandering functional reentrant wave front can result in rapid and irregular electrogram activity in human atrial tissues.

Methods and Results
The study used the explanted hearts of five human cardiac transplant recipients. Three right and two left atrial tissue samples, 3.4±0.3 mm thick, were excised and trimmed to 3.5×3.0 cm. The isolated atrium was placed endocardial surface down in a chamber with a 477 bipolar recording electrode array built into the bottom of the tissue bath. The interelectrode distance was 1.6 mm. The tissue was constantly superfused with 36.5°C oxygenated Tyrode’s solution at a rate of 10 mL/min. After eight baseline stimuli (S
1
) delivered at 400- or 600-ms cycle length from the edge of the tissue, a single premature stimulus (S
2
) was given at the center of the tissue to induce reentry. A total of nine episodes of reentry were induced with S
1
-S
2
coupling intervals of 232±29 ms (range, 190 to 290 ms) and an S
2
strength of 10±3 mA (range, 5 to 15 mA). In all samples, a single meandering reentrant wave front was induced, causing irregular and rapid bipolar electrogram activity. These wave fronts had a mean cycle length of 229±45 ms (160 to 290 ms) and persisted for 1.1±0.3 seconds (0.6 seconds to 2.5 seconds), or 5.2±1.4 (3 to 9) cycles, before spontaneous termination.

Conclusions
A single meandering functional reentrant wave front can be induced in human atrial tissues and produce rapid and irregular electrical activity.
Ischemic Preconditioning Does Not Protect Against Contractile Dysfunction in the Presence of Residual Flow
Authors: Cave Alison C. , Silverman Adam S. , Apstein Carl S.
Published: June 2012

Background
We have previously demonstrated that ischemic preconditioning (PC) does not protect when oxygen deprivation is accompanied by a high level of perfusion (hypoxia). Since clinical ischemia can vary from mild to severe, we wished to determine whether PC could protect against injury arising from low-flow ischemia.

Methods and Results
Functional recovery after 30 minutes of reperfusion was assessed in isolated, blood-perfused rat hearts (n=6 per group) subjected to (A) 30 minutes of zero-flow ischemia, (B) 30 minutes of zero-flow ischemia preceded by 3×PC (PC=5 minutes of ischemia+5 minutes of reperfusion), (C) 90 minutes of low-flow ischemia at 10% of baseline coronary flow (0.31±0.02 mL/min per gram wet wt), (D) 90 minutes of low-flow ischemia at 10% of baseline coronary flow (0.29±0.02 mL/min per gram wet wt) preceded by 3×PC. PC significantly protected against injury resulting from zero-flow ischemia (developed pressure recovered to 67±6% versus 31±12% in B and A, respectively;
P
<.05) but not resulting from low-flow ischemia (recovery of developed pressure was 40±8% versus 37±7% in C and D, respectively). Protein kinase C (PKC) is widely considered to be involved in the mechanism of PC such that prior activation and translocation of PKC by the PC protocol allows phosphorylation of the end-effector protein early during the subsequent ischemic insult, before loss of adenosine triphosphate occurs. However, because adenosine triphosphate content falls slowly during low-flow ischemia, PKC may be activated and translocated early enough to be active during this insult. If so, inhibition of PKC should decrease functional recovery in the control group. However, functional recovery in control groups was not decreased in the presence of the PKC inhibitor polymyxin B (50±6%), suggesting that if activation of PKC occurred during low-flow ischemia, it was not protective.

Conclusions
PC does not protect against contractile dysfunction in the rat when a low level (10% of baseline flow) of ischemic perfusion remains during the prolonged insult.
Conjugated Estrogens Acutely Abolish Abnormal Cold-Induced Coronary Vasoconstriction in Male Cardiac Allografts
Authors: Reis Steven E. , Bhoopalam Vishwajeth , Zell Kathleen A. , Counihan Peter J. , Smith A. J. Conrad , Pham Si , Murali Srinivas
Published: June 2012

Background
—Transplant-associated coronary arteriopathy is manifested in its early stages by paradoxical coronary artery constriction in response to endothelium-dependent vasodilator stimuli such as the cold pressor test (CPT) and is a major cause of death or retransplantation. Estrogen has vasoactive properties that abolish coronary artery endothelial dysfunction in native hearts. We hypothesized that estrogen attenuates inappropriate coronary artery constriction in cardiac allografts.

Methods and Results
—Coronary artery diameter and systemic hemodynamic responses to a 90-second CPT were measured before and 15 minutes after double-blind, randomized administration of intravenous conjugated estrogens (1.25 mg) or placebo in men with male cardiac allografts. Before estrogen, 9 men exhibited an abnormal 15.1±3.0% CPT-induced decrease in coronary artery diameter. However, repeat CPT did not induce significant coronary artery constriction when performed 15 minutes after estrogen. CPT responses before and after estrogen were significantly different (
P
=.02). Placebo did not influence coronary artery responses to CPT in 6 men. Systemic hemodynamic responses to CPT were not influenced by estrogen or placebo. Estrogen was the only significant determinant of changes in coronary artery responses to CPT.

