bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous Variability of Left Ventricular Outflow Tract Gradient in Hypertrophic Obstructive Cardiomyopathy
Authors: Kizilbash Ali M. , Heinle Sheila K. , Grayburn Paul A.
Published: June 2012

Background
—Improvement in the left ventricular outflow tract (LVOT) gradient has been used as a means of assessing response to therapy in patients with hypertrophic obstructive cardiomyopathy (HOCM). To our knowledge, no data exist regarding the spontaneous day-to-day variability of the LVOT gradient in patients with HOCM. Defining the magnitude of such variability is critical to properly understand how much improvement in LVOT gradient must be present to invoke a therapeutic response.

Methods and Results
—We studied the spontaneous variation in the continuous-wave, Doppler-derived pressure gradient on 5 consecutive days in 12 HOCM patients and 5 aortic stenosis control subjects. While in some patients the day-to-day variability in resting gradient was small, in others it varied markedly. The 95% confidence interval for attributing a change in LVOT gradient to factors other than random variation is ±32 mm Hg for resting gradient and ±50 mm Hg for provoked gradient. The mean coefficient of variation for gradient across 5 days for the group was 0.52±0.33 for resting gradient and 0.46±0.16 for provoked gradient. The day-to-day variability in pressure gradient could not be explained by changes in heart rate, blood pressure, or left ventricular end-diastolic dimension, each of which had a coefficient of variation <.11. Moreover, technical factors related to the performance or interpretation of the studies did not account for it because the coefficient of variation for gradient in aortic stenosis was <10% and interobserver and intraobserver agreement was excellent (
r
=.96 and .98, respectively).

Conclusions
—The LVOT pressure gradient varies considerably from day to day in stable patients with HOCM. A single measurement of pressure gradient is not adequate to define the severity of dynamic LVOT obstruction in HOCM.
QTc Dispersion Predicts Cardiac Mortality in the Elderly
Authors: de Bruyne M. C. , Hoes A. W. , Kors J. A. , Hofman A. , van Bemmel J. H. , Grobbee D. E.
Published: June 2012

Background
—Increased QTc dispersion has been associated with an increased risk for ventricular arrhythmias and cardiac death in selected patient populations. We examined the association between computerized QTc-dispersion measurements and mortality in a prospective analysis of the population-based Rotterdam Study among men and women aged ≥55 years.

Methods and Results
—QTc dispersion was computed with the use of the Modular ECG Analysis System as the difference between the maximum and minimum QTc intervals in 12 and 8 leads (ie, the 6 precordial leads, the shortest extremity lead, and the median of the 5 other extremity leads). After exclusion of those without a digitally stored ECG, the population consisted of 2358 men and 3454 women. During the 3 to 6.5 years (mean, 4 years) of follow-up, 568 subjects (9.8%) died. The degree of QTc dispersion was categorized into tertiles. Data were analyzed using the Cox proportional hazards model, with adjustment for age. For QTc dispersion in 8 leads, those in the highest tertile relative to the lowest tertile had a twofold risk for cardiac death (hazard ratio, 2.5; 95% confidence interval [CI], 1.6 to 4.0) and sudden cardiac death (hazard ratio, 1.9; 95% CI, 1.0 to 3.7) and a 40% increased risk for total mortality (hazard ratio, 1.4; 95% CI, 1.2 to 1.8). Additional adjustment for potential confounders, including history of myocardial infarction, hypertension, and overall QTc, did not materially change the risk estimates. Hazard ratios for QTc dispersion in 12 leads were comparable to those found for QTc dispersion in 8 leads.

Conclusions
—QTc dispersion is an important predictor of cardiac mortality in older men and women.
Quantification of Myocardial Blood Flow With Ultrasound-Induced Destruction of Microbubbles Administered as a Constant Venous Infusion
Authors: Wei Kevin , Jayaweera Ananda R. , Firoozan Soroosh , Linka Andre , Skyba Danny M. , Kaul Sanjiv
Published: June 2012

Background
—Ultrasound can cause microbubble destruction. If microbubbles are administered as a continuous infusion, then their destruction within the myocardium and measurement of their myocardial reappearance rate at steady state will provide a measure of mean myocardial microbubble velocity. Conversely, measurement of their myocardial concentration at steady state will provide an assessment of microvascular cross-sectional area. Myocardial blood flow (MBF) can then be calculated from the product of the two.

Methods and Results
—Ex vivo and in vitro experiments were performed in which either flow was held constant and pulsing interval (interval between microbubble destruction and replenishment) was altered, or vice versa. In vivo experiments were performed in 21 dogs. In group 1 dogs (n=7), MBF was mechanically altered in a model in which coronary blood volume was constant. In group 2 dogs (n=5), MBF was altered by direct coronary infusions of vasodilators. In group 3 dogs (n=9), non–flow-limiting coronary stenoses were created, and MBF was measured before and after the venous administration of a coronary vasodilator. In all experiments, microbubbles were delivered as a constant infusion, and myocardial contrast echocardiography was performed using different pulsing intervals. The myocardial video intensity versus pulsing interval plots were fitted to an exponential function:
y
=
A
(1−
e

−β
t

), where
A
is the plateau video intensity reflecting the microvascular cross-sectional area, and β reflects the rate of rise of video intensity and, hence, microbubble velocity. Excellent correlations were found between flow and β, as well as flow and the product of
A
and β.

