bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Intramuscular Injection of Plasmid DNA Encoding Angiopoietin-1 but not Angiopoietin-2 Augments Revascularization in the Rabbit Ischemic Hindlimb
Authors: Shyu Kou-Gi , Manor Orit , Magner Meredith , Yancopoulos George D. , Isner Jeffrey M.
Published: June 2012

Background
—Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have recently been identified as ligands for the endothelial cell–specific Tie2 receptor. Little is known regarding the impact of these Tie2 ligands on postnatal neovascularization. Accordingly, we tested the hypothesis that gene transfer of plasmid DNA encoding Ang1 and Ang2 could modulate collateral vessel development in a rabbit model of hindlimb ischemia.

Methods and Results
—pAng1* (n=15), pJFE control (no Ang1* insert) (n=9), pAng2 (n=9), pcDNA3 control (no Ang2 insert) (n=10), or saline (n=5) was injected intramuscularly into the rabbit ischemic hindlimb. Collateral vessel development and limb perfusion were assessed before and 30 days after treatment. Calf blood pressure ratio (ischemic to normal hindlimb) was increased 30 days after Ang1* gene transfer versus controls (Ang1*, 0.90±0.02; pJFE, 0.76±0.05; saline, 0.77±0.03;
P
<0.05). Angiographic score was higher (
P
<0.05) in the pAng1* group (0.63±0.02) than in the pJFE (0.51±0.03) or saline (0.52±0.02) group. Maximal (postpapaverine) blood flow in the ischemic limb was higher (
P
<0.05) after pAng1* (67.8±4.9 mL/min) than pJFE (51.2±4.4 mL/min) or saline (52.9±4.9 mL/min). Capillary density and capillary/muscle fiber ratio (242±12/mm
2
and 0.89±0.06, respectively) were higher (
P
<0.01) with pAng1* than pJFE (172±11/mm
2
and 0.64±0.05) or saline (166±10/mm
2
and 0.67±0.05). Neovascularization was not enhanced with pAng2.

Conclusions
—
Ang1
but not
Ang2
gene transfer produces anatomic and physiological evidence of enhanced collateral vessel formation. Ang1 may modulate neovascularization in adult animals and thus represents a feasible therapeutic strategy for patients with tissue ischemia. The role of Ang2 in postnatal neovascularization remains to be clarified.
Effects of Long-term Smoking on Myocardial Blood Flow, Coronary Vasomotion, and Vasodilator Capacity
Authors: Campisi Roxana , Czernin Johannes , Schöder Heiko , Sayre James W. , Marengo Fernando D. , Phelps Michael E. , Schelbert Heinrich R.
Published: June 2012

Background
—The effect of long-term smoking on coronary vasomotion and vasodilator capacity in healthy smokers is unknown.

Methods and Results
—Myocardial blood flow (MBF) was quantified with [
13
N]ammonia and positron emission tomography (PET) at rest, during cold pressor testing (endothelium-dependent vasomotion), and during dipyridamole-induced hyperemia in 16 long-term smokers and 17 nonsmokers. MBF at rest did not differ between the 2 groups. Cold induced similar increases in rate-pressure product (RPP) in smokers and nonsmokers. However, MBF increased only in nonsmokers and was, during cold, higher than in smokers (0.91±0.18 versus 0.78±0.14 mL · g
−1
· min
−1
,
P
<0.05). MBF normalized to the RPP (derived from the ratio of MBF ([milliliters per gram per minute] to RPP [beats per minute times millimeters of mercury] times 10 000) declined in smokers but remained unchanged in nonsmokers (0.86±0.10 versus 0.72±0.11,
P
=0.0006, and 0.99±0.25 versus 0.96±0.27,
P
=NS). The hyperemic response to dipyridamole and the myocardial flow reserve did not differ between the 2 groups. In a multiple regression model adjusted for age, sex, serum lipid levels, years of smoking, and pack-years, years of smoking was the strongest predictor of the normalized blood flow response to cold (
P
<0.001), followed by the HDL/LDL ratio.

Conclusions
—The normal hyperemic response to dipyridamole in long-term smokers indicates a preserved endothelium-independent coronary vascular smooth muscle relaxation, whereas the abnormal response to cold suggests a defect in coronary vasomotion likely located at the level of the coronary endothelium. Its severity depends on the total exposure time to smoking.
Heterogeneous Expression and Activity of Endothelial and Inducible Nitric Oxide Synthases in End-Stage Human Heart Failure
Authors: Fukuchi Mitsumasa , Hussain Sabah N. A. , Giaid Adel
Published: June 2012

Background
—Recent reports have suggested that excessive amounts of endogenous NO may contribute to the myocardial dysfunction and injury in heart failure. In the present report, we investigate the cellular expression and activity of endothelial (eNOS) and inducible (iNOS) NO synthase in failing human hearts with special reference to the underlying lesion and drug therapy.

Methods and Results
—Myocardial tissues were obtained from 28 failing human hearts with various pathogeneses and 4 nonfailing hearts as controls. Only weak or focal expression of both eNOS and iNOS was seen in ventricles of nonfailing hearts. In failing hearts, immunoreactivity and hybridization signals for eNOS were increased only in cardiac myocytes of subendocardial areas. Signals for iNOS in cardiac myocytes were consistently seen in heart failure of various pathogeneses and were apparent in both infarcted and noninfarcted regions of ischemic cardiomyopathy. Apparent signals for iNOS were also seen in infiltrating macrophages in infarcted regions of ischemic cardiomyopathy, myocarditis, and septic hearts. The expression of eNOS but not iNOS in the myocytes was intimately associated with β-adrenergic therapy before the operation, being more abundant in patients on β-blockers compared with diminished presence in patients on β-agonists. In contrast to immunohistochemical data, iNOS activity was more variable than constitutive NOS activity and correlated significantly with the density of infiltrating macrophages.

