bluuebunny/crossref_metadata_2025 huggingface dataset:
β
3
-Integrins Rather Than β
1
-Integrins Dominate Integrin-Matrix Interactions Involved in Postinjury Smooth Muscle Cell Migration
Authors: Slepian Marvin J. , Massia Stephen P. , Dehdashti Behrooz , Fritz Anne , Whitesell Luke
Published: June 2012

Background
—Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin–extracellular matrix interactions are essential for cell migration. SMCs express both β
1
- and β
3
-integrins. In this study, we examined the relative functional roles of β
1
- and β
3
-integrin–matrix interactions in postinjury SMC migration.

Methods and Results
—Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-β
1
and anti-α
v
β
3/5
antibodies (Abs) revealed expression of both β
1
- and β
3
-integrins, with β
1
observed as linear streaks and β
3
found in focal contacts. In a scrape-wound migration assay, anti-β
1
Abs (92.0±10.7% of control,
P
=.1) and 0.5 mmol/L linear RGD (105±5% of control,
P
=.2) did not alter SMC migration at 48 hours after injury. β
3
-Blockade, however, via Abs (anti-β
3/5
35.7±4.5% of control, anti-β
3
61±12% of control, both
P
<.001) and cyclic RGD (0.5 mmol/L) (12±10% of control,
P
<.001) decreased migration. Neither β
1
- nor β
3
-inhibition altered postinjury [
3
H]thymidine incorporation. In the rat carotid injury model, local adventitial polymer-based delivery of radiolabeled linear or cyclic RGD led to uptake and retention of label, for both peptides, over a 72-hour period after injury. Local arterial wall β
1
-blockade via polymer-based delivery of linear RGD had no effect on SMC migration at 4.5 days (11.5±3.2 versus 12.8 SMCs per ×600 field [control],
P
=.6) or on neointimal thickening at 14 days (I/M area ratio, 0.664±0.328 versus 1.179±0.324 [control],
P
=.6) after injury. In contrast, local β
3
-blockade via cRGD limited migration (0.8±0.8 versus 12.8±4.4 SMCs per ×600 field [control],
P
<.01) and thickening (I/M area ratio, 0.004±0.008 versus 1.179±0.324 [control],
P
<.01).

Conclusions
—In postinjury migrating SMCs, β
3
- rather than β
1
-integrin–matrix interactions are of greater functional significance in adhesive processes essential for SMC migration in vitro and in vivo. Blockade of dominant SMC integrin (β
3
)–matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.
Real-time Three-dimensional Echocardiography for Determining Right Ventricular Stroke Volume in an Animal Model of Chronic Right Ventricular Volume Overload
Authors: Shiota Takahiro , Jones Michael , Chikada Masahide , Fleishman Craig E. , Castellucci John B. , Cotter Bruno , DeMaria Anthony N. , von Ramm Olaf T. , Kisslo Joseph , Ryan Thomas , Sahn David J.
Published: June 2012

Background
—The lack of a suitable noninvasive method for assessing right ventricular (RV) volume and function has been a major deficiency of two-dimensional (2D) echocardiography. The aim of our animal study was to test a new real-time three-dimensional (3D) echo imaging system for evaluating RV stroke volumes.

Methods and Results
—Three to 6 months before hemodynamic and 3D ultrasonic study, the pulmonary valve was excised from 6 sheep (31 to 59 kg) to induce RV volume overload. At the subsequent session, a total of 14 different steady-state hemodynamic conditions were studied. Electromagnetic (EM) flow probes were used for obtaining aortic and pulmonic flows. A unique phased-array volumetric 3D imaging system developed at the Duke University Center for Emerging Cardiovascular Technology was used for ultrasonic imaging. Real-time volumetric images of the RV were digitally stored, and RV stroke volumes were determined by use of parallel slices of the 3D RV data set and subtraction of end-systolic cavity volumes from end-diastolic cavity volumes. Multiple regression analyses showed a good correlation and agreement between the EM-obtained RV stroke volumes (range, 16 to 42 mL/beat) and those obtained by the new real-time 3D method (
r
=0.80; mean difference, −2.7±6.4 mL/beat).

Conclusions
—The real-time 3D system provided good estimation of strictly quantified reference RV stroke volumes, suggesting an important application of this new 3D method.
Electropharmacologic Effects of Class I and Class III Antiarrhythmia Drugs on Typical Atrial Flutter
Authors: Tai Ching -Tai , Chen Shih-Ann , Feng An-Ning , Yu Wen-Chung , Chen Yi-Jen , Chang Mau-Song
Published: June 2012

Background
—Acute effects of class I and class III antiarrhythmia drugs on the reentrant circuit of typical atrial flutter are not fully studied. Furthermore, the critical electrophysiologic determinants of flutter termination by antiarrhythmia drugs are not clear.

Methods and Results
—The study population consisted of 36 patients (mean age, 53±17 years) with clinically documented typical atrial flutter. A 20-pole “halo” catheter was positioned around the tricuspid annulus. Incremental pacing was performed to measure the conduction velocity along the isthmus and lateral wall, and extrastimulation was performed to evaluate atrial refractory period in the baseline state and after intravenous infusion of ibutilide, propafenone, and amiodarone. Efficacy of these drugs in conversion of typical atrial flutter and patterns of termination were also determined. Ibutilide significantly increased the atrial refractory period and decreased conduction velocity in the isthmus at short pacing cycle length. It terminated atrial flutter in 8 (67%) of 12 patients after prolongation of flutter cycle length due to increase (86±19%) of conduction time in the isthmus. Propafenone predominantly decreased conduction velocity with use dependency and significantly increased atrial refractory period, but it only converted atrial flutter in 4 (33%) of 12 patients. Amiodarone had fewer effects on atrial refractory period and conduction velocity than did ibutilide and propafenone, and it terminated atrial flutter in only 4 (33%) of 12 patients. Termination of typical atrial flutter was due to failure of wave front propagation through the isthmus, which occurred with cycle length oscillation, abruptly without variability of cycle length, or after premature activation of the reentrant circuit.