Conclusions
—Conjugated estrogens acutely abolish abnormal CPT-induced coronary artery constriction in male cardiac allografts. This favorable vasomotor effect suggests that estrogen may prevent inappropriate coronary artery constriction in men with cardiac transplants.
Echo-Lucency of Computerized Ultrasound Images of Carotid Atherosclerotic Plaques Are Associated With Increased Levels of Triglyceride-Rich Lipoproteins as Well as Increased Plaque Lipid Content
Authors: Grønholdt Marie-Louise M. , Nordestgaard Børge G. , Wiebe Britt M. , Wilhjelm Jens E. , Sillesen Henrik
Published: June 2012

Background
—Echo-lucency of carotid atherosclerotic plaques on computerized ultrasound B-mode images has been associated with a high incidence of brain infarcts as evaluated on CT scans. We tested the hypotheses that triglyceride-rich lipoproteins in the fasting and postprandial state predict carotid plaque echo-lucency and that echo-lucency predicts a high plaque lipid content.

Methods and Results
—The study included 137 patients with neurological symptoms and ≥50% stenosis of the relevant carotid artery. High-resolution B-mode ultrasound images of carotid plaques were computer processed to yield a measure of echogenicity (gray-scale level). Lipoproteins were measured before and hourly for 4 hours after a standardized fatty meal. A subgroup of 58 patients underwent endarterectomy. On linear regression analysis, echo-lucency (low gray-scale level) was associated with elevated levels of fasting and postprandial plasma triglycerides (
P
=.0002 and
P
=.002), IDL cholesterol (
P
=.0009 and
P
=.006), and VLDL/chylomicron remnant cholesterol (
P
=.0003 and
P
=.0004) and triglycerides (
P
=.0003 and
P
=.003), the area under the plasma triglyceride curve 0 to 4 hours after a fatty meal (
P
=.001), and body mass index (
P
=.0001). On ANCOVA, body mass index, fasting IDL cholesterol, and fasting plasma triglycerides were independent predictors of echo-lucency. Echo-lucency was associated with increased relative plaque lipid content (
P
=.02).

Conclusions
—Increased plasma levels of triglyceride-rich lipoproteins predict echo-lucency of carotid plaques, which is associated with increased plaque lipid content. Because echo-lucency has been associated with a high incidence of brain infarcts on CT scans, triglyceride-rich lipoproteins may predict a plaque type particularly vulnerable to rupture.
Reversal of Abnormal Coronary Vasomotion by Calcium Antagonists in Patients With Hypercholesterolemia
Authors: Kaufmann Philipp A. , Frielingsdorf Jürgen , Mandinov Lazar , Seiler Christian , Hug Rosy , Hess Otto M.
Published: June 2012

Background
—It has been shown that exercise-induced coronary vasodilation of angiographically normal coronary vessels is reduced in hypercholesterolemic patients. The purpose of this study was to evaluate the effect of calcium channel blockers on coronary vasomotion of angiographically smooth coronary arteries in hypercholesterolemic patients.

Methods and Results
—A total of 57 patients were included in the present analysis. Vasomotion of angiographically normal coronary arteries was evaluated in 37 control subjects (group 1) without and 20 patients (group 2) with calcium blocker administration before physical exercise. Both groups were subdivided into subgroup A (normal cholesterol values: ≤5.5 mmol/L or 212 mg%) and subgroup B (elevated cholesterol values: >5.5 mmol/L or 212 mg%). Coronary luminal area at rest and during exercise was assessed by biplane quantitative coronary angiography. The normal vessels showed a significant increase in coronary luminal area during exercise in subgroup A (n=13) with normal cholesterol values (31%;
P
<.05) but not in subgroup B (n=24; 13%;
P
=NS). In contrast, all patients in group 2 showed similar vasodilation during exercise, namely, 22% (
P
<.05) in subgroups A (n=8) and B (n=12) (
P
<.05). Independent of the actual cholesterol level, the stenotic lesions showed coronary vasoconstriction during exercise in group 1 but vasodilation in group 2 after pretreatment with calcium antagonists.

Conclusions
—Coronary vasomotor response to exercise is inversely related to actual serum cholesterol level in angiographically normal vessels. Administration of calcium antagonists normalizes exercise-induced vasodilation and thus eliminates cholesterol-induced abnormal vasomotion, probably by a direct effect on the smooth muscles of the vasculature.
Patent Foramen Ovale Is an Important Predictor of Adverse Outcome in Patients With Major Pulmonary Embolism
Authors: Konstantinides Stavros , Geibel Annette , Kasper Wolfgang , Olschewski Manfred , Blümel Liane , Just Hanjörg
Published: June 2012

Background
—Right-to-left shunt through a patent foramen ovale is frequently diagnosed by contrast echocardiography and can be particularly prominent in the presence of elevated pressures in the right side of the heart. Its prognostic significance in patients with pulmonary thromboembolism, however, is unknown.