Conclusions
—These results suggest that whereas increased eNOS and/or iNOS expression in failing cardiac myocytes may in general contribute to myocardial dysfunction, myocyte injury or death associated with inflammatory lesions may be caused in part by abundant iNOS expression within infiltrating macrophages rather than cardiac myocytes.
Flow Regulation of 72-kD Collagenase IV (MMP-2) After Experimental Arterial Injury
Authors: Bassiouny Hisham S. , Song Ruo H. , Hong Xue F. , Singh Ashok , Kocharyan Hrachya , Glagov Seymour
Published: June 2012

Background
—MMP-2 plays a key role in basement membrane degradation and in the migration of proliferating smooth muscle cells after vascular injury. Because low flow and shear stress have been related to the localization and progression of intimal hyperplasia, we hypothesized that flow conditions modulate in vivo MMP-2 transcription and activity in a model of injury-induced intimal thickening.

Methods and Results
—The right common carotid artery (CCA) was balloon-injured in 21 New Zealand White male rabbits. Flow was thereafter preserved (normal flow, n=7), reduced by partial outflow occlusion (low flow, n=7), or increased by ligation of the left CCA (high flow, n=7). In 15 other animals (controls without injury), flow was reduced (n=5), increased (n=5), or preserved (n=5). Mean blood flow and pressure in the right CCA were measured before and after flow modulation (day 0) and before the rabbits were killed (day 7). Northern analysis, gelatin-gel zymography, and fluorometric assays were performed on day 7 to determine MMP-2 mRNA levels and activity in relation to flow and intimal thickening. Mean flow was reduced from 21±1 to 7±1 mL/min (
P
<0.05) by outflow occlusion and increased to 31±2 mL/min (
P
<0.05) by ligation of the contralateral CCA. Blood pressure was not different between the flow groups. Hemodynamic parameters were similar for days 0 and 7 after flow modulation. In the injured right CCA, there was a 186% increase in MMP-2 mRNA with normal flow (
P
<0.05), a 366% increase with low flow (
P
<0.005), and only a 38% increase with high flow (
P
>0.05) compared with the uninjured CCA with normal flow. In the uninjured CCA, MMP-2 mRNA levels were increased by only 39% and 26% in the low- and high-flow groups, respectively, compared with normal-flow controls. The zymographic signal and quantitative fluorescent activity of gelatinase were markedly increased in both injured and uninjured CCAs subjected to low flow. Intimal thickening was observed after 1 week only in CCA segments with low flow and injury.

Conclusions
—Hemodynamic forces such as low flow upregulate injury-induced MMP-2 mRNA and appear to be more important in regulating MMP-2 activity than injury alone. This may facilitate migration of the smooth muscle cells and subsequent development of intimal thickening.
Albumin Microbubble Persistence During Myocardial Contrast Echocardiography Is Associated With Microvascular Endothelial Glycocalyx Damage
Authors: Lindner Jonathan R. , Ismail Suad , Spotnitz William D. , Skyba Danny M. , Jayaweera Ananda R. , Kaul Sanjiv
Published: June 2012

Background
—We hypothesized that the persistence of albumin microbubbles within the myocardium during crystalloid cardioplegia (CP) infusion and ischemia-reperfusion (I-R) occurs because of endothelial injury.

Methods and Results
—The myocardial transit rate of albumin microbubbles was measured in 18 dogs perfused with different CP solutions and in 12 dogs undergoing I-R. Electron microscopy with cationized ferritin labeling of the glycocalyx was performed in 9 additional dogs after CP perfusion and in 3 additional dogs undergoing I-R. Microbubble transit was markedly prolonged during crystalloid CP perfusion. The addition of whole blood to the CP solution accelerated the transit rate in a dose-dependent fashion (
P
<0.05), which was greater with venous than with arterial blood (
P
<0.05). The addition of plasma or red blood cells to CP solutions was less effective in improving transit rate than addition of whole blood (
P
<0.05). Microbubble transit rate was independent of the temperature, K
+
content, pH, P
o
2
, osmolality, viscosity, and flow rate of the perfusate. Similarly, a proportion of microbubbles persisted in the myocardium after I-R, which was related to the duration of ischemia (
P
<0.01) but not of reflow. Crystalloid CP perfusion and I-R resulted in extensive loss of the endothelial glycocalyx without other ultrastructural changes. This effect was partially reversed in the case of crystalloid CP when it was followed by blood CP.

Conclusions
—Sonicated albumin microbubbles persist within the myocardium in situations in which the endothelial glycocalyx is damaged. The measurement of the myocardial transit rate of albumin microbubbles may provide an in vivo assessment of endothelial glycocalyx damage.
Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused by Tachycardia-Induced Atrial Electrical Remodeling
Authors: Fareh Samir , Villemaire Christine , Nattel Stanley
Published: June 2012

Background
—Rapid atrial activation causes electrical remodeling that promotes the occurrence and the maintenance of atrial fibrillation (AF). Although remodeling has been shown to alter electrophysiological variables, the spatial uniformity of these changes is unknown.

