bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Between Lipoproteins and the Progression of Coronary and Vein-Graft Atherosclerosis in a Controlled Trial With Gemfibrozil in Men With Low Baseline Levels of HDL Cholesterol
Authors: Syvänne Mikko , Nieminen Markku S. , Frick M. Heikki , Kauma Heikki , Majahalme Silja , Virtanen Vesa , Kesäniemi Y. Antero , Pasternack Amos , Ehnholm Christian , Taskinen Marja-Riitta
Published: June 2012

Background
—Lipid-lowering secondary-prevention trials of coronary artery disease (CAD) have implicated triglyceride-rich lipoproteins as the main determinants of angiographic progression after elevated LDL cholesterol levels have been lowered with therapy. The present study focuses on the lipoprotein determinants of angiographic CAD progression in men with low HDL cholesterol concentration as their main baseline lipid abnormality who underwent 32 months of randomized therapy with gemfibrozil or placebo.

Methods and Results
—Men who had undergone coronary bypass surgery (n=372) completed a randomized, placebo-controlled study with gemfibrozil 1200 mg/d. They were selected primarily for HDL cholesterol levels that corresponded to the lowest third for middle-aged men. Average baseline lipid and lipoprotein levels were serum triglyceride, 1.60; serum cholesterol, 5.17; ultracentrifugally separated LDL cholesterol, 3.43; HDL
2
cholesterol, 0.41; and HDL
3
cholesterol, 0.61 mmol/L. In the gemfibrozil group, these levels were reduced on average by 40%, 9%, and 6% or increased by 5% and 9%, respectively. On-trial IDL and LDL triglyceride and cholesterol levels significantly predicted global angiographic progression, taking into account changes in native segments and in bypass grafts. HDL
3
but not HDL
2
cholesterol concentration was associated with protection against progression, especially focal disease in native coronary lesions. VLDL was the lipoprotein most predictive of new lesions in vein grafts; IDL was also significantly related.

Conclusions
—This study expands the previous evidence of the triglyceride-rich lipoproteins, especially IDL, as predictors of angiographic progression of CAD but does not negate the significance of mildly elevated LDL levels. Of the HDL subfractions, only HDL
3
was protective in this group of men selected for their low initial HDL levels.
Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension
Authors: Thürmann Petra A. , Kenedi Peter , Schmidt Andor , Harder Sebastian , Rietbrock Norbert
Published: June 2012

Background
—Left ventricular hypertrophy (LVH) represents an independent risk factor in patients with essential hypertension. Because reversal of LVH may be associated with an improvement of prognosis, the influence of new antihypertensive compounds, such as angiotensin II AT
1
receptor antagonists, on LVH should be determined.

Methods and Results
—In a randomized, double-blind trial, 69 predominantly previously untreated hypertensive patients with echocardiographically proven LVH, ie, left ventricular mass index (LVMI) >134 g/m

2

in men and >110 g/m

2

in women and/or end-diastolic septal thickness >12 mm, received either the angiotensin II antagonist valsartan or atenolol for 8 months. Echocardiographic data of 58 patients were available. After 8 months of valsartan treatment (n=29), LVMI decreased from 127±23 to 106±25 g/m

2

(ratio [
R
]=0.83; 95% CI, 0.79 to 0.87;
P
<0.0001 versus baseline). Under atenolol (n=29), LVMI decreased to a smaller extent, from 127±25 to 117±27 g/m

2

(
R
=0.92; 95% CI, 0.86 to 0.98;
P
=0.0082 versus baseline). The mean reduction of LVMI came to 21 g/m

2

under valsartan and only to 10 g/m

2

under atenolol (
R
=0.91; 90% CI, 0.85 to 0.97 versus atenolol). Baseline mean blood pressure values were determined to be 163±12/101±6 mm Hg before treatment with valsartan and 160±14/103±6 mm Hg before atenolol treatment. After 8 months of treatment, mean blood pressure decreased to 146±13/90±7 mm Hg with valsartan and to 147±18/90±7 mm Hg with atenolol. Nine patients in the valsartan group and 8 patients in the atenolol group required additional medication with hydrochlorothiazide.

Conclusions
—Antihypertensive treatment with the angiotensin II antagonist valsartan for 8 months produced a significant regression of LVH in predominantly previously untreated patients with essential hypertension. The drug may be safely administered in this subset of hypertensive patients; however, the long-term benefit in terms of risk reduction has still to be evaluated in further trials.
Postinfarction Survival and Inducibility of Ventricular Arrhythmias in the Spontaneously Hypertensive Rat
Authors: Nguyen Tan , El Salibi Elias , Rouleau Jean L.
Published: June 2012

Background
—Hypertensive patients with left ventricular hypertrophy (LVH) have been found to have greater peri-infarction and postinfarction mortality. In this study, we evaluated the postinfarction survival, susceptibility to ventricular arrhythmias, and degree of LVH and cardiac fibrosis in the spontaneously hypertensive rat (SHR) and the effects of the ACE inhibitor ramipril and the direct vasodilator hydralazine on these characteristics.

Methods and Results
—An acute myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Rats were randomized to either control (n=50), hydralazine (n=41), or ramipril (n=45). Treatments were started 4 hours after infarction and continued for 8 weeks. Ramipril and hydralazine reduced arterial pressure similarly. Medications were stopped 72 hours before euthanasia, at which time hemodynamic, programmed electrophysiological stimulation (PES), and morphological studies were performed. Mortality was decreased in ramipril (56%) compared with hydralazine (78%) and control (82%) SHRs (
P
=0.008). This was accompanied by a decrease in myocardial hypertrophy and fibrosis and a decrease in inducibility of ventricular arrhythmias by PES in the ramipril group regardless of MI size. Treatment with hydralazine had little or no effect on LVH and cardiac fibrosis and did not modify inducibility of ventricular arrhythmias by PES. Ramipril but not hydralazine prevented the increase in LV end-diastolic pressure in rats with large MIs.