Conclusions
—Ibutilide, with a unique increase in atrial refractoriness, was more effective in conversion of atrial flutter than were propafenone and amiodarone.
Doppler Tissue Imaging Quantitates Regional Wall Motion During Myocardial Ischemia and Reperfusion
Authors: Derumeaux Geneviève , Ovize Michel , Loufoua Joseph , André-Fouet Xavier , Minaire Yves , Cribier Alain , Letac Brice
Published: June 2012

Background
—Quantification of regional myocardial function is a major unresolved issue in cardiology. We evaluated the accuracy of pulsed Doppler tissue imaging (DTI), a new echocardiographic technique, to quantify regional myocardial dysfunction induced by acute ischemia and reperfusion.

Methods and Results
—In nine open-chest anesthetized pigs, various degrees of regional wall motion abnormalities were induced by graded reduction of left anterior descending coronary artery (LAD) blood flow. Pulsed Doppler tissue imaging was performed from an epicardial apical four-chamber view with the sample placed within the middle part of the septal wall. Peak septal velocities were calculated during systole, isovolumic relaxation, and early and late diastole. Regional myocardial blood flow and systolic and diastolic dysfunctions were assessed by radioactive microspheres and ultrasonic crystals, respectively. Ischemia resulted in a significant rapid reduction of systolic velocities and an early decrease in the ratio of early to late diastolic velocities. Both changes were detected by pulsed DTI within 5 seconds of coronary artery occlusion. The decrease in systolic velocity significantly correlated with both systolic shortening (
r
=.90,
P
<.0001) and regional myocardial blood flow (
r
=.96,
P
<.0001) during reduction of LAD blood flow.

Conclusions
—These results suggest that DTI may be a promising new tool for the quantification of ischemia-induced regional myocardial dysfunction.
Regional In Vivo and In Vitro Characterization of Autonomic Innervation in Cardiomyopathic Human Heart
Authors: Ungerer Martin , Hartmann Franz , Karoglan Mislav , Chlistalla Andreas , Ziegler Sibylle , Richardt Gert , Overbeck Matthias , Meisner Hans , Schömig Albert , Schwaiger Markus
Published: June 2012

Background
—In contrast to healthy volunteers, regional differences of cardiac autonomic innervation have been described through the use of C
11
-hydroxyephedrine positron emission tomography (HED-PET) in the left ventricles of patients with dilated cardiomyopathy. The goal of the present study was to correlate HED-PET images with biochemical analysis of tissue samples.

Methods and Results
—To assess the significance of altered HED uptake, we used HED-PET to examine eight patients with dilated cardiomyopathy before heart transplantation. After explantation, we measured the density and affinity of uptake
1
(
3
H-mazindol binding) and tissue norepinephrine content as markers of presynaptic function, and we determined β-receptor density and affinity (
3
H-CGP 12177 binding) in the corresponding areas of the same patients. The density of uptake
1
and norepinephrine content showed marked regional variation, with highest values in the anterior septal wall and lowest in inferoapical and apical areas. Both parameters were closely correlated (
r
=.65,
P
=.05). Similarly, uptake
1
density or norepinephrine content and HED retention (PET) showed clear correlations (
r
=.63 and .60, respectively). Uptake
1
affinities did not vary significantly and were not correlated to the other parameters. β-Adrenergic receptor density showed some, albeit less pronounced, regional variation and was weakly correlated to uptake
1
density and local HED retention (
r
=.38 and .31, respectively).

Conclusions
—Uptake
1
density and tissue norepinephrine content showed marked regional variation in cardiomyopathic left ventricles. HED-PET is significantly correlated to the density but not the affinity of uptake
1
sites in the human heart, suggesting either loss of neurons or downregulation of uptake
1
in dilated cardiomyopathy. HED-PET is a valuable marker for alterations of the presynaptic sympathoadrenergic system in humans.
Transdermal Nitroglycerin Patch Therapy Improves Left Ventricular Function and Prevents Remodeling After Acute Myocardial Infarction
Authors: Mahmarian John J. , Moyé Lemuel A. , Chinoy David A. , Sequeira Rafael F. , Habib Gabriel B. , Henry W. John , Jain Avanindra , Chaitman Bernard R. , Weng C. S. Wayne , Morales-Ballejo Hugo , Pratt Craig M.
Published: June 2012

Background
—Nitrates are widely used in the treatment of angina in patients with acute myocardial infarction (AMI). Short-term administration prevents left ventricular (LV) dilation and infarct expansion. However, little information is available regarding their long-term effects on LV remodeling in patients surviving Q-wave AMI.

Methods and Results
—This was a randomized, double-blind, placebo-controlled trial designed to investigate the long-term (6-month) efficacy of intermittent transdermal nitroglycerin (NTG) patches on LV remodeling in 291 survivors of AMI. Patients meeting entry criteria had baseline gated radionuclide angiography (RNA) followed by randomization to placebo or active NTG patches delivering 0.4-, 0.8-, or 1.6-mg/h. RNA was repeated at 6 months and 6.5 days after withdrawal of double-blind medication. The primary study end point was the change in end-systolic volume index (ESVI). Both ESVI and end-diastolic volume index (EDVI) were significantly reduced with 0.4-mg/h NTG patches (−11.4 and −11.6 mL/m
2
, respectively,
P
<.03). This beneficial effect was observed primarily in patients with a baseline LV ejection fraction ≤40% (ΔESVI, −31 mL/m
2
; ΔEDVI, −33 mL/m
2
; both
P
<.05) and only at the 0.4-mg/h dose. After NTG patch withdrawal, ESVI significantly increased but did not reach pretreatment values.