Methods and Results
—Dogs subjected to rapid atrial pacing (400 bpm) for 24 hours (n=12) were compared with sham-operated dogs (instrumented but not paced, n=12). Epicardial mapping (240 bipolar electrodes) and extrastimulation at a large number of sites (mean±SEM, 66±4 per dog) were used to evaluate atrial activation and the heterogeneity of the effective refractory period (ERP), respectively. Rapid pacing increased both the percentage of sites at which AF could be induced by single premature stimuli (from 2.6±0.9% to 11.8±2.8%,
P
=0.007) and AF duration (from 39±28 to 146±49 seconds,
P
=0.03). Atrial tachycardia decreased atrial ERP (from 120±4 to 103±2 ms,
P
=0.003), increased the coefficient of variation of ERP (from 14.9±0.9% to 20.7±0.9%,
P
<0.0001), and accelerated conduction velocity (from 91±2 to 108±3 cm/s,
P
=0.0004), with no change in the wavelength. The increase in ERP heterogeneity was due both to interregional differences in the extent of ERP remodeling and to increased intersite variability within regions. Stepwise multilinear regression indicated that ERP heterogeneity was an independent determinant of the inducibility (
P
<0.0001) and duration (
P
<0.0001) of AF, whereas ERP per se and wavelength were not significant determinants. Combined mapping of AF induction and atrial ERP showed that premature extrastimuli induced AF at sites with short ERP by causing local conduction slowing and/or block in adjacent zones with longer ERP values.

Conclusions
—Atrial tachycardia causes nonuniform remodeling of atrial refractoriness that plays an important role in increasing atrial vulnerability to AF induction and the duration of induced AF.
Human Prostaglandin Transporter Gene (
hPGT
) is Regulated by Fluid Mechanical Stimuli in Cultured Endothelial Cells and Expressed in Vascular Endothelium in Vivo
Authors: Topper James N. , Cai Jiexing , Stavrakis George , Anderson Keith R. , Woolf Elizabeth A. , Sampson Barbara A. , Schoen Frederick J. , Falb Dean , Gimbrone Michael A.
Published: June 2012

Background
—biomechanical forces generated by blood flow within the cardiovascular system have been proposed as important modulators of regional endothelial phenotype and function. This process is thought to involve the regulation of vascular gene expression by physiological fluid mechanical stimuli such as fluid shear stresses.

Methods and Results
—We demonstrate sustained upregulation of a recently identified gene encoding a human prostaglandin transporter (
hPGT
) in cultured human vascular endothelium exposed to a physiological fluid mechanical stimulus in vitro. This biomechanical induction is selective in that steady laminar shear stress is sufficient to upregulate the
hPGT
gene at the level of transcriptional activation, whereas a comparable level of turbulent shear stress (a nonphysiological stimulus) is not. Various biochemical stimuli, such as bacterial endotoxin and the inflammatory cytokines recombinant human interleukin 1β cytokines (rhIL-1β) and tumor necrosis factor-α (TNF-α), did not significantly induce
hPGT
. Using a specific antiserum to hPGT, we demonstrate endothelial expression within the arterial vasculature and the microcirculation of highly vascularized tissues such as the heart.

Conclusions
—Our results identify
hPGT
as an inducible gene in vascular endothelium and suggest that biomechanical stimuli generated by blood flow in vivo may be important determinants of hPGT expression. Furthermore, this demonstration of regulated endothelial expression of hPGT implicates this molecule in the regional metabolism of prostanoids within the cardiovascular system.
Minimizing the Inhaled Dose of NO With Breath-by-Breath Delivery of Spikes of Concentrated Gas
Authors: Katayama Yoshihiko , Higenbottam Tim W. , Cremona George , Akamine Shinji , Demoncheaux Eric A. G. , Smith Adrian P. L. , Siddons Thomas E.
Published: June 2012

Background
—Pulmonary vasodilatation with a 100 ppm concentration of NO given as a short burst of a few milliliters at the beginning of each breath (NO
min
) was compared with conventionally inhaled NO, in which a full breath of 40 ppm of NO was inhaled (NO
CD
).

Methods and Results
—NO
min
was studied in 16 patients with severe pulmonary hypertension and in 16 isolated porcine lungs with experimentally induced pulmonary hypertension. We compared volumes of 8 to 38 mL of 100 ppm NO in N
2
injected at the beginning of each breath with conventional inhalation of 40 ppm NO in air. NO
CD
and NO
min
were studied in 4 pigs after inhibition of NO synthase with
N
G
-nitro-
l
-arginine methyl ester (1 to 2 mg/kg IV) had raised the pulmonary vascular resistance index (PVRI) from 4.4±0.8 to 10.0±1.6 mm Hg · L
−1
· min
−1
· kg
−1
. A similar comparison was made in 7 isolated porcine lungs after the thromboxane analogue U46619 (10 pmol · L
−1
· min
−1
) increased the mean PVRI from 4.6±0.8 to 12.2±1.3 mm Hg · L
−1
· min
−1
· kg
−1
. Patients’ mean PVRI was reduced from 29.2±3.7 to 24.0±3.1 with NO
min
and 24.5±3.3 mm Hg · L
−1
· min
−1
· m
−2
(mean±SEM) with NO
CD
. In isolated porcine lungs, there was the same reduction of PVRI for NO
min
and NO
CD
between 12.7% and 34.8%.

Conclusions
—A small volume of NO inhaled at the beginning of the breath was equally effective as NO
CD
but reduced the dose of NO per breath by 40-fold, which ranged from 1.2×10
−8
(0.4 μg) to 1.6×10
−7
mol/L (4.8 μg) compared with 5.3×10
−7
(16 μg) to 1.2×10
−6
mol/L (36 μg) per breath with NO
CD
.
Effects of Inhaled Nitric Oxide and Oxygen in High-Altitude Pulmonary Edema
Authors: Anand Inder S. , Prasad B. A. K. , Chugh Sumeet S. , Rao K. R. M. , Cornfield David N. , Milla Carlos E. , Singh Navneet , Singh Surjit , Selvamurthy William
Published: June 2012

Background
—High-altitude pulmonary edema (HAPE) is characterized by pulmonary hypertension, increased pulmonary capillary permeability, and hypoxemia. Treatment is limited to descent to lower altitude and administration of oxygen.