Conclusions
—MBF can be quantified with myocardial contrast echocardiography during a venous infusion of microbubbles. This novel approach has potential for measuring tissue perfusion in any organ accessible to ultrasound.
Right Ventricular Infarction Causes Heterogeneous Autonomic Denervation of the Viable Peri-infarct Area
Authors: Elvan Arif , Zipes Douglas P.
Published: June 2012

Background
—Because efferent autonomic pathways to the right ventricle (RV) differ from the efferent autonomic projections to the left ventricle (LV), we assessed the effects of RV infarction on this innervation.

Methods and Results
—We measured the ventricular effective refractory period (ERP) shortening in response to bilateral ansae subclaviae stimulation and ERP lengthening induced by bilateral vagal stimulation as markers of autonomic innervation before and after RV myocardial infarction (RVMI) produced by coronary ligation (n=28 dogs) or intracoronary latex injection (n=18 dogs) into a marginal branch of the right coronary artery in open-chest anesthetized dogs. In each dog, ERPs measured in viable peri-infarct area at two RV outflow tract (RVOT) sites and two septal and four lateral sites at the RV free wall after RVMI showed reduced or absent ERP shortening during bilateral ansae subclaviae stimulation laterally, septally, and at RVOT sites 3 hours after RVMI. ERP shortening in response to infused norepinephrine was still present. Bilateral vagal stimulation during background norepinephrine infusion (0.10 to 0.25 μg/kg per minute) lengthened the ERP at all test sites before latex injection. After transmural RVMI, vagally induced ERP prolongation was attenuated or lost at lateral, septal, and RVOT test sites.

Conclusions
—RVMI causes sympathetic and vagal denervation at viable sites at the RVOT, lateral, and, to a lesser extent, septal sides of the viable peri-infarct area. Autonomic denervation in the RVOT might contribute to the development of ventricular tachyarrhythmias after the acute stage of myocardial infarction involving the RV.
Adenosine Inhibits Lipopolysaccharide-Induced Secretion of Tumor Necrosis Factor-α in the Failing Human Heart
Authors: Wagner Daniel R. , McTiernan Charles , Sanders Virginia J. , Feldman Arthur M.
Published: June 2012

Background
—The proinflammatory cytokine tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of congestive heart failure. Recent studies have shown that adenosine inhibits lipopolysaccharide (LPS)-induced expression of TNF-α in macrophages and rat cardiomyocytes. The aim of this study was to determine whether adenosine has a similar effect in the failing human heart.

Methods and Results
—Left ventricular muscle strips were obtained from seven patients with end-stage congestive heart failure undergoing heart transplantation or insertion of a left ventricular assist device. The muscle strips were incubated at 37°C in 95% O
2
/5% CO
2
and stimulated with LPS (10 μg/mL). TNF-α release in the supernatant was measured with ELISA, and muscle sections were stained for TNF-α. Muscle strips released TNF-α in the absence of LPS (0.22±0.05 pg · mL
−1
· mg wet wt
−1
). TNF-α was immunolocalized to the cardiac myocyte, suggesting that the myocyte is a source for TNF-α production. Adenosine (10 μmol/L) decreased TNF-α by 40% (
P
<.05). The selective adenosine A
2
receptor agonist DPMA (10 μmol/L) decreased TNF-α release by 87% (
P
<.001), whereas ITu (10 μmol/L), an adenosine-regulating agent that increases endogenous adenosine concentration, inhibited TNF-α release by 93% (
P
<.001).

Conclusions
—Adenosine can significantly diminish TNF levels in the failing human heart and may represent a new pharmacological intervention in congestive heart failure.
Effects of Moderate Exercise Training on Thallium Uptake and Contractile Response to Low-Dose Dobutamine of Dysfunctional Myocardium in Patients With Ischemic Cardiomyopathy
Authors: Belardinelli Romualdo , Georgiou Demetrios , Ginzton Leonard , Cianci Giovanni , Purcaro Augusto
Published: June 2012

Background
—There is evidence that exercise training can induce myocardial and coronary adaptations in both animals and humans. However, the significance of these potentially important changes remains to be determined in patients with ischemic heart disease and left ventricular (LV) systolic dysfunction.

Methods and Results
—To investigate whether exercise training can improve thallium uptake and the contractile response to low-dose dobutamine of dysfunctional myocardium, 46 patients (42 men, 4 women; mean age, 57±9 years) with chronic coronary artery disease and impaired LV systolic function (ejection fraction <40%) were randomly assigned to two groups. The exercise group (n=26) underwent exercise training at 60% of peak oxygen uptake for 8 weeks. The control group (n=20) was not exercised. At baseline and after 8 weeks all patients underwent an exercise test with gas exchange analysis and stress echocardiography using low-dose dobutamine (5 to 10 μg/kg per minute) followed by thallium myocardial scintigraphy. Coronary angiography was performed in 23 patients at baseline and after 8 weeks. After 8 weeks, peak oxygen uptake increased significantly only in trained patients (24%). Significant improvements in the contractile response to dobutamine and thallium activity were observed in trained patients (28% and 31%, respectively; trained versus control:
P
<.001 for both). In a subgroup of trained patients, both improvements were correlated with an increase in the coronary collateral score (
P
<.005 and
P
<.001, respectively).