Conclusions
—In the SHR, the ACE inhibitor ramipril reduces LVH, cardiac fibrosis, and susceptibility to ventricular arrhythmias by PES and improves survival and LV function. Despite a similar decrease in arterial pressure, hydralazine does not have these beneficial effects.
Cytokine Gene Expression After Myocardial Infarction in Rat Hearts
Authors: Ono Koh , Matsumori Akira , Shioi Tetsuo , Furukawa Yutaka , Sasayama Shigetake
Published: June 2012

Background
—A large transmural myocardial infarction may initiate structural and geometric changes in the left ventricle that are commonly referred to as remodeling. Progressive, adverse remodeling of the myocardium may lead to ventricular dilatation and congestive heart failure. Recent studies have highlighted the effects of some cytokines on immune-mediated myocyte injury, postischemic myocardial inflammation, and cardiac function. However, studies of the involvement of cytokines in remodeling of the heart are few.

Methods and Results
—In a rat model of myocardial infarction, progressive dilatation of the left ventricular cavity and lack of appropriate hypertrophy of the surviving myocardium were confirmed by transthoracic echocardiography. The relative expression of mRNA for tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the infarcted and noninfarcted myocardium of these rats, as well as in a group of sham-operated animals, was assessed by the technique of quantitative polymerase chain reaction amplification. In the infarcted region, TNF-α, IL-1β, and IL-6 gene expression peaked at 1 week after infarction and decreased rapidly thereafter. In contrast, at 20 weeks after infarction, the gene expression levels of these cytokines remained significantly higher in the noninfarcted than in the infarcted zone or in the myocardium of sham-operated animals. Furthermore, the levels of these cytokines in the noninfarcted region correlated with the left ventricular end-diastolic diameter measured at 8 and 20 weeks after infarction. Among these cytokines, IL-1β expression was highest, and its level correlated well with collagen deposition in the noninfarcted myocardium at 8 and 20 weeks after surgery. At 20 weeks after infarction, immunohistochemical analysis revealed the presence of IL-1β in macrophages, endothelial cells, and vascular smooth muscle cells in the noninfarcted region, whereas no such immunoreactivity was found in the myocardium of sham-operated animals.

Conclusions
—These findings suggest the possible involvement of cytokines during the remodeling process of the noninfarcted left ventricular myocardium.
Anatomic and Functional Characteristics of a Slow Posterior AV Nodal Pathway
Authors: Medkour Djamila , Becker Anton E. , Khalife Karim , Billette Jacques
Published: June 2012

Background
—The AV node is frequently the site of reentrant rhythms. These rhythms arise from a slow and a fast pathway for which the anatomic and functional substratum remain debated. This study proposes a new explanation for dual-pathway physiology in which the posterior nodal extension (PNE) provides the substratum for the slow pathway.

Methods and Results
—The anatomic and functional properties of the PNE were studied in 14 isolated rabbit heart preparations. A PNE was found in all studied preparations. It appeared as an elongated bundle of specialized tissues lying along the lower side of Koch’s triangle between the coronary sinus ostium and compact node. No well-defined boundary separated the PNE, compact node, and lower nodal cell bundle. The electric properties of the PNE were characterized with a premature protocol and surface potential recordings from histologically controlled locations. The PNE showed cycle-length–dependent posteroanterior slow activation with a shorter refractory period (minimum local cycle length) than that of the compact node. During early premature beats resulting in block in transitional tissues, the markedly delayed PNE activation could propagate to maintain or resume nodal conduction and initiate reentrant beats. A shift to PNE conduction resulted in different patterns of discontinuity on conduction curves. Transmembrane action potentials recorded from PNE cells in 6 other preparations confirmed the slow nature of PNE potentials.

Conclusions
—The PNE is a normal anatomic feature of the rabbit AV node. It constitutes a cycle-length–dependent slow pathway with a shorter refractory period than that of the compact node. Propagated PNE activation can account for a discontinuity in conduction curves, markedly delayed AV nodal responses, and reentry. Finally, the PNE provides a substratum for the slow pathway in dual-pathway physiology.
Immediate and Long-Term Effect of Balloon Angioplasty or Stent Implantation on the Absolute and Relative Coronary Blood Flow Velocity Reserve
Authors: van Liebergen Rob A. M. , Piek Jan J. , Koch Karel T. , de Winter Robbert J. , Lie Kong I.
Published: June 2012

Background
—There is controversy regarding the immediate and long-term effects of PTCA on the coronary flow reserve.

Methods and Results
—A total of 54 patients with 1-vessel disease and normal left ventricular function were studied after balloon angioplasty (n=34) or stent implantation (n=20). Distal coronary blood flow velocity reserve (CFR) was defined as the ratio of adenosine-induced hyperemic versus baseline blood flow velocity with a 0.014-in Doppler guidewire. The relative CFR was defined as the ratio of the distal CFR and the reference CFR measured in the normal adjacent coronary artery. Hemodynamic and angiographic measurements were performed before and directly after balloon angioplasty or stent implantation and at 6-month follow-up. CFR after PTCA ≤2.5 was defined as an impaired CFR. Immediately after PTCA, CFR improved toward the range of the reference artery CFR. In both the balloon-treated and the stent-treated groups, initial high CFR values decreased and impaired CFR values increased at follow-up toward the values of the reference CFR in patients without restenosis. Impaired CFR after balloon angioplasty (33%) or stent implantation (58%) in patients without restenosis was related to an increased baseline flow velocity that normalized at follow-up. Patients with an increase of CFR after stenting were characterized by an unaltered baseline flow velocity and an increased adenosine-induced hyperemic flow velocity.