Methods and Results
—We studied the acute effects of inhaled nitric oxide (NO), 50% oxygen, and a mixture of NO plus 50% oxygen on hemodynamics and gas exchange in 14 patients with HAPE. Each gas mixture was given in random order for 30 minutes followed by 30 minutes washout with room air. All patients had severe HAPE as judged by Lake Louise score (6.4±0.7), Pa
o
2
(35±3.1 mm Hg), and alveolar to arterial oxygen tension difference (AaD
o
2
) (26±3 mm Hg). NO had a selective effect on the pulmonary vasculature and did not alter systemic hemodynamics. Compared with room air, pulmonary vascular resistance fell 36% with NO (
P
<0.001), 23% with oxygen (
P
<0.001 versus air,
P
<0.05 versus NO alone), and 54% with NO plus 50% oxygen (
P
<0.001 versus air,
P
<0.005 versus oxygen and versus NO). NO alone improved Pa
o
2
(+14%) and AaD
o
2
(−31%). Compared with 50% oxygen alone, NO plus 50% oxygen had a greater effect on AaD
o
2
(−18%) and Pa
o
2
(+21%).

Conclusions
—Inhaled NO may have a therapeutic role in the management of HAPE. The combined use of inhaled NO and oxygen has additive effects on pulmonary hemodynamics and even greater effects on gas exchange. These findings indicate that oxygen and NO may act on separate but interactive mechanisms in the pulmonary vasculature.
Vagal Cardiopulmonary Reflexes After Total Cardiac Deafferentation
Authors: Minisi Anthony J.
Published: June 2012

Background
—There are conflicting data regarding whether the primary source of afferent input for the vagal cardiopulmonary reflex emanates from receptors located in the ventricles, atria, and/or lungs. This study evaluated the effects of total cardiac deafferentation on the reflex control of efferent renal sympathetic nerve activity (RSNA) in response to a stimulus that affected all vagal receptors in the cardiopulmonary region.

Methods and Results
—Experiments were performed in 14 chloralose-anesthetized dogs with sinoaortic denervation. Reflex control of RSNA in response to blood volume expansion was measured before and after interruption of cardiac vagal afferents by pericardial lidocaine (PL). Reflex sensitivity (% change in RSNA/mm Hg change in left atrial pressure) was markedly attenuated after PL (pre, −10.9±2.2; post, −1.6±0.6;
P
=0.002). RSNA responses to intracoronary nicotine and left atrial balloon inflation were abolished after PL, confirming that cardiac afferents were interrupted. RSNA responses to lung inflation were not affected by PL, indicating that pulmonary afferents remained intact. In 8 experiments, reflex sensitivity values returned to baseline levels after the effects of PL had worn off.

Conclusions
—These results indicate that the heart provides the primary source of afferent input for the control of sympathetic outflow by the vagal cardiopulmonary reflex during changes in thoracic blood volumes and pressures.
Salt Induces Myocardial and Renal Fibrosis in Normotensive and Hypertensive Rats
Authors: Yu Henry C. M. , Burrell Louise M. , Black M. Jane , Wu Leonard L. , Dilley Rodney J. , Cooper Mark E. , Johnston Colin I.
Published: June 2012

Background
—The detrimental effects of high dietary salt intake may not only involve effects on blood pressure and organ hypertrophy but also lead to tissue fibrosis independently of these factors.

Methods and Results
—The effect of a normal (1%) or high (8%) sodium chloride diet on myocardial and renal fibrosis was assessed by quantitative histomorphometry in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The effect of salt on transforming growth factor-β
1
(TGF-β
1
) gene expression was assessed by Northern blot hybridization. A high-salt diet from 8 to 16 weeks of age resulted in increased blood pressure and left ventricular and renal hypertrophy in both WKYs and SHRs. Marked interstitial fibrosis was demonstrated in the left ventricle (LV), glomeruli, and renal tubules and in intramyocardial arteries and arterioles but not in the right ventricle. The collagen volume fraction increased significantly after high-salt diet in the LV, intramyocardial arteries and arterioles, glomeruli, and peritubular areas in both WKYs and SHRs. In the kidneys, glomerular and peritubular type IV collagen was also increased. There was overexpression of TGF-β
1
mRNA in the LV and kidneys in both rat strains after a high-salt diet (all
P
<0.001).

Conclusions
—High dietary salt led to widespread fibrosis and increased TGF-β
1
in the heart and kidney in normotensive and hypertensive rats. These results suggest a specific effect of dietary salt on fibrosis, possibly via TGF-β
1
–dependent pathways, and further suggest that excessive salt intake may be an important direct pathogenic factor for cardiovascular disease.
Development of Transplantation Vasculopathy and Progression of Donor-Transmitted Atherosclerosis
Authors: Kapadia Samir R. , Nissen Steven E. , Ziada Khaled M. , Guetta Victor , Crowe Timothy D. , Hobbs Robert E. , Starling Randall C. , Young James B. , Tuzcu E. Murat
Published: June 2012

Background
—Transplant coronary artery disease is a combination of atherosclerosis transmitted from the donor and new lesions of allograft vasculopathy. We sought to determine the morphological characteristics of allograft vasculopathy and differentiate it from donor-transmitted atherosclerosis with serial intravascular ultrasound.

