bluuebunny/crossref_metadata_2025 huggingface dataset:
Vasodilation to Bradykinin Is Mediated by an Ouabain-Sensitive Pathway as a Compensatory Mechanism for Impaired Nitric Oxide Availability in Essential Hypertensive Patients
Authors: Taddei Stefano , Ghiadoni Lorenzo , Virdis Agostino , Buralli Simona , Salvetti Antonio
Published: June 2012

Background
—In essential hypertension, endothelium-dependent vasodilation is impaired because of reduced nitric oxide (NO) availability, which is mainly caused by oxidative stress. The present study was designed to identify the mechanism(s) responsible for NO-independent vasodilation to bradykinin in patients with essential hypertension.

Methods and Results
—In 16 healthy subjects (49.5±5.8 years; 118.6±3.5/78.9±2.9 mm Hg) and 16 patients with essential hypertension (47.9±4.8 years; 154.6±4.5/102.9±3.2 mm Hg), we measured modifications in forearm blood flow (strain-gauge plethysmography) during intrabrachial infusion of bradykinin (5, 15, or 50 ng/100 mL of forearm tissue per minute) in the presence of saline, N
ω
-monomethyl-
l
-arginine (L-NMMA; used to inhibit NO synthase; 100 μg/100 mL of forearm tissue per minute), and ouabain (to block Na
+
K
+
/ATPase and prevent hyperpolarization; 0.7 μg/100 mL of forearm tissue per minute). In healthy subjects, vasodilatation to bradykinin was significantly blunted by L-NMMA and unaffected by ouabain. In hypertensive patients, vasodilatation to bradykinin was not modified by L-NMMA, but it was significantly reduced by ouabain. In an adjunctive group of 8 hypertensive patients (49.9±3.8 years; 155.9±5.5/103.7±3.9 mm Hg), the response to bradykinin was repeated during the administration of intrabrachial vitamin C (a scavenger for oxygen free radicals; 8 mg/100 mL of forearm tissue per minute). In these patients, L-NMMA–induced inhibition of vasodilation to bradykinin was restored, and ouabain was no longer effective. In a final group of 6 normotensive controls (45.9±4.1 years; 115.1±2.9/79.3±2.1 mm Hg), vasodilation to bradykinin residual to L-NMMA blockade was further inhibited by simultaneous ouabain infusion.

Conclusions
—Vasodilation to bradykinin is impaired in essential hypertensive patients because of an NO-system alteration caused by oxidative stress, and it is mediated by an alternative pathway, possibly involving endothelium-dependent hyperpolarization.
Screening of Obstructive Sleep Apnea Syndrome by Heart Rate Variability Analysis
Authors: Roche Frédéric , Gaspoz Jean-Michel , Court-Fortune Isabelle , Minini Pascal , Pichot Vincent , Duverney David , Costes Frédéric , Lacour Jean-René , Barthélémy Jean-Claude
Published: June 2012

Background
—Enhanced nocturnal heart rate variability (HRV) has been evoked in sleep-related breathing disorders. However, its capacity to detect obstructive sleep apnea syndrome (OSAS) has not been systematically determined. Thus, we evaluated the discriminant power of HRV parameters in a first group of patients (G1) and validated their discriminant capacity in a second group (G2).

Methods and Results
—In G1, 39 of 91 patients (42.8%) were identified as diseased by polysomnography, as were 24 of 52 patients (46%) in G2. Time-domain HRV variables (SD of NN intervals [SDNN], mean of the standard deviations of all NN intervals for all consecutive 5-minute segments of the recording [SDNN index], square root of the mean of the sum of the squares of differences between adjacent normal RR intervals [r-MSSD], and SD of the averages of NN intervals in all 5-minute segments of the recording [SDANN]) were calculated for daytime and nighttime periods, as well as the differences between daytime and nighttime values (Δ[D/N]). Correlations between HRV variables and OSAS status were analyzed in G1 by use of receiver-operating characteristic (ROC) curves and logistic regression analysis. By ROC curve analysis, 7 variables were significantly associated with OSAS. After adjustment for other variables through multiple logistic regression analysis, Δ[D/N]SDNN index and Δ[D/N] r-MSSD remained significant independent predictors of OSAS, with ORs of 8.22 (95% CI, 3.16 to 21.4) and 2.86 (95% CI, 1.21 to 6.75), respectively. The classification and regression tree methodology demonstrated a sensitivity reaching 89.7% (95% CI, 73.7 to 97.7) with Δ[D/N] SDNN index and a specificity of 98.1% (95% CI, 86.4 to 100) with Δ[D/N] SDNN using appropriate thresholds. These thresholds, applied to G2, yielded a sensitivity of 83% using Δ[D/N] SDNN index and a specificity of 96.5% using Δ[D/N] SDNN.

Conclusions
—Time-domain HRV analysis may represent an accurate and inexpensive screening tool in clinically suspected OSAS patients and may help focus resources on those at the highest risk.
Inhibition of Angiogenesis by Thrombospondin-1 Is Mediated by 2 Independent Regions Within the Type 1 Repeats
Authors: Iruela-Arispe M. Luisa , Lombardo Michele , Krutzsch Henry C. , Lawler Jack , Roberts David D.
Published: June 2012

Background
—Suppression of tumor growth by thrombospondin-1 (TSP-1) has been associated with its ability to inhibit neovascularization. The antiangiogenic activity of TSP-1, as defined by cornea pocket assays, was previously mapped to the amino-terminal portion of the protein within the procollagen region and the type 1 repeats.

