bluuebunny/crossref_metadata_2025 huggingface dataset:
Respiratory Muscle Dysfunction in Congestive Heart Failure
Authors: Meyer F. Joachim , Borst Mathias M. , Zugck Christian , Kirschke Andreas , Schellberg Dieter , Kübler Wolfgang , Haass Markus
Published: June 2012

Background
—In congestive heart failure (CHF), the prognostic significance of impaired respiratory muscle strength has not been established.

Methods and Results
—Maximal inspiratory pressure (Pi
max
) was prospectively determined in 244 consecutive patients (207 men) with CHF (ischemic, n=75; idiopathic dilated cardiomyopathy, n=169; age, 54±11 years; left ventricular ejection fraction [LVEF], 22±10%). Pi
max
was lower in the 244 patients with CHF than in 25 control subjects (7.6±3.3 versus 10.5±3.7 kPa;
P
=0.001). The 57 patients (23%) who died during follow-up (23±16 months; range, 1 to 48 months) had an even more reduced Pi
max
(6.3±3.2 versus 8.1±3.2 kPa in survivors;
P
=0.001). Kaplan-Meier survival curves differentiated between patients subdivided according to quartiles for Pi
max
(
P
=0.014). Pi
max
was a strong risk predictor in both univariate (
P
=0.001) and multivariate Cox proportional hazard analyses (
P
=0.03); multivariate analyses also included NYHA functional class, LVEF, peak oxygen consumption (peak V̇
o
2
), and norepinephrine plasma concentration. The areas under the receiver-operating characteristic curves for prediction of 1-year survival were comparable for Pi
max
and peak V̇
o
2
(area under the curve [AUC], 0.68 versus 0.73;
P
=0.28), and they improved with the triple combination of Pi
max
, peak V̇
o
2
, and LVEF (AUC, 0.82;
P
=0.004 compared with AUC of Pi
max
).

Conclusions
—In patients with CHF, inspiratory muscle strength is reduced and emerges as a novel, independent predictor of prognosis. Because testing for Pi
max
is simple in clinical practice, it might serve as an additional factor to improve risk stratification and patient selection for cardiac transplantation.
Premature Atherosclerosis Associated With Monogenic Insulin Resistance
Authors: Hegele Robert A.
Published: June 2012

Background
—The common insulin resistance syndrome, with obesity, dyslipidemia, hyperglycemia, and hypertension, is associated with increased risk of atherosclerosis. Early atherosclerosis in rare monogenic forms of insulin resistance, however, has not been extensively documented. Cardiovascular end points were thus evaluated in subjects with Dunnigan-type familial partial lipodystrophy (FPLD) due to mutations at
LMNA
codon 482.

Methods and Results
—FPLD subjects ≥35 years old were stratified by genotype for either the
LMNA
R482Q or R482W mutation. Twenty-three subjects were heterozygous mutation carriers, and 17 were R482/R482 homozygous family control subjects. All
LMNA
mutation carriers had FPLD with insulin resistance. In addition,
LMNA
mutation carriers had significantly more type 2 diabetes, hypertension, and dyslipidemia than normal family control subjects. Eight
LMNA
mutation carriers had coronary heart disease (CHD), compared with 1 normal control subject (OR 5.9, 95% CI 1.2 to 30.2). Six
LMNA
mutation carriers had CHD end points before age 55 years, and 4 of these, all women, had been hospitalized for CABG surgery between the ages of 35 and 54 years.