Methods and Results
—The present prospective study included 139 consecutive patients with major pulmonary embolism diagnosed on the basis of clinical, echocardiographic, and cardiac catheterization criteria. All patients underwent contrast echocardiography at presentation. The end points of the study were overall mortality and complicated clinical course during the hospital stay defined as death, cerebral or peripheral arterial thromboembolism, major bleeding, or need for endotracheal intubation or cardiopulmonary resuscitation. Patent foramen ovale was diagnosed in 48 patients (35%). These patients had a death rate of 33% as opposed to 14% in patients with a negative echo-contrast examination (
P
=.015). Logistic regression analysis demonstrated that the only independent predictors of mortality in the study population were a patent foramen ovale (odds ratio [OR], 11.4;
P
<.001) and arterial hypotension at presentation (OR, 26.3;
P
<.001). Patients with a patent foramen ovale also had a significantly higher incidence of ischemic stroke (13% versus 2.2%;
P
=.02) and peripheral arterial embolism (15 versus 0%;
P
<.001). Overall, the risk of a complicated in-hospital course was 5.2 times higher in this patient group (
P
<.001).

Conclusions
—In patients with major pulmonary embolism, echocardiographic detection of a patent foramen ovale signifies a particularly high risk of death and arterial thromboembolic complications.
Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme
Authors: Ribichini Flavio , Steffenino Giuseppe , Dellavalle Antonio , Matullo Giuseppe , Colajanni Elena , Camilla Terenzio , Vado Antonello , Benetton Gabriella , Uslenghi Eugenio , Piazza Alberto
Published: June 2012

Background
—Tissue proliferation is almost invariably observed in recurrent lesions within stents, and ACE, a factor of smooth muscle cell proliferation, may play an important role. Plasma ACE level is largely controlled by the insertion/deletion (
I/D
) polymorphism of the enzyme gene. The association among restenosis within coronary stents, plasma ACE level, and the
I/D
polymorphism is analyzed in the present prospective study.

Methods and Results
—One hundred seventy-six consecutive patients with successful, high-pressure, elective stenting of de novo lesions in the native coronary vessels were considered. At follow-up angiography, recurrence was observed in 35 patients (19.9%). Baseline clinical and demographic variables, plasma glucose and serum fibrinogen levels, lipid profile, descriptive and quantitative angiographic data, and procedural variables were not significantly different in patients with and without restenosis; mean plasma ACE levels (±SEM) were 40.8±3.5 and 20.7±1.0 U/L, respectively (
P
<.0001). Diameter stenosis percentage and minimum luminal diameter at 6 months showed statistically significant correlation with plasma ACE level (
r
=.352 and −.387, respectively
P
<.001). Twenty-one of 62 patients (33.9%) with
D/D
genotype, 13 of 80 (16.3%) with
I/D
genotype, and 1 of 34 (2.9%) with
I/I
genotype showed recurrence; the restenosis rate for each genotype is consistent with a codominant expression of the allele
D
.

Conclusions
—In a selected cohort of patients, both the
D/D
genotype of the ACE gene, and high plasma activity of the enzyme are significantly associated with in-stent restenosis. Continued study with clinically different subsets of patients and various stent designs is warranted.
Posterior Extensions of the Human Compact Atrioventricular Node
Authors: Inoue Shin , Becker Anton E.
Published: June 2012

Background
—Catheter ablation procedures have revived interest in the detailed anatomy of the specialized atrioventricular (AV) septal junctional area. The compact AV node usually is considered to have a blunt posterior end. The objective of this study was to reconstruct the human compact AV node in relation to the landmarks of Koch’s triangle, with emphasis on its posterior extension.

Methods and Results
—In 21 hearts obtained from autopsies, the AV nodal septal junctional area was removed en bloc, serially sectioned, and reconstructed. None of the hearts showed a blunt posterior ending of the compact AV node; 13 showed posterior extensions on both the right and left sides; 7 had a rightward posterior extension only; and 1 heart showed a single leftward extension. Hence, a rightward posterior extension was present in 20 of 21 hearts. Furthermore, in 16 of these 20 hearts, the rightward extension continued to the level of the coronary sinus ostium; in 7, the bundle extended beyond this anatomic landmark. The mean length of the right posterior extension was 4.4±2.0 mm; that of the leftward posterior extension was 1.8±0.9 mm. Superimposed onto the slope of the muscular AV septum, viewed from the right atrium, the rightward extension ran close to the tricuspid annulus with the leftward extension positioned superiorly.

Conclusions
—The human compact AV node contains rightward and leftward posterior extensions, with the right extension close to the tricuspid annulus. It is tempting to speculate that these extensions are involved in “slow pathway” conduction.
Colchicine Treatment for Recurrent Pericarditis
Authors: Adler Y. , Finkelstein Y. , Guindo J. , Rodriguez de la Serna A. , Shoenfeld Y. , Bayes-Genis A. , Sagie A. , Bayes de Luna A. , Spodick D. H.
Published: June 2012

Background
—The most troublesome complication of acute pericarditis is recurrent episodes of pericardial inflammation, occurring in 15% to 32% of cases. The cause of the recurrence is usually unknown, although in some cases it may be traced to viral infection or may be a consequence of coronary artery bypass grafting. The optimal method for prevention has not been fully established; accepted modalities include nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, and pericardiectomy.

Methods and Results
—Based on the proven efficacy of colchicine therapy for familial Mediterranean fever (recurrent polyserositis), several small studies have used colchicine successfully to prevent recurrence of acute pericarditis after failure of conventional treatment. Recently, we reported the results from the largest multicenter international study on 51 patients who were treated with colchicine to prevent further relapses and who were followed up for ≤10 years.