Methods and Results
—We evaluated the specificity and efficacy of different regions of TSP-1 using recombinant fragments of the protein on chorioallantoic membrane (CAM) angiogenesis and endothelial cell proliferation assays. In both assays, fragments containing the second and third type 1 repeats but not the procollagen region inhibited angiogenesis and endothelial cell proliferation. To further define the sequences responsible for the angiostatic effect of TSP-1, we used synthetic peptides. The CAM assay defined 2 sequences that independently suppressed angiogenesis. The amino-terminal end of the type 1 repeats showed higher potency for inhibiting angiogenesis driven by basic fibroblast growth factor (FGF-2), whereas the second region equally blocked angiogenesis driven by either FGF-2 or vascular endothelial growth factor (VEGF). Modifications of the active peptides revealed the specific amino acids required for the inhibitory response. One sequence included the conserved tryptophan residues in the amino-terminal end of the second and third type 1 repeats, and the other involved the amino acids that follow the CSVTCG sequence in the carboxy-terminus of these repeats. Both inhibition in the CAM assay and inhibition of breast tumor xenograft growth in nude mice were independent of the TGF-β–activating sequence located in the second type 1 repeat.

Conclusions
—These results indicate that the type 1 repeats of TSP-1 contain 2 subdomains that may independently inhibit neovascularization. They also identify 2 independent pathways by which TSP-1 can block FGF-2 and VEGF angiogenic signals on endothelial cells.
Assessment of the Treatment Effect of Enoxaparin for Unstable Angina/Non–Q-Wave Myocardial Infarction
Authors: Antman Elliott M. , Cohen Marc , Radley David , McCabe Carolyn , Rush Janet , Premmereur Jerome , Braunwald Eugene
Published: June 2012

Background
—Two phase III trials of enoxaparin for unstable angina/non–Q-wave myocardial infarction have shown it to be superior to unfractionated heparin for preventing a composite of death and cardiac ischemic events. A prospectively planned meta-analysis was performed to provide a more precise estimate of the effects of enoxaparin on multiple end points.

Methods and Results
—Event rates for death, the composite end points of death/nonfatal myocardial infarction and death/nonfatal myocardial infarction/urgent revascularization, and major hemorrhage were extracted from the TIMI 11B and ESSENCE databases. Treatment effects at days 2, 8, 14, and 43 were expressed as the OR (and 95% CI) for enoxaparin versus unfractionated heparin. All heterogeneity tests for efficacy end points were negative, which suggests comparability of the findings in TIMI 11B and ESSENCE. Enoxaparin was associated with a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment, and this benefit was sustained through 43 days. Enoxaparin’s treatment benefit was not associated with an increase in major hemorrhage during the acute phase of therapy, but there was an increase in the rate of minor hemorrhage.

Conclusions
—The accumulated evidence, coupled with the simplicity of subcutaneous administration and elimination of the need for anticoagulation monitoring, indicates that enoxaparin should be considered as a replacement for unfractionated heparin as the antithrombin for the acute phase of management of patients with high-risk unstable angina/non–Q-wave myocardial infarction.
Cellular Basis for the Brugada Syndrome and Other Mechanisms of Arrhythmogenesis Associated With ST-Segment Elevation
Authors: Yan Gan-Xin , Antzelevitch Charles
Published: June 2012

Background
—The Brugada syndrome is characterized by marked ST-segment elevation in the right precordial ECG leads and is associated with a high incidence of sudden and unexpected arrhythmic death. Our study examines the cellular basis for this syndrome.

Methods and Results
—Using arterially perfused wedges of canine right ventricle (RV), we simultaneously recorded transmembrane action potentials from 2 epicardial and 1 endocardial sites, together with unipolar electrograms and a transmural ECG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 μmol/L), a K
+
channel opener, or the combination of a Na
+
channel blocker (flecainide, 7 μmol/L) and acetylcholine (ACh, 2 to 3 μmol/L) resulted in an abbreviation of epicardial response and a transmural dispersion of repolarization, which caused an ST-segment elevation in the ECG. ACh facilitated loss of the action potential dome, whereas isoproterenol (0.1 to 1 μmol/L) restored the epicardial dome, thus reducing or eliminating the ST-segment elevation. Heterogeneous loss of the dome caused a marked dispersion of repolarization within the epicardium and transmurally, thus giving rise to phase 2 reentrant extrasystole, which precipitated ventricular tachycardia (VT) and ventricular fibrillation (VF). Transient outward current (
I
to
) block with 4-aminopyridine (1 to 2 mmol/L) or quinidine (5 μmol/L) restored the dome, normalized the ST segment, and prevented VT/VF.

Conclusions
—Depression or loss of the action potential dome in RV epicardium creates a transmural voltage gradient that may be responsible for the ST-segment elevation observed in the Brugada syndrome and other syndromes exhibiting similar ECG manifestations. Our results also demonstrate that extrasystolic activity due to phase 2 reentry can arise in the intact wall of the canine RV and serve as the trigger for VT/VF. Our data point to
I
to
block (4-aminopyridine, quinidine) as an effective pharmacological treatment.
Comparison of Naive Sixth-Grade Children With Trained Professionals in the Use of an Automated External Defibrillator
Authors: Gundry John W. , Comess Keith A. , DeRook Frances A. , Jorgenson Dawn , Bardy Gust H.
Published: June 2012

Background
—Survival after out-of-hospital cardiac arrest (OHCA) is strongly influenced by time to defibrillation. Wider availability of automated external defibrillators (AEDs) may decrease response times but only with increased lay use. Consequently, this study endeavored to improve our understanding of AED use in naive users by measuring times to shock and appropriateness of pad location. We chose sixth-grade students to simulate an extreme circumstance of unfamiliarity with the problem of OHCA and defibrillation. The children’s AED use was then compared with that of professionals.