Conclusions
—Transdermal NTG patches prevent LV dilation in patients surviving AMI. The beneficial effects are limited to patients with depressed LV function and only at the lowest (0.4-mg/h) dose. Continued administration is necessary to maintain efficacy. Whether these remodeling effects confer a clinical or survival advantage will need to be addressed in an adequately powered cardiac event trial.
Long-term
l
-Arginine Supplementation Improves Small-Vessel Coronary Endothelial Function in Humans
Authors: Lerman Amir , Burnett John C. , Higano Stuart T. , McKinley Linda J. , Holmes David R.
Published: June 2012

Background
—Coronary endothelial dysfunction is characterized by an imbalance between endothelium-derived vasodilating and vasoconstricting factors and coronary vasoconstriction in response to the endothelium-dependent vasodilator acetylcholine. Thus, the present double-blind, randomized study was designed to test the hypothesis that long-term, 6-month supplementation of
l
-arginine, the precursor of the endothelium-derived vasodilator NO, reverses coronary endothelial dysfunction to acetylcholine in humans with nonobstructive coronary artery disease.

Methods and Results
—Twenty-six patients without significant coronary artery disease on coronary angiography and intravascular ultrasound were blindly randomized to either oral
l
-arginine or placebo, 3 g TID. Endothelium-dependent coronary blood flow reserve to acetylcholine (10
−6
to 10
−4
mol/L) was assessed at baseline and after 6 months of therapy. There was no difference between the two study groups in clinical characteristics or in the coronary blood flow in the response to acetylcholine at baseline. After 6 months, the coronary blood flow in response to acetylcholine in the subjects who were taking
l
-arginine increased compared with the placebo group (149±20% versus 6±9%,
P
<0.05). This was associated with a decrease in plasma endothelin concentrations and an improvement in patients’ symptoms scores in the
l
-arginine treatment group compared with the placebo group.

Conclusions
—Long-term oral
l
-arginine supplementation for 6 months in humans improves coronary small-vessel endothelial function in association with a significant improvement in symptoms and a decrease in plasma endothelin concentrations. This study proposes a role for
l
-arginine as a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease.
Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activity in Essential Hypertension
Authors: Taddei Stefano , Virdis Agostino , Ghiadoni Lorenzo , Magagna Armando , Salvetti Antonio
Published: June 2012

Background
—Essential hypertension is associated with impaired endothelium-dependent vasodilation. Inactivation of endothelium-derived nitric oxide by oxygen free radicals participates in endothelial dysfunction in experimental hypertension. To test this hypothesis in humans, we evaluated the effect of antioxidant vitamin C on endothelium-dependent responses in essential hypertensive patients.

Methods and Results
—In 14 healthy subjects (47.1±4.8 years; blood pressure, 120.6±4.5/80.9±3.5 mm Hg) and 14 essential hypertensive patients (47.3±5.1 years; blood pressure, 153.9±7.1/102.3±4.1 mm Hg), we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg · 100 mL
−1
· min
−1
) or sodium nitroprusside (1, 2, and 4 μg/100 mL forearm tissue per minute), an endothelium-dependent and -independent vasodilator, respectively, in basal conditions and during infusion of intrabrachial vitamin C (2.4 mg/100 mL forearm tissue per minute). In hypertensive patients but not in control subjects, vitamin C increased (
P
<0.01) the impaired vasodilation to acetylcholine, whereas the response to sodium nitroprusside was unaffected. Moreover, in another 14 hypertensive patients (47.1±5.2 years; blood pressure, 155.2±6.9/103.7±4.5 mm Hg), the facilitating effect of vitamin C on vasodilation to acetylcholine was reversed by
N
G
-monomethyl-
l
-arginine (100 μg/100 mL forearm tissue per minute), a nitric oxide synthase inhibitor, suggesting that in essential hypertension superoxide anions impair endothelium-dependent vasodilation by nitric oxide breakdown. Finally, because in adjunctive 7 hypertensive patients (47.8±6.1 years; blood pressure, 155.3±6.8/103.5±4.3 mm Hg), indomethacin (50 μg/100 mL forearm tissue per minute), a cyclooxygenase inhibitor, prevented the potentiating effect of vitamin C on vasodilation to acetylcholine, it is possible that in essential hypertension a main source of superoxide anions could be the cyclooxygenase pathway.

Conclusions
—In essential hypertensive patients, impaired endothelial vasodilation can be improved by the antioxidant vitamin C, an effect that can be reversed by the nitric oxide synthase inhibitor
N
G
-monomethyl-
l
-arginine. These findings support the hypothesis that nitric oxide inactivation by oxygen free radicals contributes to endothelial dysfunction in essential hypertension.
Ventriculophasic Modulation of Atrioventricular Nodal Conduction in Humans
Authors: Skanes Allan C. , Tang Anthony S. L.
Published: June 2012

Background
—Baroreceptor-mediated phasic changes in vagal tone have been hypothesized to cause ventriculophasic sinus arrhythmia (VPSA). The objectives of this study were to demonstrate ventriculophasic modulation of AV nodal conduction and to substantiate the role of the baroreflex on ventriculophasic AV nodal conduction (VPAVN) by pharmacological perturbation of parasympathetic tone.