Conclusions
—Rare
LMNA
mutations that underlie FPLD with insulin resistance and hyperinsulinemia are also associated with early CHD, notably in women. This suggests that abnormalities of the nuclear envelope can result in a phenotype that recapitulates most of the important attributes of the common insulin resistance syndrome, including accelerated cardiovascular disease. FPLD thus appears to be an appropriate human monogenic model for the common insulin resistance syndrome.
Assessment of Myocardial Perfusion in Coronary Artery Disease by Magnetic Resonance
Authors: Schwitter J. , Nanz D. , Kneifel S. , Bertschinger K. , Büchi M. , Knüsel P. R. , Marincek B. , Lüscher T. F. , von Schulthess G. K.
Published: June 2012

Background
—Monitoring contrast medium wash-in kinetics in hyperemic myocardium by magnetic resonance (MR) allows for the detection of stenosed coronary arteries. In this prospective study, the quality of a multislice MR approach with respect to the detection and sizing of compromised myocardium was determined and compared with positron emission tomography (PET) and quantitative coronary angiography.

Methods and Results
—A total of 48 patients and 18 healthy subjects were studied by MR using a multislice hybrid echo-planar pulse sequence for monitoring the myocardial first pass kinetics of gadolinium-diethylenetriamine pentaacetic acid bismethylamide (Omniscan; 0.1 mmol/kg injected at 3 mL/s IV) during hyperemia (dipyridamole 0.56 mg/kg). Signal intensity upslope as a measure of myocardial perfusion was calculated in 32 sectors per heart from pixelwise parametric maps in the subendocardial layer and for full wall thickness. Before coronary angiography, coronary flow reserve (hyperemia induced by dipyridamole 0.56 mg/kg) was determined in corresponding sectors by
13
N-ammonia PET. Receiver-operator characteristic analysis of subendocardial upslope data revealed a sensitivity and specificity of 91% and 94%, respectively, for the detection of coronary artery disease as defined by PET (mean coronary flow reserve minus 2SD of controls) and a sensitivity and specificity of 87% and 85%, respectively, in comparison with quantitative coronary angiography (diameter stenosis ≥50%). The number of pathological sectors per patient on PET and MR studies correlated linearly (slope, 0.94;
r
=0.76;
P
<0.0001).

Conclusions
—The presented MR approach reliably identifies patients with coronary artery stenoses and provides information on the amount of compromised myocardium, even when perfusion abnormalities are confined to the subendocardial layer. This modality may qualify for its clinical application in the management of coronary artery disease.
Enhanced Response of Blood Monocytes to In Vitro Lipopolysaccharide-Challenge in Patients With Recurrent Unstable Angina
Authors: Liuzzo Giovanna , Angiolillo Dominick J. , Buffon Antonino , Rizzello Vittoria , Colizzi Christian , Ginnetti Francesca , Biasucci Luigi M. , Maseri Attilio
Published: June 2012

Background
—C-reactive protein (CRP) plasma levels have been associated with short- and long-term occurrence of coronary events. We investigated whether circulating inflammatory cell responsiveness to low-grade stimuli could contribute to the reported association between CRP and coronary events.

Methods and Results
—We studied 32 patients with unstable angina who were followed for 24 months and were free of symptoms for 6 months (group 1): 19 patients had persistently high CRP levels (>0.3 mg/dL) (group 1A); 13 patients had normal CRP levels (group 1B). During the follow-up, 12 (63%) group 1A but no group 1B patients developed an infarction or recurrence of unstable angina (
P
<0.001). Eighteen patients with chronic stable angina (group 2) and 18 healthy subjects (group 3) were studied as controls. Interleukin (IL)-6 production (median, range) by peripheral blood mononuclear cells after 4 hours of in vitro stimulation with 1 ng/mL lipopolysaccharide (LPS) was significantly higher in group 1A (4526 pg/mL, 3042 to 10 583 pg/mL) than in group 1B (1752 pg/mL, 75 to 3981 pg/mL), group 2 (707 pg/mL, 41 to 3275 pg/mL), and group 3 (488 pg/mL, 92 to 3503 pg/mL) (all
P
<0.001). No significant differences were observed among the other groups. IL-6 production after LPS-challenge was correlated with baseline CRP levels (
r
=0.42,
P
=0.005).