Methods and Results
—With the use of a mock cardiac arrest scenario, AED use by 15 children was compared with that of 22 emergency medical technicians (EMTs) or paramedics. The primary end point was time from entry onto the cardiac arrest scene to delivery of the shock into simulated ventricular fibrillation. The secondary end point was appropriateness of pad placement. All subject performances were videotaped to assess safety of use and compliance with AED prompts to remain clear of the mannequin during shock delivery. Mean time to defibrillation was 90±14 seconds (range, 69 to 111 seconds) for the children and 67±10 seconds (range, 50 to 87 seconds) for the EMTs/paramedics (
P
<0.0001). Electrode pad placement was appropriate for all subjects. All remained clear of the “patient” during shock delivery.

Conclusions
—During mock cardiac arrest, the speed of AED use by untrained children is only modestly slower than that of professionals. The difference between the groups is surprisingly small, considering the naïveté of the children as untutored first-time users. These findings suggest that widespread use of AEDs will require only modest training.
Progressive Cardiac Dysfunction and Fibrosis in the Cardiomyopathic Hamster and Effects of Growth Hormone and Angiotensin-Converting Enzyme Inhibition
Authors: Ryoke Tsutomu , Gu Yusu , Mao Lan , Hongo Minoru , Clark Ross G. , Peterson Kirk L. , Ross John
Published: June 2012

Background
—Growth hormone (GH) improves cardiac function in the rat with myocardial infarction, but its effects in a model of primary dilated cardiomyopathy have not been reported. GH effects were examined at early (4 months) and late (10 months) phases of disease in the cardiomyopathic (CM) hamster, and the combination of GH with chronic ACE inhibition was assessed in late-phase heart failure.

Methods and Results
—CM hamsters (CHF 147 line) at 4 months showed severe systolic left ventricular (LV) dysfunction with normal LV filling pressure, and at 10 months there was more severe systolic as well as diastolic dysfunction with increasing myocardial fibrosis. Recombinant human GH alone for 3 weeks at age 4 months increased LV wall thickness and reduced systolic wall stress without altering diastolic wall stress, whereas at 10 months, wall stress and fractional shortening did not improve. The LV dP/dt
max
was enhanced at both ages by GH, which at 4 months reflected increased contractility, but at 10 months was most likely caused by elevation of the LV filling pressure. The increasing degree of fibrosis correlated inversely with LV function but was unaffected by GH. In other CM hamsters, high-dose ACE inhibition alone (quinapril), started at 8 months and continued for 11 weeks, improved LV function and inhibited unfavorable remodeling, but the addition of GH for 3 weeks at age 10 months produced increased wall thickness with little additional functional benefit and increased the LV filling pressure and diastolic wall stress.

Conclusions
—GH treatment alone improved LV dysfunction at 4 months of age in CM hamsters by increasing contractility and reducing wall stress but had few beneficial effects at 10 months in severe LV failure. After chronic ACE inhibition, addition of GH at 10 months had no additional beneficial effects and further increased LV diastolic pressure. These differing effects of GH may relate to the progressive increase of LV fibrosis in the CM hamster.
Electroanatomic Left Ventricular Mapping in the Porcine Model of Healed Anterior Myocardial Infarction
Authors: Callans David J. , Ren Jian-Fang , Michele John , Marchlinski Francis E. , Dillon Stephen M.
Published: June 2012

Background
—Catheter ablation for ventricular tachycardia in healed infarction is limited to patients with inducible, tolerated arrhythmias. Strategies that would allow mapping during sinus rhythm might obviate this limitation.

Methods and Results
—Two sets of experiments were performed in adult pigs to refine a new technique for left ventricular mapping. First, detailed endocardial maps were done in 5 normal pigs and 7 pigs 6 to 10 weeks after left anterior descending coronary artery infarction to characterize electrograms in normal and infarcted tissue by electroanatomic mapping (CARTO, Biosense). Electrogram recording sites were verified by intracardiac echo (ICE, 9 MHz) and grouped by location: infarct (area of akinesis by ICE), border (0.5-cm perimeter of akinetic area), and remote. Compared with remote sites, electrograms from infarct sites had smaller amplitudes (1.2±0.5 versus 5.1±2.1 mV,
P
<0.001), longer durations (74.2±26.3 versus 36.3±6.4 ms,
P
<0.001), and more frequent notched or late components. Border zone electrograms were intermediate in amplitude and duration. Second, infarct characterization by electroanatomic mapping was compared with pathological (exclusion of triphenyltetrazolium chloride staining) and ICE measurements. Infarct size by pathology correlated with the area defined by contiguous electrograms with amplitude ≤1 mV (
r
=0.98,
P
=0.0001). Infarct size by ICE imaging correlated with the area defined by contiguous electrograms with amplitude ≤2 mV (
r
=0.95,
P
=0.0016).