Conclusions
—In light of new trial data that have accumulated in the past decade, we review the evidence for the efficacy and safety of colchicine for the prevention of recurrent episodes of pericarditis. Clinical and personal experience shows that colchicine may be an extremely promising adjunct to conventional treatment and may ultimately serve as the initial mode of treatment, especially in idiopathic cases.
Application of Serial In Vivo Magnetic Resonance Imaging to Evaluate the Efficacy of Endothelin Receptor Antagonist SB 217242 in the Rat Carotid Artery Model of Neointima Formation
Authors: Chandra Sudeep , Clark Lynne V. , Coatney Robert W. , Phan Le , Sarkar Susanta K. , Ohlstein Eliot H.
Published: June 2012

Background
—Alleviating vascular restenosis after percutaneous transluminal angioplasty remains a formidable challenge. Although multiple factors have been implicated in the pathophysiology of this vascular remodeling disorder, only limited therapeutic success has been achieved. Endothelin (ET)-1 has recently been implicated in the pathogenesis of neointimal growth. We report the in vivo efficacy of SB 217242, a nonpeptide dual ET
A
/ET
B
receptor antagonist with high oral bioavailability, in the rat carotid artery balloon angioplasty model.

Methods and Results
—The lumen volumes of carotid arteries were estimated serially with magnetic resonance imaging (MRI) at baseline and at day 7 and day 14 after balloon catheter–induced denudation of the carotid arterial wall in the rat. Histomorphometric analysis was performed at day 14 after surgery to quantitate intimal hyperplasia. Statistical analysis was performed with ANOVA followed by post hoc Newman-Keuls multiple comparison test. In comparison to vehicle-treated animals, a 20% protection (
P
<0.05) from reduction was shown in the estimated lumen volume with long-term administration of SB 217242 (15 mg/kg BID PO). Histologic analyses indicated a 42% decrease (
P
<0.05) in neointimal growth. The MRI lumen volumes had a significant correlation with the corresponding histologic indices.

Conclusions
—Serial MRI provides the opportunity to assess the progression of vascular lumen volume in vivo after balloon angioplasty. MRI measurements can, in conjunction with in vitro histologic measurements, contribute to the understanding of the actions of pharmacologic agents in experimental models of neointima formation. With the use of serial MRI and histologic measurements, it is demonstrated that protection from both lumen volume reduction and neointima formation is obtained in this model by use of a potent, nonpeptide dual ET
A
/ET
B
receptor antagonist, SB 217242. Furthermore, this study provides additional support to the implication of ET-1 in the pathophysiology of neointima formation.
Angiographic Assessment of Myocardial Reperfusion in Patients Treated With Primary Angioplasty for Acute Myocardial Infarction
Authors: van ‘t Hof Arnoud W.J. , Liem Aylee , Suryapranata Harry , Hoorntje Jan C.A. , de Boer Menko-Jan , Zijlstra Felix
Published: June 2012

Background
—The primary objective of reperfusion therapies for acute myocardial infarction is not only restoration of blood flow in the epicardial coronary artery but also complete and sustained reperfusion of the infarcted part of the myocardium.

Methods and Results
—We studied 777 patients who underwent primary coronary angioplasty during a 6-year period and investigated the value of angiographic evidence of myocardial reperfusion (myocardial blush grade) in relation to the extent of ST-segment elevation resolution, enzymatic infarct size, left ventricular function, and long-term mortality. The myocardial blush immediately after the angioplasty procedure was graded by two experienced investigators, who were otherwise blinded to all clinical data: 0, no myocardial blush; 1, minimal myocardial blush; 2, moderate myocardial blush; and 3, normal myocardial blush. The myocardial blush was related to the extent of the early ST-segment elevation resolution on the 12-lead ECG. Patients with blush grades 3, 2, and 0/1 had enzymatic infarct sizes of 757, 1143, and 1623 (
P
<0.0001), respectively, and ejection fractions of 50%, 46%, and 39%, respectively (
P
<0.0001). After a mean±SD follow-up of 1.9±1.7 years, mortality rates of patients with myocardial blush grades 3, 2, and 0/1 were 3%, 6%, and 23% (
P
<0.0001), respectively. Multivariate analysis showed that the myocardial blush grade was a predictor of long-term mortality, independent of Killip class, Thrombolysis In Myocardial Infarction grade flow, left ventricular ejection fraction (LVEF), and other clinical variables.

Conclusions
—In patients after reperfusion therapy, the myocardial blush grade as seen on the coronary angiogram can be used to describe the effectiveness of myocardial reperfusion and is an independent predictor of long-term mortality.
Endothelin-1 Inhibits Endothelin-Converting Enzyme-1 Expression in Cultured Rat Pulmonary Endothelial Cells
Authors: Naomi Shojiro , Iwaoka Taisuke , Disashi Tumba , Inoue Junnosuke , Kanesaka Yoshie , Tokunaga Hiroshi , Tomita Kimio
Published: June 2012

Background
—The lung expresses large amounts of endothelin-converting enzyme-1 (ECE-1), which catalyzes a step in the biosynthesis of potent vasoactive endothelin-1 (ET-1) from the inactive intermediate big ET-1. Because there has been no report concerning a possible relationship between ET-1 and ECE-1, we investigated the effects of ET-1 on ECE-1 expression in cultured rat pulmonary endothelial cells.