Conclusions
—Mononuclear cells of patients with recurrent phases of instability exhibit an enhanced production of IL-6 in response to low-dose of LPS, correlated with baseline CRP levels, 6 months after the last acute event. This persisting enhanced acute-phase responsiveness may help explain the association between CRP and acute coronary events.
Chromosomal Location, Exon Structure, and Vascular Expression Patterns of the Human
PDGFC
and
PDGFD
Genes
Authors: Uutela Marko , Laurén Juha , Bergsten Erika , Li Xuri , Horelli-Kuitunen Nina , Eriksson Ulf , Alitalo Kari
Published: June 2012

Background
—Platelet-derived growth factor (PDGF), which is a major mitogen for vascular smooth muscle cells and has been implicated in the pathogenesis of arteriosclerosis, is composed of dimers of PDGF-A and PDGF-B polypeptide chains, encoded by different genes. Here, we have analyzed the chromosomal localization, structure, and expression of 2 newly identified human genes of the PDGF family, called
PDGFC
and
PDGFD
.

Methods and Results
—We used fluorescence in situ hybridization to locate
PDGFC
and
PDGFD
in chromosomes 4q32 and 11q22.3 to 23.2, respectively. Exon structures of
PDGFC
and
PDGFD
were determined by sequencing from genomic DNA clones. The coding region of
PDGFC
consists of 6 and
PDGFD
of 7 exons, of which the last 2 encode the C-terminal PDGF cystine knot growth factor homology domain. An N-terminal CUB domain is encoded by exons 2 and 3 of both genes, and a region of proteolytic cleavage involved in releasing and activating the growth factor domain is located in exon 4 in
PDGFC
and exon 5 in
PDGFD
. PDGF-C was expressed predominantly in smooth muscle cells and PDGF-D in fibroblastic adventitial cells, and both genes were active in cultured endothelial cells and in a variety of tumor cell lines. Both PDGF-C and PDGF-D also stimulated human coronary artery smooth muscle cells.

Conclusions
—
PDGFC
and
PDGFD
have similar genomic structures, which resemble those of the
PDGFA
and
PDGFB
genes. Their expression in the arterial wall and cultured vascular cells suggests that they can transduce proliferation/migration signals to pericytes and smooth muscle cells.
Paclitaxel Stent Coating Inhibits Neointimal Hyperplasia at 4 Weeks in a Porcine Model of Coronary Restenosis
Authors: Heldman Alan W. , Cheng Linda , Jenkins G. Mark , Heller Phillip F. , Kim Dong-Woon , Ware Melvin , Nater Cynthia , Hruban Ralph H. , Rezai Banafsheh , Abella Benjamin S. , Bunge Katherine E. , Kinsella James L. , Sollott Steven J. , Lakatta Edward G. , Brinker Jeffrey A. , Hunter William L. , Froehlich Jeffrey P.
Published: June 2012

Background
—Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis.

Methods and Results
—Palmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 μg/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose (
P
<0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055,
P
<0.05) at the highest level tested (187 μg/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control;
P
<0.05) with increasing dose (
P
<0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control;
P
<0.05) with escalating dose (
P
<0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis.

Conclusions
—Paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis.
Mortality Associated With Congenital Heart Defects in the United States
Authors: Boneva Roumiana S. , Botto Lorenzo D. , Moore Cynthia A. , Yang Quanhe , Correa Adolfo , Erickson J. David
Published: June 2012

Background
—Surgical series and some population-based studies have documented a decrease in mortality from heart defects. Recent population-based data for the United States are lacking, however. We examined population-based data for patterns, time trends, and racial differences of mortality from heart defects for the United States from 1979 through 1997.