Conclusions
—An impaired CFR (≤2.5) is a frequent finding after balloon angioplasty or stent implantation as a result of a high baseline flow velocity. Normalization of impaired CFR at follow-up in patients without restenosis was associated with a decline of the baseline flow velocity after both balloon angioplasty and stent implantation, supporting the contention that this phenomenon relates to a slow recovery of autoregulation of the microvascular bed.
Additive Effects of Hyperinsulinemia and Ischemia on Myocardial GLUT1 and GLUT4 Translocation In Vivo
Authors: Russell Raymond R. , Yin Renfu , Caplan Michael J. , Hu Xiaoyue , Ren Jianming , Shulman Gerald I. , Sinusas Albert J. , Young Lawrence H.
Published: June 2012

Background
—Myocardial ischemia increases glucose uptake through the translocation of GLUT1 and GLUT4 from an intracellular compartment to the sarcolemma. The present study was performed to determine whether hyperinsulinemia causes translocation of myocardial GLUT1 as well as GLUT4 in vivo and whether there are additive effects of insulin and ischemia on GLUT1 and GLUT4 translocation.

Methods and Results
—Myocardial glucose uptake and transporter distribution were assessed by arteriovenous measurements, cell fractionation, and immunofluorescence. In fasted anesthetized dogs, hyperinsulinemia increased myocardial glucose extraction 3-fold (
P
<0.01) and the sarcolemmal content of GLUT4 by 90% and GLUT1 by 50% (
P
<0.05 for both) compared with saline infusion. In subsequent experiments, glucose uptake and transporter distribution were determined in ischemic and nonischemic regions of hearts from hyperinsulinemic animals during regional myocardial ischemia. Glucose uptake was 50% greater in the ischemic region (
P
<0.05). This was associated with a 20% increase in sarcolemmal GLUT1 and a 60% increase in sarcolemmal GLUT4 contents in the ischemic region (
P
<0.05 for both).

Conclusions
—Insulin stimulates myocardial glucose utilization through translocation of GLUT1 as well as GLUT4. Insulin and ischemia have additive effects to increase in vivo glucose utilization and augment glucose transporter translocation. We conclude that recruitment of both GLUT1 and GLUT4 contributes to increased myocardial glucose uptake during moderate reductions in coronary blood flow under insulin-stimulated conditions.
Metabolic Modulation of Acute Myocardial Infarction
Authors: Díaz Rafael , Paolasso Ernesto A. , Piegas Leopoldo S. , Tajer Carlos D. , Moreno Manuel Gil , Corvalán Ramón , Isea Jesús E. , Romero Graciela , (Estudios Cardiológicos Latinoamérica) Collaborative Group
Published: June 2012

Background
—Several trials have been performed in the past using glucose, insulin, and potassium infusion (GIK) for the treatment of acute myocardial infarction (AMI). Because of continuing uncertainty about the potential role of this therapeutic intervention, we conducted a randomized trial to evaluate the impact of a GIK solution during the first hours of AMI.

Methods and Results
—Four hundred seven patients with suspected AMI admitted within 24 hours of symptoms onset were enrolled. In a ratio of 2:1, 268 patients were allocated to receive GIK (high- or low-dose) and 139 to receive control. Phlebitis and serum changes in the plasma concentration of glucose or potassium were observed more often with GIK. A trend toward a nonsignificant reduction in major and minor in-hospital events was observed in patients allocated to GIK. In 252 patients (61.9%) treated with reperfusion strategies, a statistically significant reduction in mortality (relative risk [RR] 0.34; 95% CI: 0.15 to 0.78; 2
P
=0.008) and a consistent trend toward fewer in-hospital events in the GIK group were observed.

Conclusions
—Our results confirm that a metabolic modulation strategy in the first hours of an AMI is feasible, applicable worldwide, and has mild side effects. The statistically significant mortality reduction in patients who underwent a reperfusion strategy might have important implications for the management of AMI patients. It is now essential to perform a large-scale trial to reliably determine the magnitude of benefit.
Short-Term Oral Endothelin-Receptor Antagonist Therapy in Conventionally Treated Patients With Symptomatic Severe Chronic Heart Failure
Authors: Sütsch Gabor , Kiowski Wolfgang , Yan Xiao-Wei , Hunziker Patrick , Christen Stefan , Strobel Werner , Kim Jong-Hun , Rickenbacher Peter , Bertel Osmund
Published: June 2012

Background
—The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown.

Methods and Results
—Thirty-six men (mean age±SD, 55±8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4±4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], −13.9% [−16.0% to −11.7%]), pulmonary artery mean (−12.9% [−17.4% to −8.3%]) and capillary wedge (−14.5% [−20.5% to −8.5%]) pressures, and right atrial pressure (−20.2% [−29.4% to −11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (−24.2% [−28.1% to −20.3%]) and pulmonary (−19.9% [−28.4% to −11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15.2% [10.8% to 19.6%]) and systemic (−9.3% [−12.3% to −6.4%]) and pulmonary (−9.7% [−16.3% to −3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged.