Methods and Results
—ECE-1 messenger RNA (mRNA) and protein expression in cultured endothelial cells were assayed by Northern and Western blotting, respectively. Incubation with ET-1 for 6 hours caused a significant decrease in ECE-1 mRNA expression. The action of ET-1 on ECE-1 mRNA expression was antagonized by pretreatment with BQ788, a specific ETB receptor antagonist, but not by pretreatment with BQ123, a specific ETA receptor antagonist. The expression of ECE-1 protein was also inhibited at 6 hours after incubation with ET-1. The effects of ET-1 on ECE-1 mRNA and protein expression were shown to be mimicked by ionomycin, a calcium ionophore, but not by 12-
O
-tetradecanoylphorbol 13-acetate, a protein kinase C activator.

Conclusions
—The present results demonstrate that ET-1 suppressed ECE-1 protein levels by inhibiting ECE-1 mRNA expression through the ETB receptor, suggesting the existence of a feedback action of ET-1 on ECE-1 in pulmonary endothelial cells.
Attenuation of Ischemia/Reperfusion Injury in Rats by a Caspase Inhibitor
Authors: Yaoita Hiroyuki , Ogawa Kazuei , Maehara Kazuhira , Maruyama Yukio
Published: June 2012

Background
—Z-Val-Ala-Asp(OMe)-CH
2
F (ZVAD-fmk), a tripeptide inhibitor of the caspase interleukin-1β–converting enzyme family of cysteine proteases, may reduce myocardial reperfusion injury in vivo by attenuating cardiomyocyte apoptosis within the ischemic area at risk.

Methods and Results
—Sprague-Dawley rats were subjected to a 30-minute coronary occlusion followed by a 24-hour reperfusion. An inert vehicle (dimethylsulfoxide; group 1, n=8) or ZVAD-fmk, at a total dose of 3.3 mg/kg (group 2, n=8), was administered intravenously every 6 hours starting at 30 minutes before coronary occlusion until 24 hours of reperfusion. At this 24-hour point, hemodynamics were assessed by means of cardiac catheterization; then, the rats were killed, and the left ventricle was excised and sliced. The myocardial infarct size/ischemic area at risk and the count of presumed apoptotic cardiomyocytes (terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling [TUNEL]-positive cells) within the ischemic area at risk were assessed through triphenyltetrazolium chloride staining and TUNEL methods, respectively. Peak positive left ventricular dP/dt was higher (
P
=.02) and left ventricular end-diastolic pressure was lower (
P
=.04) in group 2 than in group 1. The infarct size/ischemic area at risk of group 2 (52.4±4.0%) was smaller (
P
=.02) than that of group 1 (66.6±3.7%), and TUNEL-positive cells were fewer (
P
=.0002) (group 2, 3.1±0.9%; group 1, 11.1±1.0%). Agarose gel electrophoresis revealed DNA laddering in the border zone myocardium of group 1, but DNA ladder formation was attenuated in group 2.

Conclusions
—ZVAD-fmk was effective in reducing myocardial reperfusion injury, which could at least be partially attributed to the attenuation of cardiomyocyte apoptosis.
Ultrasonic Tissue Characterization Predicts Myocardial Viability in Early Stage of Reperfused Acute Myocardial Infarction
Authors: Takiuchi Shin , Ito Hiroshi , Iwakura Katsuomi , Taniyama Yoshiaki , Nishikawa Nagahiro , Masuyama Tohru , Hori Masatsugu , Higashino Yorihiko , Fujii Kenshi , Minamino Takazo
Published: June 2012

Background
—The aim of the present study was to characterize temporal changes in cyclic variation of ultrasonic integrated backscatter (IBS), which reflects intrinsic contractile performance, in patients with reperfused acute myocardial infarction (AMI) and to elucidate the clinical value of tissue characterization in predicting myocardial viability.

Methods and Results
—We recorded short-axis IBS images before and 3, 7, and 21 days after reperfusion in 26 patients with AMI and obtained the cyclic variation of IBS in the normal and infarct zones. When cyclic variation showed synchrony and asynchrony, we expressed its magnitude as positive and negative values, respectively, called the phase-corrected magnitude. We also measured average wall motion score (dyskinesis, 4; normal, 0) of the infarct segments. The phase-corrected magnitude was lower in the infarct zone than in the normal zone before reperfusion (0.3±2.5 versus 5.2±1.7 dB,
P
<.05). At day 3, the phase-corrected magnitude increased by 2.1±2.6 dB despite no improvement in wall motion. Improvement in wall motion was observed only at day 21. The patients with the phase-corrected magnitude of ≥2.0 dB at day 3 showed significantly lower wall motion score at day 21 than did the other patients (1.7±0.6 versus 2.4±0.5,
P
<.01).