Methods and Results
—Twelve patients with infra-Hisian second-degree heart block and VPSA were studied. Incremental atrial pacing was performed until AV nodal Wenckebach block at baseline, after phenylephrine infusion, and after atropine. AV nodal conduction curves were constructed for each phase and compared. At baseline, VPAVN was present in 9 of 12 patients on the steep portion of the AV nodal conduction curves. Phenylephrine increased systolic blood pressure from 149±33 to 177±22 mm Hg (
P
<0.001) and sinus cycle length from 844±169 to 1010±190 ms (
P
<0.001) and shifted the AV nodal conduction curves up and to the right. Phenylephrine induced VPAVN in 2 of 3 patients in whom it was not present at baseline and in 11 of 12 total. Atropine abolished both VPSA and VPAVN in all patients.

Conclusions
—VPAVN was demonstrated in patients with infra-Hisian second-degree AV block. It was accentuated by phenylephrine and abolished by atropine, suggesting a baroreflex mechanism for VPSA and VPAVN.
Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo
Authors: Ferro Charles J. , Spratt James C. , Haynes William G. , Webb David J.
Published: June 2012

Background
—Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone.

Methods and Results
—Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12±2%;
P
=0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (
P
=0.6) after pretreatment with both placebo (13±1%,
P
=0.006) and enalapril (17±6%,
P
=0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ET
A
antagonist BQ-123 (100 nmol/min), and both combined. Thiorphan caused local forearm vasoconstriction (13±1%,
P
=0.0001); BQ-123 caused local vasodilatation (33±3%,
P
=0.0001). Combined thiorphan and BQ-123 caused vasodilatation (32±1%,
P
=0.0001) similar to BQ-123 alone (
P
=0.98). In a fourth study, 6 hypertensive patients (blood pressure >160/100 mm Hg) received intra-arterial thiorphan (30 nmol/min). Thiorphan caused a slowly progressive forearm vasoconstriction (10±2%,
P
=0.0001).

Conclusions
—Inhibition of local NEP causes vasoconstriction in forearm resistance vessels of both healthy volunteers and patients with hypertension. The lack of effect of ACE inhibition on the vasoconstriction produced by thiorphan and its absence during concomitant ET
A
receptor blockade suggest that it is mediated by endothelin-1 and not angiotensin II. These findings may help to explain the failure of systemic NEP inhibition to lower blood pressure.
Marked Reduction in Internal Atrial Defibrillation Thresholds With Dual-Current Pathways and Sequential Shocks in Humans
Authors: Cooper Randolph A. S. , Plumb Vance J. , Epstein Andrew E. , Kay G. Neal , Ideker Raymond E.
Published: June 2012

Background
—This study tested the ability of sequential shocks delivered through dual-current pathways to lower the atrial defibrillation threshold (ADFT) compared with a biphasic shock through a standard single-current pathway.

Methods and Results
—Electrodes were positioned in the right atrial appendage (RA), left subclavian vein (LSV), proximal coronary sinus (CSos), and distal coronary sinus (DCS) in 14 patients with chronic atrial fibrillation (170±185 days). Using a step-up protocol, we compared ADFTs for a single-current pathway (RA→DCS) that used a single 7.5/2.5-ms biphasic shock from a 150-μF capacitor with those for a dual-current pathway system (RA→DCS followed by CSos→LSV) using sequential 7.5/2.5-ms biphasic shocks with capacitor discharge waveforms for 150-μF and 600-μF capacitors. Both dual-current pathway configurations (2.0±0.4 J for 150-μF capacitance, 2.4±0.5 J for 600-μF capacitance) had a significantly lower ADFT than the single-current pathway (5.1±1.8 J). Whereas the dual-current pathway with 150-μF capacitor shocks had a significantly lower energy threshold, there was no statistical difference in terms of leading-edge voltage compared with the dual-current pathway with 600-μF capacitance shocks. There were no ventricular arrhythmias induced with appropriately synchronized shocks.

Conclusions
—For internal atrial defibrillation in humans, sequential biphasic waveforms delivered over dual-current pathways resulted in a markedly reduced (>50% reduction) ADFT compared with a single shock over a single-current pathway.
Decreased Coronary Flow Reserve in Hypertrophic Cardiomyopathy Is Related to Remodeling of the Coronary Microcirculation
Authors: Krams R. , Kofflard M. J. M. , Duncker D. J. , Von Birgelen C. , Carlier S. , Kliffen M. , Cate F. J. ten , Serruys P. W.
Published: June 2012

Background
—Ischemia occurs frequently in hypertrophic cardiomyopathy (HCM) without evidence of epicardial stenosis. This study evaluates the hypothesis that the occurrence of ischemia in HCM is related to remodeling of the coronary microcirculation.

Methods and Results
—End-diastolic septal wall thickness was significantly increased in patients with HCM (25.8±2.9 mm) in comparison with cardiac transplant recipients (control subjects: 11.4±3.0 mm;
P
<0.05). Although the diameter of the left anterior descending coronary artery was similar in both groups (3.0±0.8 versus 3.0±0.5 mm,
P
=NS), the coronary resistance reserve (CRR=CRR
basal
/CRR
hyperemic
), corrected for extravascular compression (end-diastolic left ventricular pressure), was reduced to 1.5±0.6 in HCM (
P
<.05; control, 2.6±0.8). Arteriolar lumen (AL) divided by wall area was lower in HCM (21±5% versus 30±4%;
P
<.05), and capillary density tended to decrease (from 1824±424 to 1445±513 per mm
2
,
P
=.11) in HCM. CRR was linearly related to normalized AL according to the formula CRR=0.1 AL−0.45 (
r
=.57;
P
<.05). Further analysis revealed that CRR, AL, and capillary density were all linearly related to the degree of hypertrophy.