Methods and Results
—We examined the multiple-cause mortality files compiled by the National Center for Health Statistics of the CDC from all death certificates filed in the United States. From these data, we derived death rates (deaths per 100 000 population) by the decedent’s age, race, year of death, and heart defect type. We also analyzed age at death as an indirect indicator of survival. From 1979 through 1997, mortality from heart defects (all ages) declined 39%, from 2.5 to 1.5 per 100 000 population; among infants, the decline was 39%, or 2.7% per year. In 1995 to 1997, heart defects contributed to 5822 deaths per year. Of these deaths, 51% were among infants and 7% among children 1 to 4 years old. Mortality was on average 19% higher among blacks than among whites; this gap does not appear to be closing. Age at death increased for most heart defects, although less among blacks than among whites.

Conclusions
—Mortality from heart defects is declining in the United States, although it remains a major cause of death in infancy and childhood. Age at death is increasing, suggesting that more affected persons are living to adolescence and adulthood. The racial discrepancies should be investigated to identify opportunities for prevention.
Increased Release of Arachidonic Acid and Eicosanoids in Iron-Overloaded Cardiomyocytes
Authors: Mattera Rafael , Stone Gregory P. , Bahhur Nael , Kuryshev Yuri A.
Published: June 2012

Background
—Patients with transfusional iron overload may develop a life-limiting cardiomyopathy. The sensitivity of lipid-metabolizing enzymes to peroxidative injury, as well as the reported effects of arachidonic acid (AA) and metabolites on cardiac rhythm, led us to hypothesize that iron-overloaded cardiomyocytes display alterations in the release of AA and prostaglandins.

Methods and Results
—Neonatal rat ventricular myocytes (NRVMs) cultured for 72 hours in the presence of 80 μg/mL ferric ammonium citrate displayed an increased rate of AA release, both under resting conditions and after stimulation with agonists such as [Sar
1
]Ang II. Although iron treatment did not affect overall incorporation of [
3
H]AA into NRVM phospholipids, it caused a 2-fold increase in the distribution of precursor in phosphatidylcholine species, with a proportional decrease in phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine. Increased release of AA in iron-overloaded NRVMs was reduced by the diacylglycerol lipase inhibitor
RHC80267
but was largely insensitive to inhibitors of phospholipases A
2
and C. Iron-overloaded cardiomyocytes also displayed increased production of eicosanoids and induction of cyclooxygenase-2 after stimulation with interleukin-1α.

Conclusions
—Iron overload enhances AA release and incorporation of AA into phosphatidylcholine, as well as cyclooxygenase-2 induction and eicosanoid production, in NRVMs. The effects of AA and metabolites on cardiomyocyte rhythmicity suggest a causal connection between these signals and electromechanical alterations in iron-overload–induced cardiomyopathy.
Mouse Model of Desmin-Related Cardiomyopathy
Authors: Wang Xuejun , Osinska Hanna , Dorn Gerald W. , Nieman Michelle , Lorenz John N. , Gerdes A. Martin , Witt Sandra , Kimball Thomas , Gulick James , Robbins Jeffrey
Published: June 2012

Background
—The consequence of upregulation of desmin in the heart is unknown. Mutations in desmin have been linked to desmin-related myopathy (DRM), which is characterized by abnormal intrasarcoplasmic accumulation of desmin, but direct causative evidence that a desmin mutation leads to aberrant intrasarcoplasmic desmin accumulation, aggregation, and cardiomyopathy is lacking.

Methods and Results
—Multiple transgenic mouse lines that expressed either murine wild-type desmin or a 7–amino acid deletion (R173 through E179) desmin (D7-des) mutation linked to DRM were made. The distribution of desmin protein was unchanged, and no overt phenotype was detected in the wild-type desmin transgenic mice. In contrast, the D7-des mouse heart showed aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive and characteristic of human DRM. The desmin filament network was significantly disrupted, and myofibril alignment was visibly compromised. Although systolic function at the whole-organ level was substantially conserved in the young adult animals, the ability of the heart to respond to β-agonist stimulation, as measured in the intact animal, was significantly blunted.