Methods and Results
—Intravascular ultrasound examination was performed in 93 patients at 27.2±15.0 and 369.7±23.9 days after transplantation. The maximally and minimally diseased sites were selected in each segment as defined by Coronary Artery Surgery Study classification. For each matched site, maximal plaque thickness was measured. Lesions (maximum plaque thickness ≥0.5 mm) present at baseline examination were defined as donor lesions. On follow-up, lesions that developed at previously normal sites were defined as de novo lesions. The distribution and severity of donor and de novo lesions were similar in proximal, mid, and distal segments. The de novo lesions were less focal (43% vs 74%) and more circumferential (69% vs 45%) compared with the donor lesions, but there was significant morphological heterogeneity. Similar numbers of patients with and those without donor lesions developed de novo lesions. Moreover, progression of donor lesions was not associated with the presence or absence of de novo lesions.

Conclusions
—Differentiation between early allograft vasculopathy from conventional atherosclerosis by distribution and morphology of lesions alone is difficult. Serial intravascular ultrasound imaging with early baseline examination is necessary to make this distinction. This distinction is important because the progression of donor lesions and the development of de novo lesions are independent of each other.
Effect of Glycoprotein IIb/IIIa Receptor Blockade on Recovery of Coronary Flow and Left Ventricular Function After the Placement of Coronary-Artery Stents in Acute Myocardial Infarction
Authors: Neumann Franz-Josef , Blasini Rudolf , Schmitt Claus , Alt Eckhard , Dirschinger Josef , Gawaz Meinrad , Kastrati Adnan , Schömig Albert
Published: June 2012

Background
—Apart from its established effects on vessel patency after percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor blockade by abciximab may improve myocardial perfusion by inhibition of the interaction of platelets and platelet aggregates with the microvasculature. We investigated the effect of abciximab with stent placement in acute myocardial infarction.

Methods and Results
—In a prospective randomized trial, patients undergoing stenting in acute myocardial infarction within 48 hours after onset of symptoms were randomly assigned to receive either standard-dose heparin or abciximab plus low-dose heparin. Immediately after the procedure and at 14-day angiographic follow-up, we assessed flow velocity in the recanalized vessel with the Doppler wire and regional wall motion by the centerline method. End points were changes in papaverine-induced peak flow velocities and in wall motion indices. We assigned 98 patients to standard heparin and 102 to abciximab. We obtained 152 paired flow measurements and 151 paired left ventricular function studies. Residual stenoses of the treated lesions did not differ between the 2 groups. Improvement of peak flow velocity (mean [95% CI]: 18.1 cm/s [13.6 to 22.6 cm/s], n=80, versus 10.4 cm/s [5.4 to 15.4 cm/s], n=72,
P
=0.024) and wall motion index (0.44 SD/chord [0.29 to 0.59 SD/chord], n=79 versus 0.15 SD/chord [0.00 to 0.30 SD/chord], n=72,
P
=0.007) was significantly greater in patients assigned to abciximab than in those on heparin alone. At follow-up, the abciximab group had a higher global left ventricular ejection fraction than the heparin group (62% [59% to 65%] versus 56% [53% to 59%],
P
=0.003).

Conclusions
—Abciximab had important effects beyond the maintenance of large-vessel patency. It improved the recovery of microvascular perfusion and concomitantly enhanced the recovery of contractile function in the area at risk.
Role of Tissue-Specific Blood Flow and Tissue Recruitment in Insulin-Mediated Glucose Uptake of Human Skeletal Muscle
Authors: Bonadonna Riccardo C. , Saccomani Maria Pia , Del Prato Stefano , Bonora Enzo , DeFronzo Ralph A. , Cobelli Claudio
Published: June 2012

Background
—Conflicting evidence exists concerning whether insulin-induced vasodilation plays a mechanistic role in the regulation of limb glucose uptake. It can be predicted that if insulin augments blood flow by causing tissue recruitment, this mechanism would enhance limb glucose uptake.

Methods and Results
—Twenty healthy subjects were studied with the forearm perfusion technique in combination with the euglycemic insulin clamp technique. Ten subjects were studied at physiological insulin concentrations (≈400 pmol/L) and the other 10 at supraphysiological insulin concentrations (≈5600 pmol/L). Four additional subjects underwent a saline control study. Pulse injections of a nonmetabolizable extracellular marker (1-[
3
H]-
l
-glucose) were administered into the brachial artery, and its washout curves were measured in one ipsilateral deep forearm vein and used to estimate the extracellular volume of distribution and hence the amount of muscle tissue drained by the deep forearm vein. Both during saline infusion and at physiological levels of hyperinsulinemia we observed no changes in blood flow and/or muscle tissue drained by the deep forearm vein. However, supraphysiological hyperinsulinemia accelerated total forearm blood flow (45.0±1.8 versus 36.5±1.3 mL · min
−1
· kg
−1
,
P
<0.01) and increased the amount of muscle tissue drained by the deep forearm vein (305±46 versus 229±32 g,
P
<0.05). The amount of tissue newly recruited by insulin was strongly correlated to the concomitant increase in tissue glucose uptake (
r
=0.789,
P
<0.01).

Conclusions
—Acceleration of forearm blood flow mediated by supraphysiological hyperinsulinemia is accompanied by tissue recruitment, which may be a relevant determinant of forearm (muscle) glucose uptake.
Coronary Reserve of High- and Low-Flow Regions in the Dog Heart Left Ventricle
Authors: Loncar Robert , Flesche Christian W. , Deussen Andreas
Published: June 2012

Background
—Left ventricular myocardial blood flow is spatially heterogeneous. The hypothesis we tested was whether myocardial areas with a steady-state flow <0.5 times mean flow are underperfused and areas with flow >1.5 times mean flow are overperfused.