Conclusions
—In patients with AMI, cyclic variation of IBS is blunted during ischemia but recovers much faster after reperfusion than the improvement in wall motion. The greater phase-corrected magnitude at day 3 may be a predictor of better functional improvement.
Right Bundle-Branch Block and ST-Segment Elevation in Leads V
1
Through V
3
Authors: Brugada Josep , Brugada Ramon , Brugada Pedro
Published: June 2012

Background
—Five years ago, we described a specific ECG pattern of right bundle-branch block and ST-segment elevation in leads V
1
through V
3
associated with sudden death in patients without demonstrable structural heart disease. Information on long-term outcome has become available due to pooled data on a large cohort of patients with this syndrome who are followed at 33 centers worldwide.

Methods and Results
—Data on 63 patients (57 men; mean age, 38±17 years) with the described ECG pattern were analyzed in terms of arrhythmic events and sudden death. Events were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (symptomatic patients, n=41) and for patients in whom the ECG pattern was recognized by chance or because of screening related to sudden death of a relative (asymptomatic patients, n=22). During a mean follow-up of 34±32 months, an arrhythmic event occurred in 14 symptomatic patients (34%) and 6 asymptomatic patients (27%). An automatic defibrillator was implanted in 35 patients, 15 received pharmacological therapy with β-blockers and/or amiodarone, and 13 did not receive treatment The incidence of arrhythmic events was similar in all therapy groups (log-rank 0.86); however, total mortality was 0% in the implantable defibrillator group, 26% in the pharmacological group, and 31% in the no therapy group (log-rank 0.0005). All mortality was due to sudden death.

Conclusions
—Patients without demonstrable structural heart disease and an ECG pattern of right bundle-branch block and ST-segment elevation in leads V
1
through V
3
are at risk for sudden death. Amiodarone and/or β-blockers do not protect them against sudden death, and an implantable defibrillator seems to be the present treatment of choice.
Thrombin-Induced Mitogenesis in Coronary Artery Smooth Muscle Cells Is Potentiated by Thromboxane A
2
and Involves Upregulation of Thromboxane Receptor mRNA
Authors: Zucker T.-Ph. , Bönisch D. , Muck S. , Weber A.-A. , Bretschneider E. , Glusa E. , Schrör K.
Published: June 2012

Background
—Previous studies have shown that thrombin is a potent though slow-acting mitogen for vascular smooth muscle cells (SMC). Because thrombin generation in vivo is accompanied by platelet activation, it has been suggested that platelet-derived factors might enhance thrombin-induced SMC proliferation. No information is available so far on the possible role of thromboxane A
2
.

Methods and Results
—Thrombin (1 U/mL) caused a threefold to fourfold increase of DNA synthesis in cultured bovine coronary artery SMC as assessed from [
3
H]thymidine incorporation. U 46619, a stable thromboxane A
2
mimetic, had only a minor stimulating effect on its own but potentiated the thrombin effect sixfold to sevenfold above control (
P
<.05). These findings were paralleled by a 52±5% (
P
<.05) increase in cell number at 48 hours after addition of both mitogens as compared with 24±5% with thrombin alone and no change with U 46619 alone. Thromboxane A
2
receptor mRNA was found to be upregulated sixfold 20 minutes after thrombin stimulation. Pretreatment of SMC with thrombin for 4 hours markedly increased U 46619–induced mitogen-activated protein kinase activity, indicating thrombin-induced upregulation of functional thromboxane receptors in SMC.

Conclusions
—Thrombin-induced proliferation of SMC is markedly enhanced by thromboxane A
2
. This might result in an enhancement of SMC proliferation by platelet-derived thromboxane A
2
in vivo.
Aspirin Improves Endothelial Dysfunction in Atherosclerosis
Authors: Husain Syed , Andrews Neil P. , Mulcahy David , Panza Julio A. , Quyyumi Arshed A.
Published: June 2012

Background
—The beneficial effects of aspirin in atherosclerosis are generally attributed to its antiplatelet activities, but its influence on endothelial function remains uncertain. We hypothesized that a cyclooxygenase-dependent constricting factor contributes to the endothelial dysfunction in atherosclerosis and that its action can be reversed by aspirin.

Methods and Results
—In 14 patients with coronary atherosclerosis and 5 with risk factors, we tested femoral vascular endothelial function with acetylcholine and substance P and endothelium-independent function with sodium nitroprusside before and after intravenous aspirin. Drugs were infused into the femoral artery, and Doppler flow velocity was measured. Acetylcholine-induced but not substance P–or sodium nitroprusside–induced vasodilation was lower in patients with atherosclerosis than in those with only risk factors. Aspirin had no baseline effect but improved acetylcholine-mediated vasodilation only in patients with atherosclerosis; at the peak dose, acetylcholine-mediated femoral vascular resistance index was 19±5%,
P
=.002 lower. There was a correlation between the baseline response to acetylcholine and the magnitude of improvement with aspirin (
r
=.5,
P
=.05). Thus, patients with a depressed response to acetylcholine had greater improvement with aspirin, and vice versa. The presence of atherosclerosis was an independent determinant of improvement with aspirin. Aspirin had no effect on the responses to either substance P or sodium nitroprusside.