Conclusions
—Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.
Effects of Continuous Positive Airway Pressure on Obstructive Sleep Apnea and Left Ventricular Afterload in Patients With Heart Failure
Authors: Tkacova Ruzena , Rankin Fiona , Fitzgerald Fabia S. , Floras John S. , Bradley T. Douglas
Published: June 2012

Background
—The objectives of this study were to determine the effects of continuous positive airway pressure (CPAP) on blood pressure (BP) and systolic left ventricular transmural pressure (LVP
tm
) during sleep in congestive heart failure (CHF) patients with obstructive sleep apnea (OSA). In CHF patients with OSA, chronic nightly CPAP treatment abolishes OSA and improves left ventricular (LV) ejection fraction. We hypothesized that one mechanism whereby CPAP improves cardiac function in CHF patients with OSA is by lowering LV afterload during sleep.

Methods and Results
—Eight pharmacologically treated CHF patients with OSA were studied during overnight polysomnography. BP and esophageal pressure (P
es
) (ie, intrathoracic pressure) were recorded before the onset of sleep and during stage 2 non–rapid eye movement sleep before, during, and after CPAP application. OSA was associated with an increase in systolic BP (from 120.4±7.8 to 131.8±10.6 mm Hg,
P
<0.05) and systolic LVP
tm
(from 124.4±7.7 to 137.2±10.8 mm Hg,
P
<0.05) from wakefulness to stage 2 sleep. CPAP alleviated OSA, improved oxyhemoglobin saturation, and reduced systolic BP in stage 2 sleep to 115.4±8.5 mm Hg (
P
<0.01), systolic LVP
tm
to 117.4±8.5 mm Hg (
P
<0.01), heart rate, P
es
amplitude, and respiratory rate.

Conclusions
—In CHF patients with OSA, LV afterload increases from wakefulness to stage 2 sleep. By alleviating OSA, CPAP reduces LV afterload and heart rate, unloads inspiratory muscles, and improves arterial oxygenation during stage 2 sleep. CPAP is a nonpharmacological means of further reducing afterload and heart rate during sleep in pharmacologically treated CHF patients with OSA.
Absence of Junctional Rhythm During Successful Slow-Pathway Ablation in Patients With Atrioventricular Nodal Reentrant Tachycardia
Authors: Hsieh Ming-Hsiung , Chen Shih-Ann , Tai Ching-Tai , Yu Wen-Chung , Chen Yi-Jen , Chang Mau-Song
Published: June 2012

Background
—The presence of junctional rhythm has been considered to be a sensitive marker of successful slow-pathway ablation. However, in rare cases, junctional rhythm was absent despite multiple radiofrequency applications delivered over a large area in the Koch’s triangle, and successful ablation was achieved in the absence of a junctional rhythm.

Methods and Results
—This study included 353 patients with AV nodal reentrant tachycardia (143 men and 210 women; mean age, 50±17 years) who underwent catheter ablation of the slow pathway. Combined anatomic and electrogram approaches were used to guide ablation. Inducibility of AV nodal reentrant tachycardia was assessed after each application of radiofrequency energy. Successful sites were located in the posterior area in 18 (90%) of 20 patients without junctional rhythm during slow-pathway ablation compared with 200 (60%) of 333 patients with junctional rhythm (
P
<0.001). The fast-slow form of tachycardia was more common in patients without than in those with junctional rhythm (30% versus 3%;
P
=0.001). At the successful ablation sites, patients with junctional rhythm had a higher incidence of a multicomponent or slow-pathway potential (51% versus 10%;
P
<0.001), a longer duration of the atrial electrogram (64±8 versus 50±9 ms;
P
=0.04), and a smaller atrial/ventricular electrogram amplitude ratio (0.29±0.18 versus 0.65±0.27;
P
<0.001) than those without junctional rhythm. Mean temperatures at successful sites (56±6°C versus 58±9°C;
P
=0.57) and incidence of transient AV block (2% versus 0%;
P
=0.86) were similar between patients with and without junctional rhythms. By multivariate analysis, location of ablation sites, atrial/ventricular electrogram amplitude ratio, absence of a multicomponent or slow-pathway potential, and occurrence of the fast-slow form of tachycardia were independent predictors of the absence of a junctional rhythm during successful slow-pathway ablation.

Conclusions
—In some rare cases, successful slow-pathway ablation is possible in the absence of a junctional rhythm.
Early Plus Delayed Hirudin Reduces Restenosis in the Atherosclerotic Rabbit More Than Early Administration Alone
Authors: Thome Leonard M. , Gimple Lawrence W. , Bachhuber Brian G. , McNamara Coleen A. , Ragosta Michael , Gertz S. David , Powers Eric R. , Owens Gary K. , Humphries John E. , Sarembock Ian J.
Published: June 2012

Background
—A 2-hour infusion of r-hirudin at the time of balloon angioplasty limits restenosis in atherosclerotic rabbits. Because thrombin activity in the vessel wall after angioplasty remains high for 48 to 72 hours, we hypothesized that a second infusion of hirudin at 24 hours would reduce restenosis more than early treatment alone.

Methods and Results
—Femoral atherosclerosis was induced in 35 rabbits by air desiccation injury and a high-cholesterol diet. At the time of angioplasty, rabbits were randomly assigned to 1 of 4 groups: controls: heparin bolus, saline infusion at 24 hours; early hirudin: hirudin bolus+2 hours’ infusion, saline infusion at 24 hours; delayed hirudin: heparin bolus, hirudin infusion±bolus at 24 hours; and early+delayed hirudin: hirudin bolus+2 hours’ infusion, hirudin infusion±bolus at 24 hours. Rabbits were euthanized after 28 days. The early+delayed hirudin treatment group had less loss of minimal lumen diameter by angiography at 28 days. By histomorphometry, cross-sectional area narrowing by plaque was least in the early+delayed treatment group compared with controls (
P
=0.0001), early hirudin (
P
=0.01), or delayed hirudin (
P
=0.001). The early+delayed hirudin group also had a significant reduction in absolute plaque area and an improvement in lumen area compared with the other groups. No differences were observed between treatment groups with respect to the cross-sectional area encompassed by the internal or external elastic laminae.