Methods and Results
—In anesthetized beagle dogs (n=10), the relationship between local blood flow versus
S
-adenosylhomocysteine (SAH) concentration, a measure of the free intracellular adenosine concentration, and lactate, a measure of the myocardial NADH/NAD
+
ratio, were determined under control conditions and after coronary constriction. Control local myocardial blood flow was 0.99±0.46 mL · min
−1
· g
−1
, with a coefficient of variation of 0.36±0.12 (n=256 per heart; sample wet mass, 125±30 mg). Tissue concentrations of SAH (3.4±2.5 nmol/g) and lactate (1.88±0.80 μmol/g) were not elevated in low-flow samples. However, after coronary artery constriction, poststenotic blood flow decreased from 1.00±0.27 to 0.49±0.22 mL · min
−1
· g
−1
(
P
<0.04), with significant correlation between local SAH and flow (
r
=−0.59) and lactate and flow (
r
=−0.50). Although nearly all samples from control high-flow regions showed increased SAH concentrations if relative flow after stenosis was <1.0, control low-flow samples frequently displayed low SAH concentrations. The percent reduction in flow determined the changes in the local SAH and lactate concentration, independent of the local control blood flow.

Conclusions
—When the coronary inflow is unrestricted, the oxygen supply to control low-flow regions meets metabolic demand. Flow to control high-flow regions reflects a higher local demand rather than overperfusion. Thus, blood flow heterogeneity most likely reflects differences in aerobic metabolism.
Myocardial Tissue Characterization After Acute Myocardial Infarction With Wavelet Image Decomposition
Authors: Nesković Aleksandar N. , Mojsilović Aleksandra , Jovanović Tomislav , Vasiljević Jovan , Popović Miodrag , Marinković Jelena , Bojić Milovan , Popović Aleksandar D.
Published: June 2012

Background
—Only a few texture measures can be used for texture characterization of infarcted myocardium and detection of reperfused myocardium early after infarction. This study was conducted to establish the relationship between texture properties of infarcted myocardium and infarct-related artery patency by quantitative computer analysis of 2-dimensional echocardiographic images with the wavelet-based method for texture characterization, evaluate the relationship between texture properties and myocardial viability, and correlate histopathologic changes after experimental infarction with the texture measures.

Methods and Results
—We analyzed 2-dimensional transthoracic echocardiographic images in 18 patients at different time points after infarction using the wavelet transform method. Regional wall motion of infarcted segments was analyzed on a follow-up echocardiographic study obtained 6 months after infarction. To verify the accuracy of the proposed texture measure and energy difference cutoff value, we prospectively evaluated another group of 19 patients. In addition, histopathologic changes in 9 dogs with experimental infarction were correlated with the texture measures. Sensitivity, specificity, and accuracy of the wavelet method for detection of reperfusion in the study group were 73%, 86%, and 78%, respectively, on day 2; 91%, 86%, and 89%, at 1 week; and 100%, 100%, and 100% at 3 weeks. Among 9 patients with improvement in regional wall motion on a follow-up study, 7 on day 2, 8 at 1 week, and 9 at 3 weeks were classified into the reperfused group by the wavelet method. Histopathologic features associated with the classification of reperfusion by the wavelet method were infarct transmurality (
P
=0.024) and degree of necrosis (
P
=0.028).

Conclusions
—Our clinical and experimental data suggest that the wavelet method can be used to differentiate between viable myocardium with recovery potential and definite myocardial necrosis in the early postinfarction period.
Activation of Platelets in Platelet-Rich Plasma by Rotablation Is Speed-Dependent and Can Be Inhibited by Abciximab (c7E3 Fab; ReoPro)
Authors: Williams Marlene S. , Coller Barry S. , Väänänen Heikki J. , Scudder Lesley E. , Sharma Samin K. , Marmur Jonathan D.
Published: June 2012

Background
—Rotational atherectomy with the Rotablator catheter has improved percutaneous treatment of certain coronary atherosclerotic lesions, but the “no-reflow” phenomenon remains a serious complication. Because platelet activation by rotablation may contribute to the no-reflow phenomenon, we developed an in vitro system to test the effect of rotablation on platelets in the absence or presence of platelet GP IIb/IIIa receptor blockade with abciximab.

Methods and Results
—Platelet-rich plasma (PRP) was prepared from 28 healthy human volunteers. PRP was divided into 4 samples: (1) no treatment, (2) 6D1 (anti–GP Ib), (3) c7E3 Fab (anti–GP IIb/IIIa+α
v
β
3
), and (4) c7E3 Fab+6D1. Samples were pumped through a flow chamber containing a 2.5-mm burr rotating at various speeds and then placed in an aggregometer. PRP samples tested in the absence of antibody underwent more rapid and extensive aggregation when rotablated at 150 000 and 180 000 rpm compared with 0 rpm (
P
<0.001 at both speeds). Preincubation of platelets with c7E3 Fab decreased the slope of aggregation at each rotablation speed, with 98%, 79%, and 71% reductions at 70 000, 150 000, and 180 000 rpm, respectively (
P
=0.09 for 70 000 and
P
<0.001 for both 150 000 and 180 000 rpm). Preincubation of platelets with 6D1 did not decrease the slope of aggregation at any rotablation speed (
P
>0.5,
P
=0.99, and
P
=0.091 for 70 000, 150 000, and 180 000 rpm). Platelet ATP release, a marker of granule release and cell damage, was markedly increased at 180 000 rpm (
P
=0.002 compared with 0 rpm in the control group). Electron microscopy revealed extensive rotablation-induced platelet damage at 150 000 and 180 000 rpm, and leakage of LDH confirmed platelet lysis at these speeds (
P
=0.002 and
P
<0.001 compared with 0 rpm).