Conclusions
—Decrements in CRR were related to changes of the coronary microcirculation. Both the decrease in CRR and these changes in the coronary microcirculation were related to the degree of hypertrophy. All these factors might contribute to the well-known occurrence of ischemia in this patient group.
Angiotensin II Type 1a Receptor Is Involved in the Occurrence of Reperfusion Arrhythmias
Authors: Harada Koichiro , Komuro Issei , Hayashi Doubun , Sugaya Takeshi , Murakami Kazuo , Yazaki Yoshio
Published: June 2012

Background
—A growing body of evidence has suggested that the renin-angiotensin system plays an important role in the development of cardiac hypertrophy induced by hemodynamic overload and left ventricular remodeling after myocardial infarction. The role of the renin-angiotensin system in ischemia-reperfusion (IR) injury, however, has not been established.

Methods and Results
—To determine the role of angiotensin II (Ang II) in IR injury, we examined infarct size and arrhythmias after IR using Ang II type 1a receptor (AT1a) knockout mice. The left coronary artery was occluded for 30 minutes followed by reperfusion for 120 minutes. There were no significant differences in infarct size between wild-type and knockout mice determined by dual staining with triphenyltetrazolium chloride and Evans blue dye. The number of ventricular premature beats after reperfusion in knockout mice, however, was much less than in wild-type mice. Treatment with a selective AT1 antagonist, CV-11974, before ischemia blocked reperfusion arrhythmias in wild-type mice but had no effects on infarct size.

Conclusions
—Ang II may be critically involved in the induction of ventricular arrhythmias but not in the determination of infarct size after IR.
Low Circulating Folate and Vitamin B
6
Concentrations
Authors: Robinson Killian , Arheart Kristopher , Refsum Helga , Brattström Lars , Boers Godfried , Ueland Per , Rubba Paolo , Palma-Reis Roberto , Meleady Raymond , Daly Leslie , Witteman Jacqueline , Graham Ian
Published: June 2012

Background
—A high plasma homocysteine concentration is a risk factor for atherosclerosis, and circulating concentrations of homocysteine are related to levels of folate and vitamin B
6
. This study was performed to explore the interrelationships between homocysteine, B vitamins, and vascular diseases and to evaluate the role of these vitamins as risk factors for atherosclerosis.

Methods
—In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B
12
, and vitamin B
6
.

Results
—In a conditional logistic regression model, homocysteine concentrations greater than the 80th percentile for control subjects either fasting (12.1 μmol/L) or after a methionine load (38.0 μmol/L) were associated with an elevated risk of vascular disease independent of all traditional risk factors. In addition, concentrations of red cell folate below the lowest 10th percentile (<513 nmol/L) and concentrations of vitamin B
6
below the lowest 20th percentile (<23.3 nmol/L) for control subjects were also associated with increased risk. This risk was independent of conventional risk factors and for folate was explained in part by increased homocysteine levels. In contrast, the relationship between vitamin B
6
and atherosclerosis was independent of homocysteine levels both before and after methionine loading.

Conclusions
—Lower levels of folate and vitamin B
6
confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.
Infection With
Chlamydia pneumoniae
Accelerates the Development of Atherosclerosis and Treatment With Azithromycin Prevents It in a Rabbit Model
Authors: Muhlestein Joseph B. , Anderson Jeffrey L. , Hammond Elizabeth H. , Zhao Liping , Trehan Sanjeev , Schwobe Eric P. , Carlquist John F.
Published: June 2012

Background
—
Chlamydia pneumoniae
infection has been associated with atherosclerosis by serological studies and detection of bacterial antigen within plaque. We sought to evaluate a possible causal role in an animal model.

Methods and Results
—Thirty New Zealand White rabbits were given three separate intranasal inoculations of either
C pneumoniae
(n=20) or saline (n=10) at 3-week intervals and fed chow enriched with a small amount (0.25%) of cholesterol. Immediately after the final inoculation, infected and control rabbits were randomized and begun on a 7-week course of azithromycin or no therapy. Three months after the final inoculation, rabbits were euthanatized and sections of thoracic aortas were blindly evaluated microscopically for maximal intimal thickness (MIT), percentage of luminal circumference involved (PLCI), and plaque area index (PAI) of atherosclerosis. Vascular chlamydial antigen was assessed by direct immunofluorescence. MIT differed among treatment groups (
P
=.009), showing an increase in infected rabbits (0.55 mm; SE=0.15 mm) compared with uninfected controls (0.16 mm; SE=0.06 mm) and with infected rabbits receiving antibiotics (0.20 mm; SE=0.03 mm) (both
P
<.025), whereas MIT in infected/treated versus control rabbits did not differ. PLCI also tended to differ (
P
<.1) and PAI differed significantly (
P
<.01) among groups with a similar pattern. Chlamydial antigen was detected in 2 untreated, 3 treated, and 0 control animals.

Conclusions
—Intranasal
C pneumoniae
infection accelerates intimal thickening in rabbits given a modestly cholesterol-enhanced diet. In addition, weekly treatment with azithromycin after infectious exposure prevents accelerated intimal thickening. These findings strengthen the etiologic link between
C pneumoniae
and atherosclerosis and should stimulate additional animal and human studies, including clinical antibiotic trials.
Fifteen-Year Trends in Risk Severity and Operative Mortality in Elderly Patients Undergoing Coronary Artery Bypass Graft Surgery
Authors: Ivanov Joan , Weisel Richard D. , David Tirone E. , Naylor C. David
Published: June 2012

Background
—Trends in risk-severity and operative mortality (OM) were examined in 3330 consecutive patients aged 70 years and older who underwent isolated coronary artery bypass graft surgery (CABG) between 1982 and 1996.