Conclusions
—Combined early+delayed administration of hirudin significantly reduces angiographic restenosis and cross-sectional area narrowing by plaque compared with early or late treatment alone. These results suggest that restenosis after balloon angioplasty is markedly influenced by thrombin-mediated events not only occurring early but also extending beyond the first 24 hours in this model.
Glucocorticoid-Induced Granulocytosis
Authors: Nakagawa Motohito , Terashima Takeshi , D’yachkova Yulia , Bondy Gregory P. , Hogg James C. , van Eeden Stephan F.
Published: June 2012

Background
—Glucocorticoid-induced granulocytosis has been attributed to enhanced release of polymorphonuclear leukocytes (PMNs) from bone marrow, delayed apoptosis, and reduced egress of PMNs into tissues. This study was designed to determine the relative contributions of PMNs released from the bone marrow and those entering the circulation from the marginated pool to the granulocytosis produced by a single dose of dexamethasone (2.0 mg/kg) in rabbits.

Methods and Results
—PMN transit through the mitotic and postmitotic pools of the bone marrow and rate of release of PMNs into the circulation were measured by use of the thymidine analogue 5′-bromo-2′-deoxyuridine (BrdU) to pulse-label PMNs in the bone marrow. The shift of PMNs from the marginated to the circulating pool was measured with BrdU-labeled PMNs transferred from donor rabbits to recipients before dexamethasone was delivered. The data show that dexamethasone increased bone marrow release of PMNs and shortened their transit time through the postmitotic pool (
P
<0.001) but not the mitotic pool of the bone marrow (
P
>0.05). Dexamethasone slowed the clearance of BrdU-labeled PMNs from the circulation (
P
<0.05) and lengthened their disappearance (half-life) from the circulation compared with control (half-life, 4.95 versus 9.45 hours). At 6 hours after dexamethasone, bone marrow release contributed ≈10%, mobilization from the marginated pool ≈61%, and a lengthened half-life in the circulation ≈29% to the glucocorticoid-induced granulocytosis.

Conclusions
—We conclude that a single dose of dexamethasone causes a granulocytosis primarily by a shift of PMNs from the marginated to the circulating pool, with a minor contribution from marrow release.
Enhanced Inflammatory Response to Coronary Angioplasty in Patients With Severe Unstable Angina
Authors: Liuzzo Giovanna , Buffon Antonino , Biasucci Luigi M. , Gallimore J. Ruth , Caligiuri Giuseppina , Vitelli Alessandra , Altamura Sergio , Ciliberto Gennaro , Rebuzzi Antonio G. , Crea Filippo , Pepys Mark B. , Maseri Attilio
Published: June 2012

Background
—Systemic markers of inflammation have been found in unstable angina. Disruption of culprit coronary stenoses may cause a greater inflammatory response in patients with unstable than those with stable angina. We assessed the time course of C-reactive protein (CRP), serum amyloid A protein (SAA), and interleukin-6 (IL-6) after single-vessel PTCA in 30 patients with stable and 56 patients with unstable angina (protocol A). We also studied 12 patients with stable and 15 with unstable angina after diagnostic coronary angiography (protocol B).

Methods and Results
—Peripheral blood samples were taken before and 6, 24, 48, and 72 hours after PTCA or angiography. In protocol A, baseline CRP, SAA, and IL-6 levels were normal in 87% of stable and 29% of unstable patients. After PTCA, CRP, SAA, and IL-6 did not change in stable patients and unstable patients with normal baseline levels but increased in unstable patients with raised baseline levels (all
P
<0.001). In protocol B, CRP, SAA, and IL-6 did not change in stable angina patients after angiography but increased in unstable angina patients (all
P
<0.05). Baseline CRP and SAA levels correlated with their peak values after PTCA and angiography (all
P
<0.001).

Conclusions
—Our data suggest that plaque rupture per se is not the main cause of the acute-phase protein increase in unstable angina and that increased baseline levels of acute-phase proteins are a marker of the hyperresponsiveness of the inflammatory system even to small stimuli. Thus, an enhanced inflammatory response to nonspecific stimuli may be involved in the pathogenesis of unstable angina.
Low Incidence of Myocardial Recovery After Left Ventricular Assist Device Implantation in Patients With Chronic Heart Failure
Authors: Mancini Donna M. , Beniaminovitz Ainat , Levin Howard , Catanese Katharine , Flannery Margaret , DiTullio Marco , Savin Sergey , Cordisco Marie Elena , Rose Eric , Oz Mehmet
Published: June 2012

Background
—Mechanical, histological, and biochemical improvement has been described in patients after left ventricular assist device (LVAD) support. Explantation of the LVADs without heart transplantation has been described in selected patients who received this therapy as a bridge to transplantation.