Conclusions
—High-speed rotablation induces platelet activation of PRP, leading to aggregation; pretreating PRP with abciximab decreases the aggregation. These data suggest that pretreatment of patients with abciximab may decrease rotablation-induced platelet aggregation during rotational atherectomy.
Idiopathic Dilated Cardiomyopathy
Authors: Luppi Patrizia , Rudert William A. , Zanone Maria M. , Stassi Giorgio , Trucco Giuliana , Finegold David , Boyle Gerard J. , Nido Pedro Del , McGowan Francis X. , Trucco Massimo
Published: June 2012

Background
—Many cases of idiopathic dilated cardiomyopathy (IDC) result from an inflammatory myocarditis. The specific immunological mechanisms are not yet defined. Various autoimmune diseases are associated with superantigen-triggered immune responses, resulting in massive T-cell activation and tissue damage. We studied 3 cases in a search for evidence that such a phenomenon is also implicated in IDC.

Methods and Results
—Myocardial, lymph node, and thymic tissue samples were obtained from IDC patients who were undergoing heart transplantation. Infiltrating immune-cell phenotypes and gene expression of T-cell receptor (TCR) α- and β-chain variable (Vα and Vβ) regions were analyzed by immunostaining and polymerase chain reaction. Similar technical approaches were used to assay the tissues for the presence of coxsackievirus B (CVB). In all the specimens analyzed, an overexpression of the TCR Vβ3, Vβ7, and Vβ13.1 gene families was detected among the infiltrating T cells. These tissues were also found to be CVB3-positive. In vitro exposure of peripheral blood mononuclear cells to lysates of cells infected with CVB3 was capable of stimulating expansion of the same TCR Vβ families. The TCR Vα repertoire was never found to be skewed.

Conclusions
—A superantigen-mediated immune response is involved in human heart disease. CVB3 may directly or indirectly trigger this response, suggesting a possible mechanistic link between CVB infection and myocarditis development progressing to IDC.
Enhancement of Monocyte Procoagulant Activity by Adhesion on Vascular Smooth Muscle Cells and Intercellular Adhesion Molecule-1–Transfected Chinese Hamster Ovary Cells
Authors: Marx Nikolaus , Neumann Franz-Josef , Zohlnhöfer Dietlind , Dickfeld Timm , Fischer Almuth , Heimerl Susanne , Schömig Albert
Published: June 2012

Background
—Plaque erosion is a frequent finding in sudden death due to coronary thrombosis. The present study sought to investigate whether monocyte adhesion to human aortic vascular smooth muscle cells (VSMCs) induces procoagulant activity (PCA) and whether this could be mediated by intercellular adhesion molecule-1 (ICAM-1).

Methods and Results
—We incubated mononuclear cells (MNCs) with VSMCs and ICAM-1–transfected Chinese hamster ovary (CHO) cells, investigated monocyte tissue factor (TF) mRNA expression by Northern blot analysis and TF protein expression by ELISA, and measured PCA. Incubation of MNCs with VSMCs for 6 hours increased PCA from 0.7±0.1 to 166.0±37.9 mU/10
5
cells (
P
=0.007), which could be inhibited in a dose-dependent manner by the addition of blocking anti–ICAM-1 monoclonal antibodies. Prestimulation of VSMCs with interleukin-1β enhanced surface ICAM-1 expression significantly but did not induce PCA in VSMCs. Incubation of MNCs with prestimulated VSMCs led to a further increase in PCA to 239.9±27.9 mU/10
5
cells (
P
=0.02 compared with incubation with unstimulated VSMCs). Incubation of MNCs with VSMCs enhanced TF mRNA after 2 hours and significantly increased TF protein content after 6 hours. Incubation of purified monocytes with ICAM-1–transfected CHO cells increased PCA from 1.2±0.2 to 81.9±3.3 mU/10
5
cells (
P
<0.001 compared with incubation with untransfected CHO cells) after 6 hours. This effect could be inhibited significantly by the addition of blocking anti-CD18, anti-CD11b, or anti-CD11c monoclonal antibodies. Similar results were obtained for MNCs.

Conclusions
—Monocyte adhesion to VSMCs induces TF mRNA and protein expression and monocyte PCA, which is regulated by β
2
-integrin–mediated monocyte adhesion to ICAM-1 on VSMCs.
Attenuation of Cyclic Nucleotide–Mediated Smooth Muscle Relaxation in Blacks as a Cause of Racial Differences in Vasodilator Function
Authors: Cardillo Carmine , Kilcoyne Crescence M. , Cannon Richard O. , Panza Julio A.
Published: June 2012

Background
—Vasodilator reactivity is attenuated in normotensive blacks, and this may contribute to their enhanced susceptibility to hypertension and its complications. However, the mechanisms responsible for this phenomenon are unknown. We therefore studied nitric oxide (NO)–dependent and –independent vasorelaxation in healthy blacks and whites to investigate the nature of racial differences in vasodilator function.

Methods and Results
—Forearm flow responses to intra-arterial infusion of increasing doses of acetylcholine (a vasodilator that stimulates endothelial release of NO), sodium nitroprusside (an exogenous NO donor), and isoproterenol (a β-adrenergic agonist whose vasodilator effect stems from the combination of direct smooth muscle stimulation and endothelial NO release) were studied in 18 normotensive whites and 18 blacks by use of strain-gauge plethysmography. A blunted vasodilator response to acetylcholine (7.2±1.1 versus 14.4±1.8 mL · min
−1
· dL
−1
;
P
<0.001) and sodium nitroprusside (8.2±1.1 versus 12.1±1.3 mL · min
−1
· dL
−1
;
P
<0.001) was observed in blacks compared with whites, suggesting decreased cGMP-mediated smooth muscle relaxation. The vasodilator effect of isoproterenol was lower in blacks than in whites both before (10.9±1.7 versus 14.9±1.5 mL · min
−1
· dL
−1
;
P
=0.006) and after
N
G
-monomethyl-
l
-arginine (6.1±1.2 versus 10.1±0.8 mL · min
−1
· dL
−1
;
P
<0.001), implying that cAMP-dependent vasodilator response to isoproterenol is diminished in blacks. No significant difference was observed in the hyperemic response to forearm ischemia.