Conclusions
—Moderate exercise training improves both thallium activity and the contractile response of dysfunctional myocardium to low doses of dobutamine in patients with ischemic cardiomyopathy. The implication of this study is that even a short-term exercise training may improve quality of life by improvement of LV systolic function during mild-to-moderate physical activity in patients with ischemic cardiomyopathy.
Beneficial Effects of Leukocyte Depletion of Transfused Blood on Postoperative Complications in Patients Undergoing Cardiac Surgery
Authors: van de Watering Leo M.G. , Hermans Jo , Houbiers Jos G.A. , van den Broek Pieter J. , Bouter Hens , Boer Fred , Harvey Mark S. , Huysmans Hans A. , Brand Anneke
Published: June 2012

Background—
Leukocytes in transfused blood are associated with several posttransfusion immunomodulatory effects. Although leukocytes play an important role in reperfusion injury, the contribution of leukocytes in transfused blood products has not been investigated. To estimate the role and the timing of leukocyte filtration of red cells in cardiac surgery, we performed a randomized study.

Methods and Results—
Patients scheduled for cardiac surgery were randomly allocated to receive either packed cells without buffy coat (PC, n=306), fresh-filtered units (FF, n=305), or stored-filtered units (SF, n=303) when transfusion was indicated. We evaluated the periods of hospitalization and stay at the intensive care unit, and the occurrences of postoperative complications up to 60 days after surgery. The average hospital stay was 10.7 days, of which 3.2 days were in the intensive care unit, without significant differences between the groups. In the PC trial arm, 23.0% of the patients had infections versus 16.9% and 17.9% of the patients in the leukocyte-depleted trial arms (
P
=.13). Within 60 days, 45 patients had died, 24 patients in the PC trial arm (7.8%), versus 11 (3.6%) and 10 (3.3%) patients in the FF and SF trial arms, respectively (
P
=.015).

Conclusions—
In cardiac surgery patients, especially when more than three blood transfusions are required, leukocyte depletion by filtration results in a significant reduction of the postoperative mortality that can only partially be explained by the higher incidence of postoperative infections in the PC group.
Expression of Costimulatory Molecules B7–1, B7–2, and CD40 in the Heart of Patients With Acute Myocarditis and Dilated Cardiomyopathy
Authors: Seko Yoshinori , Takahashi Naoyuki , Ishiyama Shigeru , Nishikawa Toshiro , Kasajima Takeshi , Hiroe Michiaki , Suzuki Shin , Ishiwata Sugao , Kawai Sachio , Azuma Miyuki , Yagita Hideo , Okumura Ko , Yazaki Yoshio
Published: June 2012

Background
—In patients with acute myocarditis and dilated cardiomyopathy (DCM), we previously reported that antigen-specific T cells infiltrate the heart and play an important role in the myocardial damage involved. For antigen-specific T-cell activation to occur, it is necessary for T cells to receive a costimulatory signal provided by costimulatory molecules expressed on antigen-presenting cells (APCs) as well as the main signal provided by binding of T-cell receptors to the antigen.

Methods and Results
—To investigate the roles of the costimulatory molecules B7–1, B7–2, and CD40 in the development of acute myocarditis and DCM, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and DCM. We also examined the expression of a cytolytic factor, perforin, in the infiltrating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, because both killer lymphocytes are thought to damage B7–1–expressing APCs. We found that B7–1, B7–2, and CD40 were moderately to strongly expressed in the cardiac myocytes of patients with acute myocarditis. Weak to moderate expression of these antigens was also found in the cardiac myocytes of patients with DCM. There was infiltration of perforin-expressing CTLs and NK cells in the myocardial tissues of patients with acute myocarditis and DCM.

Conclusions
—Our findings strongly suggest that expression of B7–1, B7–2, and CD40 antigens on cardiac myocytes may make them APCs for CTLs and NK cells and that they may play an important role in the direct myocardial damage by these killer cells in acute myocarditis and DCM.
Phenotypic Characterization of a Novel Long-QT Syndrome Mutation (R1623Q) in the Cardiac Sodium Channel
Authors: Kambouris Nicholas G. , Nuss H. Bradley , Johns David C. , Tomaselli Gordon F. , Marban Eduardo , Balser Jeffrey R.
Published: June 2012

Background
—A heritable form of the long-QT syndrome (LQT3) has been linked to mutations in the cardiac sodium channel gene (SCN5A). Recently, a sporadic
SCN5A
mutation was identified in a Japanese girl afflicted with the long-QT syndrome. In contrast to the heritable mutations, this externally positioned domain IV, S4 mutation (R1623Q) neutralized a charged residue that is critically involved in activation-inactivation coupling.

Methods and Results
—We have characterized the R1623Q mutation in the human cardiac sodium channel (hH1) using both whole-cell and single-channel recordings. In contrast to the autosomal dominant LQT3 mutations, R1623Q increased the probability of long openings and caused early reopenings, producing a threefold prolongation of sodium current decay. Lidocaine restored rapid decay of the R1623Q macroscopic current.

Conclusions
—The R1623Q mutation produces inactivation gating defects that differ mechanistically from those caused by LQT3 mutations. These findings provide a biophysical explanation for this severe long-QT phenotype and extend our understanding of the mechanistic role of the S4 segment in cardiac sodium channel inactivation gating and class I antiarrhythmic drug action.
Functional and Metabolic Evaluation of the Athlete’s Heart By Magnetic Resonance Imaging and Dobutamine Stress Magnetic Resonance Spectroscopy
Authors: Pluim Babette M. , Lamb Hildo J. , Kayser Hein W. M. , Leujes Ferre , Beyerbacht Hugo P. , Zwinderman Aeilko H. , van der Laarse Arnoud , Vliegen Hubert W. , de Roos Albert , van der Wall Ernst E.
Published: June 2012

Background
—The question of whether training-induced left ventricular hypertrophy in athletes is a physiological rather than a pathophysiological phenomenon remains unresolved. The purpose of the present study was to detect any abnormalities in cardiac function in hypertrophic hearts of elite cyclists and to examine the response of myocardial high-energy phosphate metabolism to high workloads induced by atropine-dobutamine stress.