Methods and Results
—The proportion of elderly patients rose significantly over time (
P
<.001). Crude OM among the elderly was 7.2% in 1982 to 1986, fell to 4.4% in 1987 to 1991, but did not improve thereafter. Logistic regression analysis of OM was used to construct relative risk groups (low, medium, or high). The prevalence of high-risk elderly patients rose significantly over time (
P
=.001) from 16.2% in 1982 to 1986 to 19.5% in 1987 to 1991 and 26.9% in 1992 to 1996. OM in high-risk patients fell significantly (
P
=.044) from 17.2% in 1982 to 1986 to 9.1% in 1987 to 1991 and was 8.9% in 1992 to 1996. Contemporary independent predictors of OM among elderly patients were poor ventricular function (LV grade 2 to 3, odds ratio [OR], 2.6; 95% confidence interval [CI], 1.3 to 5.2; and LV grade 4, OR, 10.7; 95% CI, 4.4 to 26); previous CABG (OR, 3.7; 95% CI, 2.0 to 7.0), female sex (OR, 1.8; 95% CI, 1.1 to 2.8), peripheral vascular disease (OR, 1.8; 95% CI, 1.1 to 2.8), and diabetes (OR, 1.7; 95% CI, 1.1 to 2.7). Previous angioplasty was protective (OR, 0.3; 95% CI, 0.1 to 0.9).

Conclusions
—OM in elderly patients has declined significantly in recent years despite an increase in the prevalence and severity of their risk factors. A careful weighing of risk, rather than advanced age alone, should determine who is offered surgical revascularization. In this regard, poor ventricular function and repeat CABG continue to have the greatest impact on OM in elderly patients.
Endothelin Receptors in the Failing and Nonfailing Human Heart
Authors: Pönicke Klaus , Vogelsang Magdalene , Heinroth Moritz , Becker Karin , Zolk Oliver , Böhm Michael , Zerkowski Hans-Reinhard , Brodde Otto-Erich
Published: June 2012

Background
—In patients with chronic heart failure (CHF), plasma endothelin-1 (ET-1) levels are increased. We studied whether the cardiac ET-receptor system is altered in CHF patients.

Methods and Results
—We assessed ET-evoked inositol phosphate (IP) formation in slices from right atria and left ventricles from 6 potential heart transplant donors (NFH) and 15 patients with end-stage CHF; in membranes from the same tissues, we studied ET-induced inhibition of isoprenaline- and forskolin-stimulated adenylyl cyclase and ET-receptor density. ET (10
−9
to 10
−6
mol/L, ET-1 >>> ET-3) increased IP formation in right atria and left ventricles through ET
A
-receptor stimulation in a concentration-dependent manner; no difference in potency or efficacy between NFH and CHF hearts was observed. ET-1 (10
−10
to 10
−6
mol/L), via ET
A
-receptor stimulation, inhibited isoprenaline- and forskolin-stimulated adenylyl cyclase in right atria but not in left ventricles, whereas carbachol inhibited adenylyl cyclase in both tissues; again, the potency and efficacy of ET- or carbachol-induced adenylyl cyclase inhibition was not different between NFH and CHF hearts. [
125
I]ET-1 binding revealed the coexistence of ET
A
and ET
B
receptors in both tissues; however, the density of ET
A
receptors was not significantly different between NFH and CHF hearts. Finally, the immunodetectable amount of left ventricular G
q/11
protein did not differ between NFH and CHF hearts.

Conclusions
—In the human heart, ET
A
and ET
B
receptors coexist; however, only ET
A
receptors are of functional importance. In right atria, ET
A
receptors couple to IP formation and inhibition of adenylyl cyclase; in left ventricles, they couple only to IP formation. In end-stage CHF, the functional responsiveness of the cardiac ET
A
-receptor system is not altered.
Circadian Variations in the Occurrence of Cardiac Arrests
Authors: Peckova Monika , Fahrenbruch Carol E. , Cobb Leonard A. , Hallstrom Alfred P.
Published: June 2012

Background
—Patterns of temporal variation of cardiac arrests may be important for understanding mechanisms leading to the onset of acute cardiovascular disorders. Previous studies reported diurnal variation of the onset of cardiac arrests, with high incidence in the morning and in the evening, lack of daily variation during the week, and some seasonal variation. The association between the time of day and recurrent cardiac arrests has not been previously examined.

Methods and Results
—We explored temporal variation in 6603 out-of-hospital cardiac arrests attended by the Seattle Fire Department. The data exhibit diurnal variation, with a low incidence at night and two peaks of approximately the same size (at 8 to 11
am
and 4 to 7
pm
). The evening peak is attributed primarily to the patients found in ventricular fibrillation, whereas arrests that show other rhythms exhibit mainly a morning peak. Cardiac arrests associated with survival have more pronounced diurnal variation than episodes in which survival did not occur. This difference persists after adjustment for rhythm. For 597 patients who had at least two separate cardiac arrests, we found no overall association between the times of day of the recurrent arrests. For women, however, the times of day of the first and second arrests were closer to each other than one would expect if the times were entirely unrelated.

Conclusions
—Cardiac arrests do not occur randomly during the day, but rather follow certain periodic patterns. These patterns are probably associated with patterns of daily activities. The hypothesis that cardiac arrests are triggered by a person’s activity rather than by some underlying characteristics of his or her disease is supported by the lack of association between the times of the first and second arrests in the patients with recurrent arrests.
Improved Assessment of Coronary Stenosis Severity Using the Relative Flow Velocity Reserve
Authors: Baumgart Dietrich , Haude Michael , Goerge Guenter , Ge Junbo , Vetter Sabine , Dagres Nikolaos , Heusch Gerd , Erbel Raimund
Published: June 2012

Background
—Myocardial fractional flow reserve (FFR) is based on pressure measurements. We have now sought to establish a Doppler-based concept of relative flow velocity reserve (RFVR) for the functional assessment of stenosis severity in epicardial coronary arteries. A clear threshold value to discriminate the functional severity of a coronary stenosis does not exist for coronary flow velocity reserve (CVR) based on intracoronary Doppler measurements. In contrast, the concept of FFR, which is based on intracoronary pressure measurements, has been extensively validated. An FFR value below 0.75 reliably indicates a significant stenosis.