Conclusions
—Compared with whites, healthy blacks have reduced vasodilation in response to NO-dependent and -independent stimuli. This difference seems to be related to an attenuation in cyclic nucleotide–mediated vascular smooth muscle relaxation and may play a role in the increased prevalence of hypertension and its complications in blacks.
Induction of Neurally Mediated Syncope With Adenosine
Authors: Mittal Suneet , Stein Kenneth M. , Markowitz Steven M. , Slotwiner David J. , Rohatgi Sameer , Lerman Bruce B.
Published: June 2012

Background
—Tilt testing is used to establish the diagnosis of neurally mediated syncope. However, applicability of the tilt test is limited by test sensitivity and length of time required to perform the test. We hypothesized that adenosine could facilitate the induction of neurally mediated syncope through its sympathomimetic effects and therefore could be used as an alternative to routine tilt testing.

Methods and Results
—In protocol 1, the yield of adenosine tilt testing (12 mg while upright, followed by 60° tilt for 5 minutes) and a 15-minute isoproterenol tilt test were compared in 84 patients with a negative 30-minute drug-free tilt test. In protocol 2, 100 patients underwent an initial adenosine tilt test followed by our routine tilt test (30-minute drug-free tilt followed by a 15-minute isoproterenol tilt). Six additional control patients underwent microneurography of the peroneal nerve to compare the sympathomimetic effects during bolus administration of adenosine and continuous infusion of isoproterenol. In protocol 1, the yields of adenosine (8 of 84, 10%) and isoproterenol (7 of 84, 8%) tilt testing were comparable (
P
=NS). In protocol 2, the yields of adenosine (19 of 100, 19%) and routine (22 of 100, 22%) tilt testing were also comparable (
P
=NS). Although the yield of adenosine tilt testing was comparable in both protocols, patients with a negative adenosine tilt test but a positive routine tilt test usually required isoproterenol to elicit the positive response. Microneurography confirmed discordant sympathetic activation after adenosine and isoproterenol administration.

Conclusions
—Adenosine is effective for the induction of neurally mediated syncope, with a diagnostic yield comparable to routine tilt testing. However, the discordant results obtained with adenosine and the isoproterenol phase of routine tilt testing suggest that adenosine and isoproterenol tilt testing may have complementary roles in eliciting a positive response. Therefore, a tilt protocol that uses an initial adenosine tilt followed, if necessary, by an isoproterenol tilt would be expected to increase the overall yield and reduce the duration of tilt testing.
Endothelial Dysfunction, Impaired Endogenous Fibrinolysis, and Cigarette Smoking
Authors: Newby David E. , Wright Robert A. , Labinjoh Catherine , Ludlam Christopher A. , Fox Keith A. A. , Boon Nicholas A. , Webb David J.
Published: June 2012

Background
—Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P–induced tPA release in vivo in humans.

Methods and Results
—Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (
P
<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (
P
=0.03) and release of tPA antigen (
P
=0.04) and activity (
P
<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively.

Conclusions
—Cigarette smoking causes marked inhibition of substance P–induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.
Effect of Biphasic Shock Duration on Defibrillation Threshold With Different Electrode Configurations and Phase 2 Capacitances
Authors: Schauerte Patrick N. , Ziegert Kathrin , Waldmann Matthias , Schöndube Friedrich A. , Birkenhauer Frank , Mischke Karl , Grossmann Marius , Hanrath Peter , Stellbrink Christoph
Published: June 2012

Background
—The defibrillation threshold (DFT) may be affected by biphasic shock duration (BSD), electrode configuration, and capacitance. The upper limit of vulnerability (ULV) may be used to estimate the DFT. For different lead configurations and phase 2 capacitances, we investigated in 18 pigs whether the use of ULV may predict waveforms with lowest DFT.

Methods and Results
—DFT and ULV were determined by up-down protocols for 10 BSDs. ULVs were measured by T-wave scanning during ventricular pacing (cycle length 500 ms). In protocol 1 (n=6), a pectoral “active can” was combined with an electrode in the superior vena cava as common cathode and a right ventricle electrode as anode (AC+SVC). In protocol 2 and protocol 3 (n=6 each), only the “active can” was used as proximal electrode (AC). Capacitance was 150 μF during both phases in protocol 1 and protocol 3 but 150 μF (phase 1) and 300 μF (phase 2) in protocol 2. ULV and DFT demonstrated a linear correlation in each protocol (
r
=0.78 to 0.84). Lowest DFTs were found at 10 ms for AC+SVC and at 14 ms for AC (
P
<0.001). At optimal BSDs, voltage DFTs did not differ significantly between AC (527±57 V) and AC+SVC (520±70 V). Switching capacitors for phase 2 in a way that reduced leading-edge voltage by 50% while doubling capacity did not change BSD for optimal voltage DFT but increased minimum DFT from 527±57 V to 653±133 V (
P
=0.04).

Conclusions
—The BSD with lowest DFT is shorter for AC+SVC than for AC. There is no significant difference in voltage DFT between both at optimal BSD. A lower phase 2 capacitance reduces DFTs irrespective of BSD. Because strength-duration curves for DFT and ULV correlate for different BSDs, lead systems, and phase 2 capacitances, ULV determination may allow the prediction of waveforms with lowest DFT.