Conclusions
—Cyclooxygenase-dependent, endothelium-derived vasoconstrictor release modulates acetylcholine-induced peripheral vasodilation in patients with atherosclerosis. Improvement of endothelial dysfunction with aspirin may improve vasodilation, reduce thrombosis, and inhibit progression of atherosclerosis and provides a pathophysiological basis for the beneficial effects of aspirin in atherosclerosis.
Coronary Artery Responses to Physiological Stimuli Are Improved by Deferoxamine but not by
l
-Arginine in Non–Insulin-Dependent Diabetic Patients With Angiographically Normal Coronary Arteries and No Other Risk Factors
Authors: Nitenberg Alain , Paycha Frédéric , Ledoux Séverine , Sachs Régis , Attali Jean-Raymond , Valensi Paul
Published: June 2012

Background
—Acetylcholine produces coronary artery (CA) constriction in diabetic patients, suggesting an impairment of endothelium-dependent dilation. In diabetes, multiple metabolic abnormalities may inactivate nitric oxide through oxygen free radical production.

Methods and Results
—To examine the mechanism of this abnormal response, two physiological tests (ie, a cold pressor test [CPT] and coronary flow increase induced by an injection of 10 mg papaverine [PAP] in the distal left anterior descending CA) were performed before and after either intravenous
l
-arginine (625 mg/min×10 minutes) or intravenous deferoxamine (50 mg/min×10 minutes) in 22 normotensive nonsmoking diabetic patients with angiographically normal CAs and normal cholesterol. Coronary surface areas were measured with quantitative angiography. Before the administration of
l
-arginine or deferoxamine, CPT induced CA constriction in both groups (−14±10% and −15±11%, respectively; each
P
<.001), and PAP injection in distal LAD did not modify significantly proximal LAD dimensions. In the 10 diabetic patients receiving
l
-arginine, responses to CPT and PAP were not modified. Conversely, in the 12 patients receiving deferoxamine, CA dilated in response to the two tests (+10±9% after CPT and +22±7% after PAP, each
P
<.001). Intracoronary isosorbide dinitrate, an endothelium-independent dilator, produced similar dilation in the two groups (+47±19% and +41±15%, respectively; each
P
<.001).

Conclusions
—This study shows that (1) responses of angiographically normal CAs to CPT and to flow increase are impaired in diabetic patients; (2) abnormal responses are not improved by
l
-arginine, suggesting that a deficit in substrate for nitric oxide synthesis is not involved; and (3) deferoxamine restores a vasodilator response to the two tests, suggesting that inactivation of NO by oxygen species might be partly responsible for the impairment of CA dilation in diabetic patients.
Tachycardia Preconditions Infarct Size in Dogs
Authors: Domenech Raúl J. , Macho Pilar , Vélez Diego , Sánchez Gina , Liu Xueliang , Dhalla Naranjan
Published: June 2012

Background
—Myocardial ischemic preconditioning is a well-known phenomenon, however there is scant information in regard to nonischemic preconditioning.

Methods and Results
—We studied in anesthetized dogs the preconditioning effect of tachycardia and the mediation of adenosine and protein kinase C in this process. In a control group the anterior descending coronary artery was occluded for 60 minutes and reperfused for 270 minutes. Heart rate was kept constant at 120±5 cycles/min and aortic pressure changes were damped. The infarct size (necrotic volume/risk region volume×100) was 15.8±1.5%. In another group of dogs a similar protocol was followed, but five periods of tachycardia (213±12 cycles/min), 5 minutes in duration each, with 5 minutes of intervening periods at control heart rate, were induced previous to the coronary occlusion. The infarct size was reduced by 46% (
P
<.001) with respect to the nonpreconditioned group. This effect was not due to changes in collateral flow nor risk region size. During tachycardia, myocardial interstitial adenosine increased about twofold (
P
<.05); no metabolic, hemodynamic, or ECG evidences of ischemia were observed and the transmural vasodilatory reserve was preserved. The blockade of adenosine receptors with 8 phenyltheophylline, before or after the preconditioning tachycardia, reverted its protecting effect but it did not modify infarct size in nonpreconditioned dogs. No changes in cytosolic or particulate protein kinase C activity or translocation of α-, β-, ε-, and ζ- protein kinase C isozyme by effect of tachycardia or ischemia were observed between preconditioned and nonpreconditioned dogs.

Conclusions
—Tachycardia, in the absence of ischemia, mimics the preconditioning effect of ischemia in the dog. This effect is mediated by adenosine but not by changes in protein kinase C activity or its translocation.
Cell Cycle Progression
Authors: Braun-Dullaeus Ruediger C. , Mann Michael J. , Dzau Victor J.
Published: June 2012

Abstract
—Entry into and progression of vascular cells through the cell cycle is considered a key event in vascular proliferative diseases. Multiple growth factors and cytokines have been found to regulate vascular cell proliferation. However, the machinery regulating cell cycle represents the “final common pathway” of these signaling cascades and thus provides an attractive therapeutic target for the prevention of vascular proliferative diseases. This review focuses on the current understanding of the regulation of the cell cycle machinery especially as it relates to vascular cell biology and the feasibility of targeting cell cycle for the prevention of restenosis after balloon angioplasty and bypass vein graft disease.
Percutaneous Transluminal Coronary Angioplasty Reverses Vasoconstriction of Stenotic Coronary Arteries in Hypertensive Patients
Authors: Frielingsdorf Jürgen , Kaufmann Philipp , Suter Thomas , Hug Rosy , Hess Otto M.
Published: June 2012

Background
—Endothelial dysfunction of coronary arteries with impaired vasodilation has been reported in patients with arterial hypertension. However, the effect of dynamic exercise on coronary vasomotion of a stenotic vessel segment before and after PTCA has not yet been evaluated in these patients.