Methods and Results
—We studied 21 elite cyclists and 12 healthy control subjects. Left ventricular mass, volume, and function were determined by cine MRI. Myocardial high-energy phosphates were examined by
31
P magnetic resonance spectroscopy. There were no significant differences between cyclists and control subjects for left ventricular ejection fraction (59±5% versus 61±4%), left ventricular cardiac index (3.4±0.4 versus 3.4±0.4 L · min
−1
· m
−2
), peak early filling rate (562±93 versus 535±81 mL/s), peak atrial filling rate (315±93 versus 333±65 mL/s), ratio of early and atrial filling volumes (3.0±1.0 versus 2.6±0.6), mean acceleration gradient of early filling (5.2±1.4 versus 5.8±1.9 L/s
2
), mean deceleration gradient of early filling(−3.1±0.9 versus −3.2±0.7 L/s
2
), mean acceleration gradient of atrial filling (3.6±1.8 versus 4.5±1.7 L/s
2
), and atrial filling fraction (0.23±0.06 versus 0.26±0.04, respectively). Cyclists and control subjects showed similar decreases in the ratio of myocardial phosphocreatine to ATP measured with
31
P magnetic resonance spectroscopy during atropine-dobutamine stress (1.41±0.20 versus 1.41±0.18 at rest to 1.21±0.20 versus 1.16±0.13 during stress, both
P
=NS).

Conclusions
—Left ventricular hypertrophy in cyclists is not associated with significant abnormalities of cardiac function or metabolism as assessed by MRI and spectroscopy. These observations suggest that training-induced left ventricular hypertrophy in cyclists is predominantly a physiological phenomenon.
A Common Mutation in the Lipoprotein Lipase Gene (N291S) Alters the Lipoprotein Phenotype and Risk for Cardiovascular Disease in Patients With Familial Hypercholesterolemia
Authors: Wittekoek Marianne E. , Pimstone Simon N. , Reymer Paul W. A. , Feuth Lisette , Botma Gert-Jan , Defesche Joep C. , Prins M. , Hayden Michael R. , Kastelein John J. P.
Published: June 2012

Background
—Recently, a mutation in the lipoprotein lipase (LPL) gene (N291S) has been reported in 2% to 5% of individuals in western populations and is associated with increased triglyceride (TG) and reduced HDL cholesterol (HDLC) concentrations.

Methods and Results
—Here we report a significant alteration in biochemical and clinical phenotype in subjects with familial hypercholesterolemia (FH) who are heterozygous for this N291S LPL mutation. Sixty-four FH heterozygotes carrying the N291S mutation had significantly a higher TG level (
P
=.004), a higher ratio of total cholesterol to HDLC (
P
<.001), and lower HDLC concentrations (
P
=.002) compared with 175 FH heterozygotes without this LPL mutation. Moreover, the N291S mutation conferred a significantly greater risk for developing cardiovascular disease in FH heterozygotes compared with FH heterozygotes without this LPL mutation (odds ratio, 3.875;
P
=.006).

Conclusions
—These data provide evidence that a common LPL variant (N291S) significantly influences the biochemical phenotype and risk for cardiovascular disease in patients with FH.
Progression of Myocardial Necrosis During Reperfusion of Ischemic Myocardium
Authors: Matsumura Kaname , Jeremy Richmond W. , Schaper Jutta , Becker Lewis C.
Published: June 2012

Background
—The occurrence of myocyte necrosis during reperfusion of ischemic myocardium is controversial. This study measured myocardial 2-deoxyglucose uptake, correlated with histology, to determine whether loss of viability occurred during reperfusion of ischemic myocardium.

Methods and Results
—In 12 anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes before 4 hours reperfusion. Myocardial blood flow was measured by microspheres and the tracers
14
C-2-deoxyglucose and
18
F-2-deoxyglucose were injected intravenously after 5 and 180 minutes of reperfusion, respectively. After 240 minutes, the heart was stained with thioflavin-S (size of no-reflow zone) and triphenyl-tetrazolium chloride (TTC, extent of necrosis). Samples from normal, salvaged, and necrotic myocardium were counted for
14
C- and
18
F-deoxyglucose and microspheres. With the use of a three-compartment model of 2-deoxyglucose uptake, the rate constant
k
3
for phosphorylation of
14
C- and
18
F-2-deoxyglucose was calculated for each sample. Viability was defined as
k
3
≥ 0.125 min
-1
(predictive accuracy 88% versus electron microscopy and 97% versus TTC). Among 58 samples from no-reflow regions, 97% were nonviable after 5 minutes of reperfusion (
k
3
=0.096±0.027 min
-1
). Among 164 samples from salvaged myocardium, 95% were viable after both 5 and 180 minutes of reperfusion (
k
3
=0.170±0.056 min
-1
P
<.01 versus no-reflow). Among 179 samples from infarcted myocardium, mean
k
3
after 5 minutes of reperfusion was 0.184±0.070 min
-1
and 65% of samples were viable, but after 180 minutes of reperfusion mean
k
3
had decreased to 0.077±0.032 min
-1
(
P
<.0001) and 98% of samples were nonviable.