Conclusions
—Electroanatomic mapping during sinus rhythm allows accurate 3D characterization of infarct architecture and defines the relationship of electrophysiological and anatomic abnormalities. This technique may prove useful in devising anatomically based strategies for ablation of ventricular tachycardia.
Central Pulmonary Artery Lesions in Chronic Obstructive Pulmonary Disease
Authors: Russo Aldo , De Luca Massimo , Vigna Carlo , Vincenzo De Rito  , Pacilli Michele , Lombardo Antonella , Armillotta Michele , Fanelli Raffaele , Loperfido Francesco
Published: June 2012

Background
—In patients with acute pulmonary embolism, transesophageal echocardiography (TEE) often reveals presumably thrombotic lesions within the central pulmonary arteries (CPAs). These CPA lesions, when found in patients with primary pulmonary hypertension, have been attributed to in situ thrombosis or atherosclerosis. We hypothesized that similar CPA lesions may also develop in patients with chronic obstructive pulmonary disease (COPD) in the absence of pulmonary embolism.

Methods and Results
—We examined by TEE 25 patients with COPD and 27 control patients with left heart disease. None of the patients had previous pulmonary embolism or ileofemoral and popliteal vein thrombosis. By use of TEE, CPA lesions were found in 12 COPD patients (48%) and 2 control patients (7.4%) (
P
<0.01). When CPA lesions were subdivided into types 1 (protruding and mobile) and 2 (wall-adherent), type 1 lesions proved to be uncommon, being found within the pulmonary trunk in 12% and 3.7% of COPD and control patients, respectively (
P
=NS). Conversely, type 2 lesions, which were always localized in the right pulmonary artery, were frequent in COPD patients (36%) and rare in control patients (3.7%) (
P
<0.01). When available, helical CT and MR angiography confirmed TEE findings, supporting an atherosclerotic origin of type 2 lesions, which were different from typical thrombotic lesions. FEV
1
/FVC ratio, RV/TLC ratio, Pa
o
2
, hematocrit value, and pulmonary artery systolic pressure were not significantly different in COPD patients with and without CPA lesions. At TEE, however, COPD patients with CPA lesions showed a larger size of the main and right pulmonary arteries.

Conclusions
—TEE often reveals CPA lesions in stable patients with COPD even in the absence of significant pulmonary hypertension and not in close relation with the severity of pulmonary dysfunction.
Local Perivascular Delivery of Basic Fibroblast Growth Factor in Patients Undergoing Coronary Bypass Surgery
Authors: Laham Roger J. , Sellke Frank W. , Edelman Elazer R. , Pearlman Justin D. , Ware J. Anthony , Brown David L. , Gold Jeffrey P. , Simons Michael
Published: June 2012

Background
—Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium.

Methods and Results
—We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 μg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 μg of bFGF (n=8), 100 μg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0±6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-μg bFGF group had angina, whereas all patients in the 100-μg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7±3.7% to 23.8±5.7%,
P
=0.06), no significant change in the 10-μg bFGF group, and significant improvement in the 100-μg bFGF group (19.2±5.0% to 9.1±5.9%,
P
=0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-μg bFGF group (10.7±3.9% to 3.7±6.3%,
P
=0.06).

Conclusions
—This study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.
Physiologically Assessed Coronary Collateral Flow and Intracoronary Growth Factor Concentrations in Patients With 1- to 3-Vessel Coronary Artery Disease
Authors: Fleisch Martin , Billinger Michael , Eberli Franz R. , Garachemani Ali R. , Meier Bernhard , Seiler Christian
Published: June 2012

Background
—The purpose of this study was to test the hypothesis that there is a relation between collateral flow and intracoronary concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and that the combined concentrations of both growth factors and the extent of coronary artery disease (CAD) play a role as covariables in such an association.

Methods and Results
—In 76 patients undergoing balloon angioplasty, a collateral flow index (CFI, no units) was determined with sensor-tipped guidewires. Simultaneously, serum concentrations of bFGF and VEGF, obtained at the aortic root from the ostium of the collateralized coronary artery (n=76) and from the distal position of the occluded coronary artery (n=34), were determined. There was a direct correlation between CFI and distal VEGF (
r
=0.33,
P
=0.05) but not bFGF concentrations. Focusing on the proximal sampling site, there was a direct correlation between CFI and both bFGF (
r
=0.29,
P
=0.01) and VEGF concentrations (
r
=0.44,
P
<0.0001). The sum of the concentrations of both growth factors was directly associated with CFI irrespective of the proximal (
r
=0.51,
P
<0.0001) or distal sampling site (
r
=0.34,
P
=0.048). There was a trend toward higher proximal VEGF concentrations in patients with higher numbers of coronary stenotic lesions (
r
=0.25,
P
=0.03).

Conclusions
—In patients with CAD, there is an association between a directly measured index of collateral flow and intracoronary concentrations of bFGF and VEGF. This direct relation is dependent on the site of blood sampling within the coronary artery tree. The association is closest when the combined bFGF and VEGF concentrations are taken into account. In the case of VEGF, it is influenced by the degree of coronary atherosclerosis.
Relation Between Lesion Characteristics and Risk With Percutaneous Intervention in the Stent and Glycoprotein IIb/IIIa Era
Authors: Ellis Stephen G. , Guetta Victor , Miller Dave , Whitlow Patrick L. , Topol Eric J.
Published: June 2012

Background
—The currently used American College of Cardiology/American Heart Association lesion classification scheme dates from an era when balloon angioplasty was the only percutaneous treatment available and major complications occurred in ≈7% of patients. Major advances in treatment options would suggest that this scheme may be outmoded, but the schemes that have been suggested to update lesion classification have not been widely accepted.