Methods and Results
—RFVR is calculated as the ratio between distal CVR in the stenosed target vessel and distal CVR in a nonstenotic reference vessel. In 21 patients, RFVR was determined in 24 target vessels by use of intracoronary adenosine and correlated to the FFR, determined as the ratio of mean poststenotic to aortic pressures, in the target vessel. Stenosis severity was classified according to quantitative coronary angiography analysis. Reference diameter was 3.0±0.4 mm (mean±SD), and area stenosis was 74±15% (range, 40% to 95%). CVRs in the target and reference vessels were 2.1±0.5 and 2.6±0.7, respectively. FFR ranged from 0.49 to 0.99 (mean, 0.81±0.15) and RFVR from 0.53 to 1.0 (mean, 0.82±0.13). Poststenotic CVR did not correlate with either percent area stenosis (
r
=0.27,
P
=NS) or FFR (
r
=0.33,
P
=NS). In contrast, FFR as well as RFVR showed a curvilinear relation to percent area stenosis (
r
=0.89,
P
<0.0001 and
r
=0.79,
P
<0.0001, respectively). There was a close linear correlation between FFR and RFVR (
r
=0.91,
P
<0.0001).

Conclusions
—RFVR correlates closely to FFR and to percent area stenosis, whereas the correlation of CVR with FFR and percent area stenosis is rather poor. RFVR is a promising new concept for assessment of coronary stenosis severity and clinical decision making based on Doppler measurements.
Acute Effects of Toborinone on Vascular Capacitance and Conductance in Experimental Heart Failure
Authors: Semeniuk Lisa M. , Belenkie Israel , Tyberg John V.
Published: June 2012

Background
—Toborinone (OPC-18790), a phosphodiesterase III inhibitor, enhances cardiac contractility and is an arterial dilator. However, its effects on the venous system have not yet been clearly defined. Because toborinone administration reduces left ventricular (LV) end-diastolic pressure, it is probably also a venodilator. Because of the known arterial effects and the hypothesized venous effects, we compared changes in systemic vascular conductance (the inverse of resistance) with changes in venous capacitance.

Methods and Results
—In 15 anesthetized, splenectomized dogs (10 treatment, 5 control), pressures were measured in the right atrium, aorta, portal vein, and LV. A cuff constrictor was placed around the portal vein. Cardiac output was measured by thermodilution, and splanchnic vascular capacitance was measured by blood-pool scintigraphic methods. Data were collected at baseline, after induction of heart failure (microsphere embolization into the left coronary artery), and then after toborinone boluses of 0.1, 0.2, 0.4, and 0.8 mg/kg. Heart failure was associated with decreased capacitance and conductance (to 87±3% and 64±4% of baseline values, respectively,
P
<0.05). After administration of the lower doses of toborinone, capacitance increased more than conductance; however, the effects were more balanced at the higher doses. Compared with nitroglycerin, hydralazine, and enalaprilat (results of an earlier study) in the same model, toborinone increased capacitance to a degree similar to that with nitroglycerin, at higher doses increased conductance similarly to hydralazine, and increased both capacitance and conductance considerably more than did enalaprilat.

Conclusions
—Toborinone is a potent balanced venous and arterial dilator in experimental acute heart failure. These marked effects suggest that it may prove to be a clinically important alternative to other vasodilators.
Adenosine Concentrations in the Interstitium of Resting and Contracting Human Skeletal Muscle
Authors: Hellsten Ylva , Maclean Dave , Rådegran Göran , Saltin Bengt , Bangsbo Jens
Published: June 2012

Background
—Adenosine has been proposed to be a locally produced regulator of blood flow in skeletal muscle. However, the fundamental questions of to what extent adenosine is formed in skeletal muscle tissue of humans, whether it is present in the interstitium, and where it exerts its vasodilatory effect remain unanswered.

Methods and Results
—The interstitial adenosine concentration was determined in the vastus lateralis muscle of healthy humans via dialysis probes inserted in the muscle. The probes were perfused with buffer, and the dialysate samples were collected at rest and during graded knee extensor exercise. At rest, the interstitial concentration of adenosine was 220±100 nmol/L and femoral arterial blood flow (FaBF) was 0.19±0.02 L/min. When the subjects exercised lightly, at a work rate of 10 W, there was a markedly higher (1140±540 nmol/L;
P
<0.05) interstitial adenosine concentration and a higher FaBF (2.22±0.18 L/min;
P
<0.05) compared with at rest. When exercise was performed at 20, 30, 40, or 50 W, the concentration of adenosine was moderately greater for each increment, as was the level of leg blood flow. The interstitial concentrations of ATP, ADP, and AMP increased from rest (0.13±0.03, 0.07±0.03, and 0.07±0.02 μmol/L, respectively) to exercise (10 W; 2.00±1.32, 2.08±1.23, and 1.65±0.50 μmol/L, respectively;
P
<0.05).

Conclusions
—The present study provides, for the first time, interstitial adenosine concentrations in human skeletal muscle and demonstrates that adenosine and its precursors increase in the exercising muscle interstitium, at a rate associated with intensity of muscle contraction and the magnitude of muscle blood flow.
Effects of Postshock Atrial Pacing on Atrial Defibrillation Outcome in the Isolated Sheep Heart
Authors: Skanes A. C. , Gray R. A. , Zuur C. L. , Jalife J.
Published: June 2012

Background
—Failed atrial defibrillation shocks are associated with organization of postshock activity and a substantial postshock electrical quiescence. We investigated the ability of a train of pacing stimuli to capture or locally entrain atrial myocardium during the quiescent period after low-energy shocks and to alter defibrillation outcome.