Conclusions
—A large proportion of samples from infarcted myocardium are viable at the end of the ischemic period but lose viability during the first hours of reperfusion.
Heterogeneous Immediate Effects of Partial Left Ventriculectomy on Cardiac Performance
Authors: Gorcsan John , Feldman Arthur M. , Kormos Robert L. , Mandarino William A. , Demetris Anthony J. , Batista Randas J. V.
Published: June 2012

Background
—Partial left ventriculectomy (PLV) is a novel surgical treatment for severe heart failure consisting of resection of a large wedge of myocardium to reduce wall stress and restore the normal mass-volume ratio. Although ejection fraction (EF) has been shown to improve after PLV, few other physiological data describing its immediate effects on left ventricular (LV) performance are available.

Methods and Results
—Eight patients, 58±5 years old, with severe clinical heart failure and EF of 12±3% were studied before and immediately after PLV. LV performance was assessed by the predominantly load-insensitive measures of pressure-area relations with high-fidelity pressure catheters and transesophageal automated echocardiographic measures of cross-sectional area as a surrogate for volume. LV end-diastolic volume decreased from 200±60 to 89±17 mL, EF increased from 12±3% to 41±8%, and right ventricular (RV) fractional area change increased from 24±12% to 37±16% (all
P
<.05 versus before). Changes in pressure-area relations were variable: end-systolic elastance, 6.5±3.4 to 4.3±2.5 mm Hg/cm
2
and preload recruitable stroke work, 33±16 to 34±19 mm Hg (
P
=NS versus before). End-diastolic stiffness increased from 0.13±0.06 to 0.19±0.07 mm Hg/cm
2
(
P
<.05 versus before). Improvement in LV performance was inversely correlated with semiquantitative histological assessment of myocardial fibrosis and positively correlated with nuclear enlargement and hyperchromasia, indicative of myocyte hypertrophy. No long-term follow-up data were available.

Conclusions
—PLV resulted in reductions in LV volumes, increases in EF and RV ejection, but increases in LV stiffness. Estimates of LV performance revealed variable results associated with the degree of myocardial fibrosis. Further study of these effects in relation to patient outcome is warranted.
Randomized, Double-Blind, Placebo-Controlled Study of Ascorbate on the Preventive Effect of Nitrate Tolerance in Patients With Congestive Heart Failure
Authors: Watanabe Hideki , Kakihana Masaaki , Ohtsuka Sadanori , Sugishita Yasuro
Published: June 2012

Background
—Reduced cGMP production caused by increased superoxide has been proposed as a mechanism of nitrate tolerance during continuous nitrate therapy. This study was designed to evaluate the effects of ascorbate, an antioxidant, on the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.

Methods and Results
—Twenty patients with congestive heart failure were randomized to receive intravenous infusion of nitroglycerin concomitantly with placebo (placebo group, n=10) or intravenous ascorbate (vitamin C group, n=10). After baseline measurements were obtained, dose titration was started by the infusion of nitroglycerin at a rate of 0.5 μg/kg per minute (titration period). Measurements of hemodynamic parameters and blood sampling were performed serially at 0, 6, 12, 18, and 24 hours after the titration period. At baseline, mean pulmonary artery pressure (MPAP, mm Hg), mean pulmonary capillary wedge pressure (PCWP, mm Hg), plasma vitamin E level (μmol/L), and platelet cGMP level (pmol/10
9
platelets) were comparable in the two groups (placebo group: MPAP, 48±6; PCWP, 24±4; cGMP, 0.76±0.12; vitamin E, 18.2±1.2; vitamin C: MPAP, 49±7; PCWP, 24±4; cGMP, 0.71±0.16; vitamin E, 18.6±1.3). In both groups, at 6 hours after the titration period, MPAP and PCWP were significantly decreased (placebo group: MPAP, 26±5; PCWP, 15±4; vitamin C: MPAP, 26±4; PCWP, 16±4), and platelet cGMP was significantly increased (placebo group: 2.42±0.24; vitamin C: 2.26±0.26). However, at 18 hours after titration, in the placebo group, MPAP (44±5) and PCWP (23±4) were increased, and platelet cGMP (0.85±0.20) and plasma vitamin E levels (12.4±1.4) were significantly decreased. In contrast, in the vitamin C group, MPAP (31±6), PCWP (17±5), platelet cGMP (2.49±0.23), and plasma vitamin E levels (17.6±1.4) were maintained for 18 hours after the titration period.

Conclusions
—These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.
Expression of G
qα
and PLC-β in Scar and Border Tissue in Heart Failure Due to Myocardial Infarction
Authors: Ju Haisong , Zhao Shufang , Tappia Paramjit S. , Panagia Vincenzo , Dixon Ian M. C.
Published: June 2012

Background
—Large transmural myocardial infarction (MI) leads to maladaptive cardiac remodeling and places patients at increased risk of congestive heart failure. Angiotensin II, endothelin, and α
1
-adrenergic receptor agonists are implicated in the development of cardiac hypertrophy, interstitial fibrosis, and heart failure after MI. Because these agonists are coupled to and activate G
qα
protein in the heart, the aim of the present study was to investigate G
qα
expression and function in cardiac remodeling and heart failure after MI.