Methods and Results
—Four thousand one hundred eighty-one consecutive patients (6676 lesions) formed a training set and 2146 patients (4231 lesions) formed a validation set treated from 1995 to 1997 at a single center used by 3 hospital groups. Twenty-seven pretreatment candidate variables were analyzed with the use of stepwise proportional logistic regression, and 9 (nonchronic total occlusion with TIMI flow 0, degenerated vein graft, vein graft age >10 years, lesion length ≥10 mm, severe calcium, lesion irregularity, large filling defect, angulated ≥45 degrees plus calcium, and eccentricity) were independently correlated (
P
<0.05) with ranked adverse outcome (death, Q-wave or creatine kinase ≥3× normal myocardial infarction, or emergency coronary artery bypass grafting≫creatine kinase 2 to 3× myocardial infarction≫possibly related to non–Q-wave myocardial infarction≫no complication). A scheme based on these findings and the old American College of Cardiology/American Heart Association scheme were found to have c-statistics in the validation set of 0.672 and 0.620 (
P
=0.010 vs old scheme), respectively.

Conclusions
—Appreciation of these contemporary risk factors for complications of coronary intervention may assist in patient selection and in risk adjustment for comparison of outcomes between providers.
Induction of Nitric Oxide Synthase and Dual Effects of Nitric Oxide and Cyclooxygenase Products in Regulation of Arterial Contraction in Human Septic Shock
Authors: Stoclet J. C. , Martínez M. C. , Ohlmann P. , Chasserot S. , Schott C. , Kleschyov A. L. , Schneider F. , Andriantsitohaina R.
Published: June 2012

Background
—The role of endogenous nitric oxide (NO) and cyclooxygenase metabolites was investigated in contractile responses of small omental arteries from patients with hyperdynamic septic shock.

Methods and Results
—Expression of inducible NO synthase (immunostaining) and a high but variable level of NO production (NO spin trapping) was detected in arteries from patients with septic shock. In these vessels, ex vivo contractile responses to the thromboxane A
2
analogue U46619 and to low concentrations of norepinephrine (NE) (up to 10 μmol/L) were not significantly different from controls. However, higher concentrations of NE caused pronounced fading of contraction in septic but not in nonseptic arteries. Exposure to either the NO synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester or the cyclooxygenase inhibitor indomethacin had no effect in control vessels. However, both inhibitors increased the response to the contractile effects of the 2 agonists only in patients with septic shock. In contrast to
N
G
-nitro-
l
-arginine methyl ester, which decreased the threshold concentration of the fading effect of NE, indomethacin abolished this effect in arteries from septic patients.

Conclusions
—These results provide direct evidence for the induction of NO synthase in small arteries from patients with septic shock. They suggest that in these arteries, increased production of NO, in conjunction with vasodilatory cyclooxygenase metabolites, contributes to counteract hyperreactivity to agonists and decreases the cyclooxygenase product–mediated pronounced fading of contraction caused by a high concentration of NE.
Feasibility of In Vivo Intravascular Ultrasound Tissue Characterization in the Detection of Early Vascular Transplant Rejection
Authors: Jeremias Allen , Kolz Mathew L. , Ikonen Tuija S. , Gummert Jan F. , Oshima Akio , Hayase Motoya , Honda Yasuhiro , Komiyama Nobuyuki , Berry Gerald J. , Morris Randall E. , Yock Paul G. , Fitzgerald Peter J.
Published: June 2012

Background
—Unprocessed ultrasound radiofrequency (RF) signal analysis has been shown to distinguish different tissue structures more reliably than gray-scale interpretation of conventional ultrasound images.

Methods and Results
—The objective of this study was to test the feasibility of in vivo intravascular ultrasound (IVUS) RF signal analysis in an animal model of allograft rejection. Six cynomolgus monkeys underwent transplantation of 3-cm aortic allograft segments distal to the renal arteries from immunologically mismatched donors. IVUS imaging with a 30-MHz system was performed 84 to 105 days after the operation. RF signals were acquired from cross sections of the recipient and the allograft aortas in real time with a digitizer at 500 MHz with 8-bit resolution. Sixty-five cross sections and 68 regions of interest (31 in host aorta and 37 in allograft) were analyzed in the adventitial layer with a total number of 8568 vectors processed. For each region of interest, a weighted-average attenuation was calculated on the basis of the attenuation and length for each individual vector. Histological examination was performed at every cross section imaged by IVUS. When the gray-scale images of conventional IVUS scored by an independent observer were compared, no distinction between adventitia of the native aorta and allograft was possible. Analysis of the average RF backscatter power also showed no significant difference (70.32±3.55 versus 70.72±3.38 dB). However, the average attenuation of allografts was significantly lower than that of the host aortas (2.64±1.38 versus 4.02±1.16 dB/mm,
P
<0.001). Histology demonstrated a marked adventitial inflammatory response in all allografts, with no inflammation observed in the host aortas.

Conclusions
—In vivo IVUS tissue characterization can be performed during routine imaging. In this model of transplant vasculopathy, RF attenuation measurements were more sensitive than visual or quantitative gray-scale analysis.
Statin-Sensitive Dysregulated AT1 Receptor Function and Density in Hypercholesterolemic Men
Authors: Nickenig Georg , Bäumer Anselm T. , Temur Yavuz , Kebben Daniela , Jockenhövel Friedrich , Böhm Michael
Published: June 2012

Background
—Hypercholesterolemia causes an upregulation of vascular angiotensin II type 1 (AT1) receptor expression in cell culture and animal models. The presented studies were undertaken to examine AT1 receptor overexpression in hypercholesterolemic men and therapeutic interventions thereof by HMG CoA reductase inhibitors (statins).