Methods and Results
—High-resolution video imaging of near-defibrillation-threshold atrial shocks was performed in 12 Langendorff-perfused sheep hearts. A train of 10 pacing stimuli (10-ms pulse width, 200-ms cycle length) was coupled to the shock at various delays in 7 hearts. Coupling intervals of 40 to 130 ms were investigated for feasibility of capture of the first pacing stimulus. The success rate of capture was 0, 0.08±0.08, 0.43±0.13, 0.73±0.13, and 0.11±0.1 for 40-, 60-, 80-, 100-, and 120-ms coupling intervals, respectively (
P
<0.001). In 5 experiments, the coupling interval was fixed at 100 ms (highest success, see above), and the pacing stimulus amplitude was varied between 1.0, 2.0, and 4.0 V. Successful capture rates were 0.38±0.08, 0.75±0.08, and 0.64±0.08, respectively (
P
<0.003 for 1.0 versus 2.0 V,
P
=0.2 for 2.0 versus 4.0 V). Rates of successful defibrillation for the groups without and with pacing were 0.56±0.07 and 0.64±0.04, respectively (
P
=0.3). With capture of the first pacing stimulus, the rate of successful defibrillation rose to 0.75±0.05 (
P
<0.01); it remained unchanged without capture (0.48±0.07 versus 0.56±0.07 for no pacing).

Conclusions
—Pacing during the quiescent period that follows defibrillation shocks is feasible. A pacing train whose first pacing stimulus successfully captures during the quiescent period of near-defibrillation-threshold shocks appears to alter the outcome.
Angiotensin Production by the Heart
Authors: van Kats Jorge P. , Danser A. H. Jan , van Meegen Jan R. , Sassen Loes M. A. , Verdouw Pieter D. , Schalekamp Maarten A. D. H.
Published: June 2012

Background
—Beneficial effects of ACE inhibitors on the heart may be mediated by decreased cardiac angiotensin II (Ang II) production.

Methods and Results
—To determine whether cardiac Ang I and Ang II are produced in situ or derived from the circulation, we infused
125
I-labeled Ang I or II into pigs (25 to 30 kg) and measured
125
I-Ang I and II as well as endogenous Ang I and II in cardiac tissue and blood plasma. In untreated pigs, the tissue Ang II concentration (per gram wet weight) in different parts of the heart was 5 times the concentration (per milliliter) in plasma, and the tissue Ang I concentration was 75% of the plasma Ang I concentration. Tissue
125
I-Ang II during
125
I-Ang II infusion was 75% of
125
I-Ang II in arterial plasma, whereas tissue
125
I-Ang I during
125
I-Ang I infusion was <4% of
125
I-Ang I in arterial plasma. After treatment with the ACE inhibitor captopril (25 mg twice daily), Ang II fell in plasma but not in tissue, and Ang I and renin rose both in plasma and tissue, whereas angiotensinogen did not change in plasma and fell in tissue. Tissue
125
I-Ang II derived by conversion from arterially delivered
125
I-Ang I fell from 23% to <2% of
125
I-Ang I in arterial plasma.

Conclusions
—Most of the cardiac Ang II appears to be produced at tissue sites by conversion of in situ–synthesized rather than blood-derived Ang I. Our study also indicates that under certain experimental conditions, the heart can maintain its Ang II production, whereas the production of circulating Ang II is effectively suppressed.
Determination of Right Ventricular Structure and Function in Normoxic and Hypoxic Mice
Authors: Scherrer-Crosbie Marielle , Steudel Wolfgang , Hunziker Patrick R. , Foster Gary P. , Garrido Leoncio , Liel-Cohen Noah , Zapol Warren M. , Picard Michael H.
Published: June 2012

Background
—Noninvasive cardiac evaluation is of great importance in transgenic mice. Transthoracic echocardiography can visualize the left ventricle well but has not been as successful for the right ventricle (RV). We developed a method of transesophageal echocardiography (TEE) to evaluate murine RV size and function.

Methods and Results
—Normoxic and chronically hypoxic mice (F
io
2
=0.11, 3 weeks) and agarose RV casts were scanned with a rotating 3.5F/30-MHz intravascular ultrasound probe. In vivo, the probe was inserted in the mouse esophagus and withdrawn to obtain contiguous horizontal planes at 1-mm intervals. In vitro, the probe was withdrawn along the left ventricular posterior wall of excised hearts. The borders of the RV were traced on each plane, allowing calculation of diastolic and systolic volumes, RV mass, RV ejection fraction, stroke volume, and cardiac output. RV wall thickness was measured. Echo volumes obtained in vitro were compared with cast volumes. Echo-derived cardiac output was compared with measurements of an ascending aortic Doppler flow probe. Echo-derived RV free wall mass was compared with true RV free wall weight. There was excellent agreement between cast and TEE volumes (
y
=0.82
x
+6.03,
r
=0.88,
P
<0.01) and flow-probe and echo cardiac output (
y
=1.00
x
+0.45,
r
=0.99,
P
<0.0001). Although echo-derived RV mass and wall thickness were well correlated with true RV weight, echo-derived RV mass underestimated true weight (
y
=0.53
x
+2.29,
r
=0.81,
P
<0.0001). RV mass and wall thickness were greater in hypoxic mice than in normoxic mice (0.78±0.19 versus 0.51±0.14 mg/g,
P
<0.03, 0.50±0.03 versus 0.38±0.03 mm,
P
<0.04).

Conclusions
—TEE with an intravascular ultrasound catheter is a simple, accurate, and reproducible method to study RV size and function in mice.