Conclusions
—Upregulation of desmin protein at moderate levels is not detrimental. However, the D7-des mutation is dominant negative, and expression of the mutant protein leads to the appearance of aggregates that are characteristic of and diagnostic for human desmin-related cardiomyopathy.
Role of Variability in Microvascular Resistance on Fractional Flow Reserve and Coronary Blood Flow Velocity Reserve in Intermediate Coronary Lesions
Authors: Meuwissen Martijn , Chamuleau Steven A. J. , Siebes Maria , Schotborgh Carl E. , Koch Karel T. , de Winter Robbert J. , Bax Matthijs , de Jong Angelina , Spaan Jos A. E. , Piek Jan J.
Published: June 2012

Background
—Fractional flow reserve (FFR) and coronary blood flow velocity reserve (CFR) represent physiological quantities used to evaluate coronary lesion severity and to make clinical decisions. A comparison between the outcomes of both diagnostic techniques has not been performed in a large cohort of patients with intermediate coronary lesions.

Methods and Results
—FFR and CFR were assessed in 126 consecutive patients with 150 intermediate coronary lesions (between 40% and 70% diameter stenosis by visual assessment). Agreement between outcomes of FFR and CFR, categorized at cut-off values of 0.75 and 2.0, respectively, was observed in 109 coronary lesions (73%), whereas discordant outcomes were present in 41 lesions (27%). In 26 of these 41 lesions, FFR was <0.75 and CFR≥2.0 (group A); in the remaining 15 lesions, FFR was ≥0.75 and CFR<2.0 (group B). Minimum microvascular resistance, defined as the ratio of mean distal pressure to average peak blood flow velocity during maximum hyperemia, showed a large variability (overall range, 0.65 to 4.64 mm Hg · cm
−1
· s
−1
) and was significantly higher in group B than in group A (2.42±0.77 versus 1.91±0.70 mm Hg · cm
−1
· s
−1
;
P
=0.034).

Conclusions
—Our findings demonstrate the prominent role of microvascular resistance in modulating the relationship between FFR and CFR and emphasize the importance of combined pressure and flow velocity measurements to evaluate coronary lesion severity and microvascular involvement.
Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated Stents in Human Coronary Arteries
Authors: Sousa J. Eduardo , Costa Marco A. , Abizaid Alexandre , Abizaid Andrea S. , Feres Fausto , Pinto Ibraim M. F. , Seixas Ana C. , Staico Rodolfo , Mattos Luiz A. , Sousa Amanda G. M. R. , Falotico Robert , Jaeger Judith , Popma Jeffrey J. , Serruys Patrick W.
Published: June 2012

Background
—Restenosis remains an important limitation of interventional cardiology. Therefore, we aimed to determine the safety and efficacy of sirolimus (a cell-cycle inhibitor)-coated BX
Velocity
stents.

Methods and Results
—Thirty patients with angina pectoris were electively treated with 2 different formulations of sirolimus-coated stents (slow release [SR], n=15, and fast release [FR], n=15). All stents were successfully delivered, and patients were discharged without clinical complications. Independent core laboratories analyzed angiographic and 3D volumetric intravascular ultrasound data (immediately after procedure and at 4-month follow-up). Eight-month clinical follow-up was obtained for all patients. There was minimal neointimal hyperplasia in both groups (11.0±3.0% in the SR group and 10.4±3.0% in the FR group,
P
=NS) by ultrasound and quantitative coronary angiography (in-stent late loss, 0.09±0.3 mm [SR] and −0.02±0.3 mm [FR]; in-lesion late loss, 0.16±0.3 mm [SR] and −0.1±0.3 mm [FR]). No in-stent or edge restenosis (diameter stenosis ≥50%) was observed. No major clinical events (stent thrombosis, repeat revascularization, myocardial infarction, or death) had occurred by 8 months.