Methods and Results
—Effects of AT1 receptor activation were measured by assessing the blood pressure increase after infusion of angiotensin II in normo- (cholesterol 181±11 mg/dL) and hypercholesterolemic (cholesterol 294±10 mg/dL) men (n=19 and 20, respectively). AT1 receptor expression was assessed on isolated platelets. Some patients were investigated before and after cholesterol-lowering therapy with statins. Hypercholesterolemia led to a significant increase of angiotensin II-induced blood pressure elevation. AT1 receptor expression was significantly enhanced in hypercholesterolemic individuals (B
max
=5.2±1.2 fmol/mg protein) compared with normocholesterolemic men (B
max
=2.1±0.2 fmol/mg protein). Cholesterol-lowering treatment with statins reversed the elevated blood pressure response to angiotensin II infusion (
P
<0.05) and downregulated AT1 receptor density (
P
<0.05).

Conclusions
—Hypercholesterolemia induces AT1 receptor overexpression and enhances biological effects of angiotensin II in men. These findings provide novel insights into the pathogenesis of hypertension and atherosclerosis and may initiate rational and new therapeutic concepts.
Opening and Closing Characteristics of the Aortic Valve After Different Types of Valve-Preserving Surgery
Authors: Leyh Rainer G. , Schmidtke Claudia , Sievers Hans-Hinrich , Yacoub Magdi H.
Published: June 2012

Background
—The surgical approach to aortic root aneurysm and/or dissection remains controversial. The use of valve-sparing operations, which are thought to have many advantages, is increasing. We hypothesized that the particular technique and type of surgery could influence valve motion characteristics and function. Therefore, we studied the instantaneous opening and closing characteristics of the aortic valve after the main 2 types of valve-sparing surgery.

Methods and Results
—In 20 patients (10 with tube replacement of the aortic root, group A; and 10 with separate replacement of the sinuses of Valsalva, group B) and 10 controls (group C), transthoracic and transesophageal studies on aortic valve dynamics were performed. Three distinct phases of aortic valve motion were identified. They were as follows: (1) a rapid opening, with a velocity of 20.9±4.2 cm/s in group C, 27.1±10.9 cm/s in group B (
P
=NS), and 58.3±18.4 cm/s in group A (group A versus group C,
P
<0.001; group A versus group B,
P
=0.001); (2) a slow systolic closure, with 12.5±6.6% and 10.8±2.2% of maximal opening in groups C and B, respectively (
P
=NS), and 3.8±1.6% in group A (group A versus group C,
P
=0.001; group A versus group B,
P
<0.001); and (3) a rapid closing movement, with a velocity of 26.3±5.6 cm/s in group C, 32.4±11.4 cm/s in group B (
P
=NS), and 21.8±3.5 cm/s in group A (group A versus group C,
P
=NS; group A versus group B,
P
=0.008). The pressure strain of the elastic modulus was different in groups C and B only at the commissures (682±145 g/cm
2
versus 1896±726 g/cm
2
, respectively;
P
<0.001). At all root levels, the distensibility was reduced in group A (
P
<0.001). Systolic contact of aortic cusps and wall occurred only in group A.

Conclusions
—Near-normal opening and closing characteristics can be achieved by a technique that preserves the shape and independent mobility of the sinuses of Valsalva.
Cardiovascular Abnormalities in Transgenic Mice With Reduced Brown Fat
Authors: Cittadini Antonio , Mantzoros Christos S. , Hampton Thomas G. , Travers Kerry E. , Katz Sarah E. , Morgan James P. , Flier Jeffrey S. , Douglas Pamela S.
Published: June 2012

Background
—A new model of murine obesity has recently been developed through transgenic ablation of brown adipose tissue that manifests typical metabolic complications of obesity, including insulin resistance and non–insulin-dependent diabetes mellitus. The cardiovascular phenotype has not been defined.

Methods and Results
—Transthoracic echocardiography, aortic catheterization, isolated whole-heart studies, and morphometric histology defined cardiac structure and function in 30 transgenic mice with reduced brown fat and 30 matched wild-type controls. Obesity was indicated by a 77% increase in body weight and was accompanied by elevated systemic pressures (mean aortic blood pressure 85±1 versus 66±2 mm Hg;
P
<0.01), left ventricular dilation and hypertrophy (mass/body weight 4.0±0.2 versus 2.7±0.3 mg/g;
P
<0.01), and high cardiac output (cardiac index 3.2±0.4 versus 2.4±0.1 mL · kg
−1
· min
−1
;
P
<0.01). Baseline functional parameters assessed in vitro were not different, but after imposition of zero-flow ischemia, significant relaxation impairment developed in obese mice. Although morphometrically determined myocyte diameters were similar, the percentage of interstitial fibrosis was significantly increased in transgenic mice compared with wild-type controls (7.5±2% versus 4.2±0.2%;
P
<0.01).