Methods and Results
—A retrospective review of patients receiving a mechanical bridge to transplantation at Columbia Presbyterian Hospital after July 21, 1991, was performed to determine the incidence of patients in whom the device was successfully explanted. From August 1, 1996, to February 1, 1998, we prospectively attempted to identify potential explant candidates by the use of exercise testing. During this time, we recruited 39 consecutive patients after insertion of the Thermo Cardiosystems vented electric device to participate in the following study. Approximately 3 months after device implantation, a maximal exercise test with hemodynamic monitoring and respiratory gas analysis was performed with the LVAD in the automated mode. The electric device was interfaced with a pneumatic console such that the rate could be decreased to 20 cycles/min. Hemodynamic measurements were recorded as the device rate was decreased. A repeat exercise test was then performed if the patient remained hemodynamically stable. A retrospective chart review of 111 LVAD recipients at our institution identified only 5 successful explant patients. Eighteen of the 39 patients were studied. Fifteen patients exercised with maximal device support. At peak exercise, V̇
o
2
averaged 14.5±3.6 mL · kg
−1
· min
−1
; LVAD flow, 8.0±1.3 L/min; Fick cardiac output, 11.4±3.3 L/min; and pulmonary capillary wedge pressure, 13±4 mm Hg. Seven patients remained normotensive and could exercise at a fixed rate of 20 cycles/min. In these patients, peak V̇
o
2
declined from 17.3±3.9 to 13.0±6.1 mL · kg
−1
· min
−1
. In one of these patients, the device was explanted.

Conclusions
—Significant myocardial recovery after LVAD therapy in patients with end-stage congestive heart failure occurs in a small percentage of patients. Most of these patients have dilated cardiomyopathy. Exercise testing may be a useful modality to identify those patients in whom the device can be explanted.
Percutaneous Transluminal Septal Myocardial Ablation in Hypertrophic Obstructive Cardiomyopathy
Authors: Faber Lothar , Seggewiss Hubert , Gleichmann Ulrich
Published: June 2012

Background
—Percutaneous transluminal septal myocardial ablation (PTSMA) has been introduced as an alternative procedure for reducing the left ventricular outflow tract gradient (LVOTG) in hypertrophic obstructive cardiomyopathy. We report on the acute and mid-term results in 91 symptomatic patients with respect to intraprocedural myocardial contrast echocardiography (MCE).

Methods and Results
—PTSMA was intended for 46 women and 45 men (54.1±15.5 years). In 2 patients, the intervention could not be completed. In the first 30 patients the target vessel was determined by probatory balloon occlusion alone and in the remainder by additional intraprocedural MCE. Resting LVOTG was reduced from 73.8±35.4 to 16.6±18.1 and nostextrasystolic LVOTG from 149.3±42.5 to 61.9±43.0 mm Hg (
P
<0.0001 each). In 10 (11%) patients, permanent DDD pacemaker implantation was necessary. Two (2%) patients died, 1 from ventricular fibrillation associated with treatment for chronic obstructive pulmonary disease after 9 days and 1 from fulminant pulmonary embolism after 2 days. After 3 months, mean New York Heart Association class was reduced from 2.8±0.6 to 1.1±1.0 (
P
<0.0001). The LVOTG remained reduced to 14.6±25.5 mm Hg at rest and 49.1±48.7 mm Hg (
P
<0.0001 each). Four patients underwent successful repeat PTSMA. Determination of the target vessel by MCE was associated with a higher rate of acute (92% vs 70%;
P
<0.01) and mid-term (94% vs 64%;
P
<0.01) success.

Conclusions
—PTSMA is a promising nonsurgical technique for reduction of symptoms and LVOTG in hypertrophic obstructive cardiomyopathy. MCE has been shown to be a useful addition to probatory balloon occlusion for target vessel selection. Prospective, long-term observations of larger populations and a comparison with the established forms of therapy are necessary to determine the definitive significance of PTSMA.
Diagnostic Value of Plasma Levels of Brain Natriuretic Peptide in Arrhythmogenic Right Ventricular Dysplasia
Authors: Matsuo Kiyotaka , Nishikimi Toshio , Yutani Chikao , Kurita Takashi , Shimizu Wataru , Taguchi Atsushi , Suyama Kazuhiro , Aihara Naohiko , Kamakura Shiro , Kangawa Kenji , Takamiya Makoto , Shimomura Katsuro
Published: June 2012

Background
—Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by local or diffuse wall motion abnormalities in the right ventricle (RV), associated with recurrent ventricular tachycardia (VT) of RV origin. Brain natriuretic peptide (BNP) was first isolated from a porcine brain extract. In humans, BNP is expressed predominantly in the ventricles of failing hearts, and its expression has been observed primarily in myocytes in the interstitial fibrous area in dilated cardiomyopathy. We hypothesized that BNP is increasingly secreted from the residual myocytes within the atrophic tissue in patients with ARVD.

Methods and Results
—Plasma BNP levels were measured in 17 patients with ARVD, 12 patients with idiopathic RV outflow tract tachycardia (RVOT), and 120 control subjects. We performed cardiac catheterization, RV endomyocardial biopsy, electron- beam CT, and biventricular endomyocardial mapping in the ARVD patients. There was a significant increase in plasma BNP levels in the ARVD patients compared with the RVOT patients and control subjects (61.4±59.6 pg/mL versus 8.3±5.5 pg/mL and 9.3±5.8 pg/mL;
P
<0.0001, respectively). The plasma BNP levels had no correlation with any of the hemodynamic data, but they had a significant correlation with the RV ejection fraction (
r
=−0.588,
P
=0.025) and with the fractionated-area scores (
r
=0.705,
P
=0.005). Light microscopic immunohistochemistry showed strong BNP immunoreactivity in residual myocytes with fibrofatty replacement.

Conclusions
—These results suggest that plasma BNP levels were not increased in RVOT patients but were increased in ARVD patients, and that the increased BNP levels indicate the severity of both the RV dysfunction and the arrhythmogenic substrate.
Insulin Induces Upregulation of Vascular AT
1
Receptor Gene Expression by Posttranscriptional Mechanisms
Authors: Nickenig Georg , Röling Jörg , Strehlow Kerstin , Schnabel Petra , Böhm Michael
Published: June 2012

Background
—An interaction of insulin with angiotensin II effects could be pathophysiologically important for the pathogenesis of atherosclerosis and hypertension.