Methods and Results
—MI was produced in rats by ligation of the left coronary artery, and G
qα
protein concentration, localization, and mRNA abundance were noted in surviving left ventricle remote from the infarct and in border and scar tissues from 8-week post-MI hearts with moderate heart failure. Immunohistochemical staining localized elevated G
qα
expression in the scar and border tissues. Western analysis confirmed significant upregulation of G
qα
proteins in these regions versus controls. Furthermore, Northern analysis revealed that the ratios of G
qα
/GAPDH mRNA abundance in both scar and viable tissues from experimental hearts were significantly increased versus controls. Increased expression of phospholipase C (PLC)-β
1
and PLC-β
3
proteins was apparent in the scar and viable tissues after MI versus controls and is associated with increased PLC-β
1
activity in experimental hearts. Furthermore, inositol 1,4,5-tris-phosphate is significantly increased in the border and scar tissues compared with control values.

Conclusions
—Upregulation of the G
qα
/PLC-β pathway was observed in the viable, border, and scar tissues in post-MI hearts. G
qα
and PLC-β may play important roles in scar remodeling as well as cardiac hypertrophy and fibrosis of the surviving tissue in post-MI rat heart. It is suggested that the G
qα
/PLC-β pathway may provide a possible novel target for altering postinfarct remodeling.
Differential Effects of Anti–β
2
-Glycoprotein I Antibodies on Endothelial Cells and on the Manifestations of Experimental Antiphospholipid Syndrome
Authors: George Jacob , Blank Miri , Levy Yair , Meroni Pierluigi , Damianovich Maya , Tincani Angela , Shoenfeld Yehuda
Published: June 2012

Background
—The antiphospholipid syndrome (APS) entails a prothrombotic state associated with the presence of anticardiolipin antibodies (aCL). aCL were shown to promote endothelial cell and platelet activation and to induce an APS-like syndrome in mice when administered intravenously. Recent data suggest that aCL target the plasma cofactor β
2
-glycoprotein I (β2GPI) rather than negatively charged phospholipids. However, it has not been determined whether different epitope-specific anti-β2GPI antibodies obtained from one patient possess pathogenic properties.

Methods and Results
—Three β2GPI-binding IgM monoclonal antibodies (mAbs) (ILA-1, ILA-3, and ILA-4) were cloned from a patient with APS. The three antibodies were shown to bind β2GPI immobilized on irradiated plates, yet only ILA-1 bound β2GPI coated onto nonirradiated plates. Furthermore, when using the anti-β2GPI enzyme-linked immunosorbent assay, ILA-1 was the only mAb inhibited by fluid phase β2GPI. ILA-1 and ILA-3, but not ILA-4, induced adherence of U937 cells to endothelial cells in vitro (reflecting activation of endothelial cells). mAbs ILA-1 and ILA-3 as opposed to ILA-4 induced significant expression of adhesion molecules when preincubated with human umbilical vein endothelial cells. Passive administration of ILA-1 and ILA-3 to pregnant BALB/c mice induced clinical findings consistent with APS (increased fetal resorptions, reduced platelet counts, and prolonged activated partial thromboplastin time), whereas both ILA-4 and the control human IgM did not produce similar effects.

Conclusions
—The results of the study demonstrate the differential effects of various populations of anti-β2GPI antibodies on endothelial cell activation and on experimental APS.
Aortocoronary Saphenous Vein Graft Disease
Authors: Motwani Joseph G. , Topol Eric J.
Published: June 2012

Abstract
—Aortocoronary saphenous vein graft disease, with its increasing clinical sequelae, presents an important and unresolved dilemma in cardiological practice. During the 1st month after bypass surgery, vein graft attrition results from thrombotic occlusion, while later the dominant process is atherosclerotic obstruction occurring on a foundation of neointimal hyperplasia. Although the risk factors predisposing to vein graft atherosclerosis are broadly similar to those recognized for native coronary disease, the pathogenic effects of these risk factors are amplified by inherent deficiencies of the vein as a conduit when transposed into the coronary arterial circulation. A multifaceted strategy aimed at prevention of vein graft disease is emerging, elements of which include: continued improvements in surgical technique; more effective antiplatelet drugs; increasingly intensive risk factor modification, in particular early and aggressive lipid-lowering drug therapy; and a number of evolving therapies, such as gene transfer and nitric oxide donor administration, which target vein graft disease at an early and fundamental level. At present, a key measure is to circumvent the problem of vein graft disease by preferential selection of arterial conduits, in particular the internal mammary arteries, for coronary bypass surgery whenever possible.
Requisite Role of Cardiac Myocytes in Coronary α
1
-Adrenergic Constriction
Authors: Tiefenbacher Christiane P. , DeFily David V. , Chilian William M.
Published: June 2012

Background
—α-Adrenergic activation in vivo causes constriction of coronary arterioles, but, paradoxically, in vitro these microvessels do not contract to this stimulus. We hypothesized that cardiac myocytes have a requisite role in α
1
-adrenergic coronary arteriolar constriction through the release of myocyte-derived contractile factor(s).

Methods and Results
—Administration of the α
1
-adrenergic agonist phenylephrine did not constrict isolated coronary arterioles, but constriction was observed to supernatant obtained from phenylephrine-treated cardiac myocytes. Constriction to the supernatant was blocked by administration of an endothelin-A antagonist to the microvessel preparation or an α-adrenergic antagonist to the myocytes and was augmented after administration of an adenosine antagonist. Administration of phenylephrine to the myocytes increased endothelin-1 levels in the supernatant, but only to subthreshold concentrations.

Conclusions
—Cardiac myocytes have a requisite role in constriction of coronary resistance vessels to α
1
-adrenergic stimuli, which may be mediated by endothelin-1 and other unidentified myocyte-derived vasoconstrictors.
Increased Availability and Open Probability of Single L-Type Calcium Channels From Failing Compared With Nonfailing Human Ventricle
Authors: Schröder Frank , Handrock Renate , Beuckelmann Dirk J. , Hirt Stephan , Hullin Roger , Priebe Leo , Schwinger Robert H. G. , Weil Joachim , Herzig Stefan
Published: June 2012

Background
—The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings.