Conclusions
—Transgenic ablation of brown adipose tissue is associated not only with obesity but also with systemic hypertension, left ventricular hypertrophy with eccentric remodeling and fibrosis, and high cardiac output, a unique constellation of findings strikingly similar to that seen in human obesity. Mice with reduced brown fat may serve as a new model for the cardiovascular morbid complications associated with obesity in humans.
Classic Preconditioning Decreases the Harmful Accumulation of Nitric Oxide During Ischemia and Reperfusion in Rat Hearts
Authors: Csonka Csaba , Szilvássy Zoltán , Fülöp Ferenc , Páli Tibor , Blasig Ingolf E. , Tosaki Arpad , Schulz Richard , Ferdinandy Péter
Published: June 2012

Background
—The role of NO in the mechanism of preconditioning is not understood. Therefore, we studied the effect of preconditioning and subsequent ischemia/reperfusion on myocardial NO content in the presence of an NO synthase (NOS) inhibitor.

Methods and Results
—Isolated working rat hearts were subjected to preconditioning protocols of 3 intermittent periods of rapid pacing or no-flow ischemia of 5 minutes’ duration each followed by a test 30 minutes of global no-flow ischemia and 15 minutes of reperfusion. Test ischemia/reperfusion resulted in a deterioration of myocardial function and a considerable increase in cardiac NO content as assessed by electron spin resonance. Preconditioning improved postischemic myocardial function and markedly decreased test ischemia/reperfusion-induced NO accumulation. In the presence of 4.6 μmol/L
N
G
-nitro-
l
-arginine (LNA), basal cardiac NO content decreased significantly, although test ischemia/reperfusion-induced functional deterioration and NO accumulation were not affected in nonpreconditioned hearts. However, the protective effects of preconditioning on both test ischemia/reperfusion-induced functional depression and NO accumulation were abolished. When 4.6 μmol/L LNA was administered after preconditioning, it failed to block the effect of preconditioning. In the presence of 46 μmol/L LNA, ischemia/reperfusion-induced NO accumulation was significantly decreased and postischemic myocardial function was improved in nonpreconditioned hearts.

Conclusions
—Our results show that (1) although NO synthesis by the heart is necessary to trigger classic preconditioning, preconditioning in turn attenuates the accumulation of NO during ischemia/reperfusion, and (2) blockade of ischemia/reperfusion-induced accumulation of cardiac NO by preconditioning or by an appropriate concentration of NOS inhibitor alleviates ischemia/reperfusion injury as demonstrated by enhanced postischemic function.
Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart
Authors: Sun Wei , Sarma Jonnalagedda S. M. , Singh Bramah N.
Published: June 2012

Background
—To overcome the side effects of amiodarone (AM), its noniodinated analogue, dronedarone (SR), was synthesized. In this study, its electrophysiological effects were compared with those of AM in rabbit hearts.

Methods and Results
—Five animal groups (n=7 each) for 3 weeks received daily oral treatment of 1 of these regimens: (1) control, vehicle only; (2) AM 50 mg/kg (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia. Action potentials were recorded from isolated papillary muscle and sinoatrial node by microelectrode techniques. The short-term effects were studied in controls (n=5) at various concentrations of SR (0 to 10 μmol/L) in tissue bath. Action potential duration at 50% (APD
50
) and 90% (APD
90
) repolarization and upstroke dV/dt (V
max
) at various cycle lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals (
P
<0.0001 for all). Ventricular APD
50
and APD
90
were lengthened by 20% to 49% as a function of dose (
P
<0.005 to <0.0001) and cycle length (
P
<0.001). SR100 effects were greater than those of AM100 (
P
<0.002). V
max
was decreased by both AM100 (
P
<0.0001) and SR100 (
P
<0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group (
P
<0.0001 for all).

Conclusions
—The electrophysiological effects of dronedarone are similar to those of AM but more potent, despite deletion of iodine from its molecular structure, a finding of importance for the development of future class III antiarrhythmic compounds.
Comparative Effects of Low and High Doses of the Angiotensin-Converting Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart Failure
Authors: Packer Milton , Poole-Wilson Philip A. , Armstrong Paul W. , Cleland John G. F. , Horowitz John D. , Massie Barry M. , Rydén Lars , Thygesen Kristian , Uretsky Barry F.
Published: June 2012

Background
—Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits.

Methods and Results
—We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction ≤30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (
P
=0.128) but a significant 12% lower risk of death or hospitalization for any reason (
P
=0.002) and 24% fewer hospitalizations for heart failure (
P
=0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication.

Conclusions
—These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.
Ventilatory and Heart Rate Responses to Exercise
Authors: Robbins Mark , Francis Gary , Pashkow Fredric J. , Snader Claire E. , Hoercher Kathy , Young James B. , Lauer Michael S.
Published: June 2012

Background
—An abnormally low chronotropic response and an abnormally high ventilatory response (V̇
e
/V̇
co
2
) to exercise are common in patients with severe heart failure, but their relative prognostic impacts have not been well explored.