Methods and Results
—We examined the effect of insulin on AT
1
receptor gene expression in cultured vascular smooth muscle cells (VSMCs). A 24-hour incubation with insulin (100 nmol/L) produced a 2-fold increase in AT
1
receptor density on VSMCs, as assessed by radioligand binding assays. This enhanced AT
1
receptor expression was caused by a time- and concentration-dependent upregulation of the AT
1
receptor mRNA levels, as assessed by Northern analysis. The maximal effect was detected after a 24-hour incubation of cells with 100 nmol/L insulin (270±20%). AT
1
receptor upregulation was caused by a stabilization of the AT
1
receptor mRNA, because the AT
1
receptor mRNA half-life was prolonged from 5 hours under basal conditions to 10 hours after insulin stimulation. In contrast, insulin had no influence on AT
1
receptor gene transcription, as assessed by nuclear run-on assays. The insulin-induced AT
1
receptor upregulation was followed by an increased functional response, because angiotensin II evoked a significantly elevated intracellular release of calcium in cells that were preincubated with 100 nmol/L insulin for 24 hours. The insulin-induced AT
1
receptor upregulation was dependent on tyrosine kinases, as assessed by experiments with the tyrosine kinase inhibitor genistein. Furthermore, experiments using the intracellular calcium chelator bis(2-amino-5-methylphenoxy)ethane-
N
,
N
,
N
′,
N
′-tetraacetic acid tetraacetoxymethyl ester suggest that intracellular calcium release may be involved in AT
1
receptor regulation.

Conclusions
—Insulin-induced upregulation of the AT
1
receptor by posttranscriptional mechanisms may explain the association of hyperinsulinemia with hypertension and arteriosclerosis, because activation of the AT
1
receptor plays a key role in the regulation of blood pressure and fluid homeostasis.
Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates
Authors: Harker Laurence A. , Marzec Ulla M. , Kelly Andrew B. , Chronos Nicolas R. F. , Sundell I. Birgitta , Hanson Stephen R. , Herbert J.-M.
Published: June 2012

Background
—A recent study showed that clopidogrel reduces thrombo-occlusive complications in patients with symptomatic atherosclerosis more effectively than aspirin.

Methods and Results
—The effects of clopidogrel and aspirin have been compared, singly and in combination, for measurements of
111
In-labeled platelets and
125
I-labeled fibrin deposition in baboon models of arterial thrombosis and related to platelet aggregation and expression of activation epitopes induced by ADP, collagen, and thrombin receptor agonist peptide (TRAP) and to template bleeding times (BTs). Low-dose oral clopidogrel (0.2 mg · kg
−1
· d
−1
) produced cumulative (1) intermediate decreases in
111
In-platelet and
125
I-fibrin deposition for segments of prosthetic vascular graft, deployed endovascular metallic stents, and endarterectomized aorta (
P
<0.009 in all cases); (2) elimination of ADP-induced platelet aggregation (
P
<0.001); (3) modest inhibition of collagen-induced platelet aggregation (
P
<0.01); (4) no reduction in TRAP-induced platelet aggregation; and (5) minimal prolongation of BTs (
P
=0.03). High-dose oral clopidogrel (≥2 mg/kg) produced the same effects within 3 hours. The effects of clopidogrel dissipated over 5 to 6 days. Aspirin 10 mg · kg
−1
· d
−1
alone did not decrease
111
In-platelet and
125
I-fibrin deposition on segments of vascular graft but detectably decreased
111
In-platelet and
125
I-fibrin accumulation on stents (
P
<0.01), minimally inhibited ADP- and collagen-induced platelet aggregation (
P
<0.05 in both cases), and minimally prolonged BTs (
P
=0.004). Within 3 hours of aspirin administration, the antithrombotic effects of acute high-dose or chronic low-dose clopidogrel were substantially enhanced, and BTs were modestly prolonged without inhibiting platelet aggregation induced by TRAP (
P
<0.001 in all cases compared with clopidogrel alone).

Conclusions
—Clopidogrel produces irreversible, dose-dependent, intermediate reduction in thrombosis that is substantially enhanced by the addition of aspirin. The effects of combining aspirin and clopidogrel need to be evaluated in patients at risk of vascular thrombosis.
Expression of Functional Angiotensin-Converting Enzyme and AT
1
Receptors in Cultured Human Cardiac Fibroblasts
Authors: Hafizi Sassan , Wharton John , Morgan Kevin , Allen Sean P. , Chester Adrian H. , Catravas John D. , Polak Julia M. , Yacoub Magdi H.
Published: June 2012

Background
—Angiotensin II (Ang II) has been implicated in the development of cardiac fibrosis. The aims of the present study were to examine expression and activity of ACE and of angiotensin receptors in human cardiac fibroblasts cultured from dilated cardiomyopathic and ischemic hearts. The effects of Ang II on fibroblasts were also investigated.

Methods and Results
—Human cardiac fibroblasts were cultured from ventricular and atrial myocardium and characterized immunohistochemically. Expression of ACE and the angiotensin AT
1
receptor was demonstrated in cardiac fibroblasts by reverse transcriptase–polymerase chain reaction and radioligand binding. Functional ACE activity, measured by radiolabeled substrate conversion assay, was detected in both ventricular (V
max
· K
m
−1
· mg
−1
, 0.031±0.010; n=13) and atrial (0.034±0.012; n=6) fibroblasts. Fibroblast ACE activity was increased after 48 hours of treatment with basic fibroblast growth factor, dexamethasone, and phorbol ester. Ang II did not affect DNA synthesis but stimulated [
3
H]proline incorporation in cardiac fibroblasts (20.0±4.0% increase above control by 10 μmol/L;
P
<0.05, n=7), which was abolished by losartan 10 μmol/L but not PD123319 1 μmol/L. Ang II also stimulated a rise in intracellular calcium (basal, 56±1 nmol/L; Ang II, 355±24 nmol/L) via the AT
1
receptor, as shown by complete inhibition with losartan.