Methods and Results
—We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n=16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba
2+
). Peak average currents were significantly enhanced in heart failure (38.2±9.3 fA) versus nonfailing control hearts (13.2±4.5 fA,
P
=0.02) because of an elevation of channel availability (55.9±6.7% versus 26.4±5.3%,
P
=0.001) and open probability within active sweeps (7.36±1.51% versus 3.18±1.33%,
P
=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n=11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of α
1C
- and β-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure.

Conclusions
—Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.
Feasibility of Combined Percutaneous Transluminal Angioplasty and Minimally Invasive Direct Coronary Artery Bypass in Patients With Multivessel Coronary Artery Disease
Authors: Cohen Howard A. , Zenati Marco , Smith A.J. Conrad , Lee Joon S. , Chough Simon , Jafar Zubair , Counihan Peter , Izzo Mark , Burchenal J.E. , Feldman Arthur M. , Griffith Bartley
Published: June 2012

Background
—Angioplasty has become an accepted treatment of patients with coronary artery disease and is now commonly used to treat patients with multivessel disease. The major disadvantage of angioplasty has been restenosis requiring repeat interventions with resultant loss of initial cost savings. Compared with the right and the circumflex coronary arteries, the left anterior descending artery (LAD) has been more adversely affected by restenosis. Recently, minimally invasive direct coronary artery bypass (MIDCAB) to the LAD through a small left anterior thoracotomy using the left internal mammary artery has been performed in some centers with excellent early results and with reduced costs compared with standard bypass surgery.

Methods and Results
—We retrospectively reviewed the first 31 consecutive patients treated in our institution with integrated coronary revascularization (ICR): MIDCAB to the LAD combined with PTCA of the other diseased vessels in patients with multivessel disease. Postoperative angiography in 84% of patients revealed a patent anastomosis and normal flow in the graft and bypassed vessel. Thirty-eight (97%) of 39 vessels were successfully treated percutaneously. At a mean follow-up of 7 months, all patients are currently asymptomatic. There have been 2 adverse clinical events, both related to angioplasty and not to MIDCAB. The average length of stay at the hospital after MIDCAB was 2.79±1.05 days.

Conclusions
—These preliminary results with ICR are encouraging and suggest that a randomized, prospective clinical trial comparing ICR with standard coronary artery bypass surgery for the revascularization of symptomatic patients with multivessel disease involving the LAD is warranted.
Altered Cardiovascular Variability in Obstructive Sleep Apnea
Authors: Narkiewicz Krzysztof , Montano Nicola , Cogliati Chiara , van de Borne Philippe J. H. , Dyken Mark E. , Somers Virend K.
Published: June 2012

Background
—Altered cardiovascular variability is a prognostic indicator for cardiovascular events. Patients with obstructive sleep apnea (OSA) are at an increased risk for cardiovascular disease. We tested the hypothesis that OSA is accompanied by alterations in cardiovascular variability, even in the absence of overt cardiovascular disease.

Methods and Results
—Spectral analysis of variability of muscle sympathetic nerve activity, RR interval, and blood pressure were obtained during undisturbed supine rest in 15 patients with moderate-to-severe OSA, 18 patients with mild OSA, and 16 healthy control subjects in whom sleep disordered breathing was excluded by complete overnight polysomnography. Patients with OSA were newly diagnosed, never treated for OSA, and free of any other known diseases. Patients with moderate-to-severe OSA had shorter RR intervals (793±27 ms) and increased sympathetic burst frequency (49±4 bursts/min) compared with control subjects (947±42 ms; 24±3 bursts/min;
P
=0.008 and
P
<0.001, respectively). In these patients, total variance of RR was reduced (
P
=0.01) and spectral analysis of RR variability showed an increase in low frequency normalized units, a decrease in high frequency normalized units, and an increase in the ratio of low to high frequency (all
P
<0.05). Even though blood pressure was similar to that of the control subjects, blood pressure variance in patients with moderate-to-severe OSA was more than double the variance in control subjects (
P
=0.01). Patients with mild OSA also had a reduction in RR variance (
P
=0.02) in the absence of any significant difference in absolute RR interval. For all patients with OSA, linear regression showed a positive correlation (
r
=0.40;
P
=0.02) between sleep apnea severity and blood pressure variance.

Conclusions
—Cardiovascular variability is altered in patients with OSA. This alteration is evident even in the absence of hypertension, heart failure, or other disease states and may be linked to the severity of OSA. Abnormalities in cardiovascular variability may be implicated in the subsequent development of overt cardiovascular disease in patients with OSA.
Abciximab (ReoPro, Chimeric 7E3 Fab) Demonstrates Equivalent Affinity and Functional Blockade of Glycoprotein IIb/IIIa and α
v
β
3
Integrins
Authors: Tam Susan H. , Sassoli Patricia M. , Jordan Robert E. , Nakada Marian T.
Published: June 2012

Background
—Large, randomized, and blinded clinical trials (EPIC, EPILOG, and CAPTURE) have demonstrated that abciximab (ReoPro, chimeric 7E3 Fab) markedly reduces thrombotic events associated with percutaneous transluminal coronary interventions. The marked early benefits at 30 days were sustained at 6 months and 3 years. Initially developed because of its efficacy in blocking GP IIb/IIIa (α
IIb
/β
3
) receptors on platelets, abciximab also binds with equivalent affinity to α
v
β
3
.