Methods and Results
—Consecutive patients with heart failure referred for metabolic stress testing who were not taking β-blockers or intravenous inotropes (n=470) were followed for 1.5 years. The chronotropic index was calculated while peak V̇
o
2
and V̇
e
/V̇
co
2
were directly measured. Chronotropic index and peak V̇
o
2
were considered abnormal if in the lowest 25th percentiles of the patient cohort, whereas V̇
e
/V̇
co
2
was considered abnormal if in the highest 25th percentile. For comparative purposes, a group of 17 healthy controls underwent metabolic testing as well. Compared with controls, heart failure patients had markedly abnormal ventilatory and chronotropic responses to exercise. In the heart failure cohort, there were 71 deaths. In univariate analyses, predictors of death included high V̇
e
/V̇
co
2
, low chronotropic index, low V̇
o
2
, low resting systolic blood pressure, and older age. Nonparametric Kaplan-Meier plots demonstrated that by dividing the population according to peak V̇
e
/V̇
co
2
and peak V̇
o
2
, it is possible to identify low, intermediate, and very high risk groups. In multivariate analyses, the only independent predictors of death were high V̇
e
/V̇
co
2
(adjusted relative risk [RR] 3.20, 95% CI 1.95 to 5.26,
P
<0.0001) and low chronotropic index (adjusted RR 1.94, 95% CI 1.18 to 3.19,
P
=0.0009).

Conclusions
—The ventilatory and chronotropic responses to exercise are powerful and independent predictors of heart failure mortality.
Myocardial Oxygen Consumption Is Unchanged but Efficiency Is Reduced in Patients With Essential Hypertension and Left Ventricular Hypertrophy
Authors: Laine Hanna , Katoh Chietsugu , Luotolahti Matti , Yki-Järvinen Hannele , Kantola Ilkka , Jula Antti , Takala Teemu O. , Ruotsalainen Ulla , Iida Hidehiro , Haaparanta Merja , Nuutila Pirjo , Knuuti Juhani
Published: June 2012

Background
—Patients with hypertension and left ventricular hypertrophy (LVH) are prone to develop heart failure. We tested the hypothesis that compensatory LVH is associated with normalization of myocardial oxygen consumption and that this occurs at the expense of a decrease in the ratio between cardiac work and oxygen consumption (efficiency).

Methods and Results
—Nine hypertensive men with LVH (LVH+) (age 42±2 years), left ventricular mass index (LVMI) 161±8 g/m
2
, blood pressure (BP) 145±16/88±10 mm Hg (mean±SD); 8 hypertensive men without LVH (LVH−) (age 39±5 years, LVMI 107±15 g/m
2
, BP 140±15/90±11 mm Hg); and 10 normotensive men (CONT) were studied. Myocardial blood flow, oxygen consumption, and glucose uptake were measured during euglycemic hyperinsulinemia using PET techniques. LV dimensions, volumes, and workload were determined by echocardiography, and efficiency was calculated. Myocardial workload (2.5±0.8 versus 3.0±0.6 versus 2.3±0.5 mm Hg · mL · min
−1
· g
−1
for CONT versus LVH− versus LVH+;
P
<0.05, LVH− versus LVH+), myocardial blood flow (0.84±0.16 versus 1.06±0.22 versus 0.81±0.09 mL · g
−1
· min, respectively;
P
<0.05, LVH− versus other groups) and oxygen consumption (0.09±0.02 versus 0.14±0.03 versus 0.11±0.01 ml · g
−1
· min
−1
, respectively;
P
<0.05, LVH− versus other groups) were increased in the LVH− group. Myocardial efficiency was reduced in the LVH+ group (18.1±4.1% versus 15.1±2.3% versus 13.5±1.9%, respectively;
P
<0.05, LVH+ versus CONT).

Conclusions
—Myocardial oxygen consumption per unit weight is increased in hypertensive patients without LVH but is normal in those with LVH. The normalization of oxygen consumption via hypertrophy occurs at the expense of efficiency, which may predispose hypertensive patients with LVH to heart failure.
Long-Term Effects of Pravastatin on Plasma Concentration of C-reactive Protein
Authors: Ridker Paul M. , Rifai Nader , Pfeffer Marc A. , Sacks Frank , Braunwald Eugene
Published: June 2012

Background
—Elevated plasma concentrations of C-reactive protein (CRP) are associated with increased cardiovascular risk. We evaluated whether long-term therapy with pravastatin, an agent that reduces cardiovascular risk, might alter levels of this inflammatory parameter.

Methods and Results
—CRP levels were measured at baseline and at 5 years in 472 randomly selected participants in the Cholesterol and Recurrent Events (CARE) trial who remained free of recurrent coronary events during follow-up. Overall, CRP levels at baseline and at 5 years were highly correlated (
r
=0.60,
P
<0.001). However, among those allocated to placebo, median CRP levels and the mean change in CRP tended to increase over time (median change, +4.2%;
P
=0.2 and mean change, +0.07 mg/dL;
P
=0.04). By contrast, median CRP levels and the mean change in CRP decreased over time among those allocated to pravastatin (median change, −17.4%;
P
=0.004 and mean change, −0.07 mg/dL;
P
=0.002). Thus, statistically significant differences were observed at 5 years between the pravastatin and placebo groups in terms of median CRP levels (difference, −21.6%;
P
=0.007), mean CRP levels (difference, −37.8%;
P
=0.002), and absolute mean change in CRP (difference, −0.137 mg/dL;
P
=0.003). These effects persisted in analyses stratified by age, body mass index, smoking status, blood pressure, and baseline lipid levels. Attempts to relate the magnitude of change in CRP to the magnitude of change in lipids in both the pravastatin and placebo groups did not reveal any obvious relationships.

Conclusions
—Among survivors of myocardial infarction on standard therapy plus placebo, CRP levels tended to increase over 5 years of follow-up. In contrast, randomization to pravastatin resulted in significant reductions in this inflammatory marker that were not related to the magnitude of lipid alterations observed. Thus, these data further support the potential for nonlipid effects of this agent.