Conclusions
—We have demonstrated expression and activity of ACE and AT
1
receptor in cultured human cardiac fibroblasts. In addition, cardiac fibroblasts respond to Ang II with AT
1
receptor–mediated collagen synthesis. The presence of local ACE and AT
1
receptors in human fibroblasts suggests their involvement in the development of cardiac fibrosis.
Usefulness of Electron Beam Tomography in Adolescents and Young Adults With Heterozygous Familial Hypercholesterolemia
Authors: Gidding Samuel S. , Bookstein Lisa C. , Chomka Eva V.
Published: June 2012

Background
—Because of the success of secondary prevention of coronary events by intense risk factor modification, a more precise measure of atherosclerosis in youth would have great clinical value both in the design of clinical trials for the demonstration of the usefulness of coronary disease prevention early in life and in guiding therapy. Identification of calcium in coronary arteries by electron beam tomography has been associated with severity of atherosclerosis in adults.

Methods and Results
—Twenty-nine youths 11 to 23 years old with familial hypercholesterolemia (average LDL cholesterol, 5.95 mmol/L) underwent electron beam tomography as well as comprehensive risk factor assessment with measurement of total cholesterol, triglycerides, HDL cholesterol, lipoprotein (a), apolipoprotein E phenotype, blood pressure, body mass index, and history of tobacco use. Significant coronary calcium was identified in 7 of 29 subjects. Increased body mass index was significantly associated with the presence of coronary calcium (25.3 versus 20.6 kg/m
2
,
P
<0.03). No other risk factors were associated with the presence of coronary calcium.

Conclusions
—Coronary calcium, uncommonly identified before the fourth decade, was found in a significant percentage of adolescents and young adults with familial hypercholesterolemia. Overweight may increase the likelihood of coronary calcium being present in individuals already at high risk.
Nonischemic Chest Pain Induced by Coronary Interventions
Authors: Jeremias Allen , Kutscher Sven , Haude Michael , Heinen Dagmar , Holtmann Gerald , Senf Wolfgang , Erbel Raimund
Published: June 2012

Background
—Chest pain frequently occurs without any signs of ischemia within the first 24 hours after coronary interventions. To test the hypothesis that this pain may be due to local vessel injury (“stretch pain”), we performed a prospective study enrolling patients after PTCA, stent implantation, or diagnostic coronary angiography alone.

Methods and Results
—A total of 145 patients after coronary angiography were evaluated by a validated questionnaire for quantifying postinterventional chest pain within 24 hours. To detect myocardial ischemia, all patients were evaluated with a 12-lead ECG and cardiac isoenzymes immediately after the procedure and the morning after. After stent implantation, 21 of the 51 patients (41.2%) developed chest pain, compared with 4 of the 33 patients (12.1%) undergoing PTCA and 6 of the 61 patients (9.8%) with a diagnostic angiography (
P
<0.001). Of these 31 patients who developed chest pain, only 3 (9.7%) felt that the pain was similar to previously experienced angina pectoris. The minimal lumen diameter after intervention was significantly larger in the stent group than in the PTCA group (3.14±0.75 versus 1.95±0.67 mm;
P
<0.001). No patient had changes in the ECG compared with before intervention, but 3 patients after stent implantation had a rise in cardiac isoenzymes. No other major adverse cardiac events occurred until discharge.

Conclusions
—Nonischemic chest pain develops in almost half of all patients undergoing stent implantation and seems to be related to vessel overexpansion caused by the stent in the diseased vessel segment.
Ten-Year Follow-Up of the First Megatrial Testing Thrombolytic Therapy in Patients With Acute Myocardial Infarction
Authors: Franzosi Maria Grazia , Santoro Eugenio , De Vita Claudio , Geraci Enrico , Lotto Antonio , Maggioni Aldo P. , Mauri Francesco , Rovelli Fausto , Santoro Luigi , Tavazzi Luigi , Tognoni Gianni
Published: June 2012

Background
—We conducted a 10-year follow-up of the 11 712 patients with acute myocardial infarction randomized in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-1 study, the first large trial assessing thrombolytic therapy.

Methods and Results
—Information on survival at 10 years was obtained for the 93% of all randomized patients through the census offices of their towns of residence. The difference in survival produced by streptokinase and sustained up to 1 year was still significant at 10 years (log-rank test,
P
=0.02), with the absolute benefit of 19 (95% CI 1 to 37) lives saved per 1000 patients treated. The time dependence of the extent of the benefit was confirmed, as the higher mortality rate reductions found in patients treated earlier were still present at 10 years. In the overall population, most of the benefit was obtained before hospital discharge (RR 0.81, 95% CI 0.72 to 0.90), since no difference in survival between thrombolyzed and control patients discharged alive was found at 10 years (RR 0.98, 95% CI 0.90 to 1.06). However, a slight albeit nonsignificant divergence of the survival curves of patients randomized within the first hour was observed [90 (95% CI 34 to 146) lives saved per 1000 at 10 years versus 72 (95% CI 37 to 107) lives saved at hospital discharge].

Conclusions
—The benefits of a single intravenous infusion of 1.5 million units of streptokinase in prolonging survival of patients with acute myocardial infarction is sustained up to 10 years, with a still-evident trend in favor of the patients admitted earlier.