Methods and Results
—Coronary vasomotion of a normal and a stenotic vessel segment was studied in 39 patients with coronary artery disease during supine bicycle exercise before and 9±3 months after PTCA. Luminal area changes were determined by biplane quantitative coronary arteriography. There were 21 normotensive and 18 hypertensive patients who did not differ with regard to clinical characteristics. Percent area stenosis decreased after PTCA from 90% to 39% (
P
<0.001) in normotensive and from 86% to 33% (
P
<0.001) in hypertensive patients. Exercise-induced vasomotion of the normal vessel segment was significantly different between normotensives and hypertensives before (+19% versus +1%,
P
<0.01) and after (+16% versus +3%,
P
<0.01) PTCA. In contrast, stenotic vessel segments showed vasoconstriction in both normotensive and hypertensive patients (Δexercise, −11% versus – 20%,
P
=NS), which was reversed after PTCA (+3% versus +2%,
P
=NS).

Conclusions
—Normal coronary arteries show reduced vasodilation during exercise in hypertensive patients that may be explained by the presence of endothelial dysfunction. Stenotic vessels demonstrate paradoxical vasoconstriction during exercise in both normotensive and hypertensive patients. PTCA reverses vasoconstriction by elimination of the flow-limiting stenosis and prevention of coronary stenosis narrowing during exercise in normotensive and hypertensive patients.
Transfection of Inducible Nitric Oxide Synthase Gene Causes Apoptosis in Vascular Smooth Muscle Cells
Authors: Iwashina Masatora , Shichiri Masayoshi , Marumo Fumiaki , Hirata Yukio
Published: June 2012

Background
—Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in a variety of physiological processes including vascular remodeling. To elucidate whether endogenous NO generated by iNOS is involved in the programmed cell death (apoptosis) of the vasculature, iNOS cDNA– expressing construct was transfected into rat and human vascular smooth muscle cells (VSMCs) by lipofection.

Methods and Results
—VSMCs transiently transfected with iNOS cDNA functionally expressed 130 kd iNOS protein with full catalytic activity to generate massive NO in proportion to the doses of cDNA used; its enzymatic activity as well as NO production was completely blocked by an NOS inhibitor,
N
G
-monomethyl-
l
-arginine (LNMMA). Overexpression of iNOS led to a marked inhibition of DNA synthesis as well as induction of apoptosis in VSMCs. Evidence for apoptotic cell death was provided by internucleosomal DNA fragmentation by agarose gel electrophoresis, positive staining for TdT-mediated dUTP biotin nick end-labeling, and appearance of hypodiploid cells by flow cytometry analysis. Apoptosis after transfection with iNOS cDNA was abrogated by LNMMA. Transfection of iNOS cDNA caused accumulation of the tumor suppressor gene
p53
but not of
bcl-2
, which was also blocked by LNMMA.

Conclusions
—These results demonstrate that massive generation of endogenous NO derived from iNOS overexpression leads to a marked apoptosis in VSMCs, thus suggesting an important role of NO as a proapoptotic factor for VSMCs in the process of vascular remodeling.
Atrioventricular Conduction During Long-Term Follow-Up of Patients With Sick Sinus Syndrome
Authors: Andersen Henning Rud , Nielsen Jens Cosedis , Thomsen Poul Erik Bloch , Thuesen Leif , Vesterlund Thomas , Pedersen Anders Kirstein , Mortensen Peter Thomas
Published: June 2012

Background
—It has been claimed that patients with sick sinus syndrome have an increased risk of developing AV block, but this has never been assessed prospectively. The aim of the present study was to evaluate in a prospective trial AV conduction during the long-term follow-up of patients with sick sinus syndrome.

Methods
—Two hundred twenty-five consecutive patients with sick sinus syndrome and intact AV conduction were randomized to undergo single-chamber atrial pacing (110 patients) or single-chamber ventricular pacing (115 patients). Follow-up after 3 months and then yearly included measurement of the PQ interval and, in patients with atrial pacemakers, determination of the atrial stimulus–Q intervals at pacing rates of 100 and 120 bpm. The occurrence of AV block in the atrial group was recorded. During follow-up (mean, 5.5±2.4 years), there was no change in PQ interval in either group and no change in atrial stimulus–Q intervals or Wenckebach block point in the atrial group. Four of 110 patients in the atrial group developed grade 2 to 3 AV block that required upgrading of the pacemaker (0.6% per year). Two of these 4 patients had right bundle-branch block at pacemaker implantation.

Conclusions
—AV conduction, estimated as PQ interval and atrial stimulus–Q interval at atrial pacing rates of 100 and 120 bpm and the Wenckebach block point, remains stable during long-term follow-up. Thus, treatment with single-chamber atrial pacing is safe and can be recommended to patients with sick sinus syndrome without bundle-branch block.