Methods and Results
—This study presents a detailed characterization of the α
v
β
3
interaction, including the ability of abciximab to (1) bind with comparable affinity to α
v
β
3
and GP IIb/IIIa, (2) inhibit α
v
β
3
and GP IIb/IIIa–mediated cell adhesion in vitro with IC
50
values approximating binding
K
D
values, and (3) redistribute between GP IIb/IIIa and α
v
β
3
integrins in vitro.

Conclusions
—As an antagonist of not only GP IIb/IIIa but also α
v
β
3
, abciximab may provide additional clinical benefit in preventing α
v
β
3
-mediated effects such as thrombin generation, clot retraction, or smooth muscle cell migration and proliferation. Abciximab binds with equivalent affinity to both GP IIb/IIIa and α
v
β
3
and redistributes between the 2 integrin receptors in vitro. Abciximab has been previously shown to circulate on platelets for up to 2 weeks. Taken together, these findings suggest that abciximab may have the ability to inhibit both GP IIb/IIIa and α
v
β
3
for extended periods.
Cyclosporin A Inhibits Apoptosis of Human Endothelial Cells by Preventing Release of Cytochrome C From Mitochondria
Authors: Walter Dirk H. , Haendeler Judith , Galle Jan , Zeiher Andreas M. , Dimmeler Stefanie
Published: June 2012

Background
—Several experimental and clinical studies suggest that cyclosporin A (CSA) treatment reduces transplant atherosclerosis. Because oxidized LDL (oxLDL) is believed to play a key role in the development of atherogenesis, causing injury to the endothelium, and has been shown to induce apoptosis of endothelial cells, we investigated whether CSA inhibits oxLDL-induced apoptosis.

Methods and Results
—Apoptosis was induced in human umbilical venous endothelial cells (HUVECs) by incubation of 10 μg/mL oxLDL for 18 hours. Coincubation with CSA dose dependently decreased oxLDL-induced apoptosis, with a maximal effect at 10 μmol/L. In addition, tumor necrosis factor-α– and angiotensin II–induced apoptosis was significantly prevented by CSA treatment, suggesting a general apoptosis-suppressive effect of CSA. CSA has been shown to inhibit disruption of the mitochondrial membrane function, which plays a key role in apoptosis induction. Indeed, oxLDL treatment triggered the release of cytochrome C from the mitochondria into the cytosol, indicating disturbance of the mitochondrial membrane. CSA (10 μmol/L) completely inhibited the oxLDL-induced release of cytochrome C. Moreover, tumor necrosis factor-α– and angiotensin II–induced cytochrome C release was prevented by CSA treatment.

Conclusions
—OxLDL induces dysfunction of the mitochondrial membrane, leading to cytochrome C release into the cytosol, and thereby stimulates apoptosis of human endothelial cells. Apoptosis suppression by CSA correlates with the prevention of mitochondrial dysfunction and thus indicates the importance of mitochondrial destabilization in oxLDL-induced apoptosis signaling. The inhibition of apoptosis by CSA might preserve the function of the endothelium and may at least in part contribute to the antiatherogenic effects of CSA in transplant atherosclerosis.
Relation of
Helicobacter pylori
Infection to 13-Year Mortality and Incident Ischemic Heart Disease in the Caerphilly Prospective Heart Disease Study
Authors: Strachan David P. , Mendall Michael A. , Carrington David , Butland Barbara K. , Yarnell John W. G. , Sweetnam Peter M. , Elwood Peter C.
Published: June 2012

Background
—Associations have been suggested between
Helicobacter pylori
seropositivity, cardiovascular risk factors, and ischemic heart disease (IHD). The effect of this common infection on mortality is uncertain.

Methods and Results
—Plasma specimens collected during 1979 to 1983 from 1796 men in Caerphilly, South Wales, were analyzed for IgG antibodies to
H pylori
. Cause of death and occurrence of incident IHD events were ascertained over an average of 13.7 years from death certificates, hospital records, and ECG changes at 5-yearly follow-up examinations. Seventy percent of men were seropositive. The prevalence of IHD at entry was similar in men with and without
H pylori
antibodies (odds ratio [OR], 1.10; 95% CI, 0.87 to 1.40). Seropositivity was significantly (
P
<0.05) associated with poorer socioeconomic status currently and in childhood, shorter stature, and poorer ventilatory function at entry but not with age, smoking, body mass index, blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, fibrinogen, plasma viscosity, or heat shock protein antibodies. Thirteen-year incidence of IHD was not significantly associated with
H pylori
(OR, 1.05; 95% CI, 0.80 to 1.39), but there was a stronger relationship with all-cause mortality (OR, 1.46; 95% CI, 1.12 to 1.92) and fatal IHD (OR, 1.54; 95% CI, 1.03 to 2.30). After adjustment for cardiovascular risk factors and both adult and childhood socioeconomic status, ORs were slightly reduced and lost statistical significance (OR=1.32 [95% CI, 0.99 to 1.78] for all-cause mortality and OR=1.52 [95% CI, 0.99 to 2.34] for fatal IHD).

Conclusions
—
H pylori
infection is unlikely to be as strong a risk factor for IHD as some previous studies have suggested, but its relationship to mortality, including fatal IHD, deserves further investigation. The mechanism underlying these associations is unlikely to involve hypertension, circulating lipid profile, fibrinogen, or cross-reacting antibodies to bacterial heat shock proteins.