Conclusions
—The implantation of sirolimus-coated BX Velocity stents is feasible and safe and elicits minimal neointimal proliferation. Additional placebo-controlled trials are required to confirm these promising results.
The Phytoestrogen Genistein Produces Acute Nitric Oxide–Dependent Dilation of Human Forearm Vasculature With Similar Potency to 17β-Estradiol
Authors: Walker H. A. , Dean T. S. , Sanders T. A. B. , Jackson G. , Ritter J. M. , Chowienczyk P. J.
Published: June 2012

Background
—Genistein, a phytoestrogen, may have estrogenic cardioprotective actions. We investigated whether genistein influences endothelium-dependent vasodilation in forearm vasculature of healthy human subjects and compared the effects of genistein with those of 17β-estradiol.

Methods and Results
—The brachial arterial was cannulated with a 27-gauge needle for drug infusion. Forearm blood flow responses were measured with strain-gauge plethysmography. Genistein (10 to 300 nmol/min, each dose for 6 minutes) produced a dose-dependent increase in forearm blood flow from 3.4±0.3 to 9.6±1.3 mL · min
−1
· 100 mL forearm
−1
(mean±SEM) in men (n=9,
P
<0.0001 by ANOVA). The mean forearm venous concentration of genistein during infusion of the highest dose was 1.8±0.3 μmol/L in 6 additional men. Genistein produced a similar increase in blood flow in premenopausal women. Daidzein, another phytoestrogen, was ineffective, but equimolar concentrations of 17β-estradiol caused similar vasodilation to genistein. Responses to genistein and 17β-estradiol were inhibited to the same degree by the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine. A threshold dose of genistein potentiated the endothelium-dependent vasodilator acetylcholine but not the endothelium-independent vasodilator nitroprusside.

Conclusions
—Genistein causes
l
-arginine/NO-dependent vasodilation in forearm vasculature of human subjects with similar potency to 17β-estradiol and potentiates endothelium-dependent vasodilation to acetylcholine.
Ventricular Preexcitation in Children and Young Adults
Authors: Basso Cristina , Corrado Domenico , Rossi Lino , Thiene Gaetano
Published: June 2012

Background
—Sudden death (SD) in ventricular preexcitation (VP) syndrome is believed to be the result of atrial fibrillation with rapid ventricular response over the accessory pathway. Previous reports are anecdotal and often lack autopsy validation.

Methods and Results
—Prevalence and clinicopathological features of VP were investigated in a series of 273 SDs in children and young adults (aged ≤35 years). Site of accessory atrioventricular (AV) connection was predicted by 12-lead ECG. Right and left AV ring together with the sinoatrial and AV septal junction were studied in serial histological sections. Ten patients (3.6%; male, mean age 24±7 years) had VP: 8 had Wolff-Parkinson-White (WPW) and 2 had Lown-Ganong-Levine (LGL) syndrome. Six patients had previous symptoms, and SD occurred at rest in all but 1. Pathological substrates of LGL consisted of AV-node hypoplasia and right-sided atrio-Hisian tract, respectively. In the 8 WPW patients, 10 total accessory AV pathways consisting of ordinary myocardium were found (7 left lateral, 2 right posterolateral, and 1 septal). These pathways were close to the endocardium (mean distance, 750±530 μm) and 310±190 μm thick. In 4 WPW patients (50%), isolated acute atrial myocarditis was found, which was polymorphous in 1 and lymphocytic in 3.

Conclusions
—VP accounted for 3.6% of SD in young people and was not preceded by warning symptoms in 40%. A left accessory pathway was the most frequent substrate, and its subendocardial location supports the feasibility of catheter ablation. Isolated atrial myocarditis may act as a trigger of paroxysmal atrial fibrillation that leads to SD.
Effectiveness of a Nonselective ET
A/B
and a Selective ET
A
Antagonist in Rats With Monocrotaline-Induced Pulmonary Hypertension
Authors: Jasmin Jean-François , Lucas Martin , Cernacek Peter , Dupuis Jocelyn
Published: June 2012

Background
—Both nonselective ET
A/B
receptor and selective ET
A
receptor antagonists can reduce pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) in various animal models. Depending on their net effects after blockade of endothelial and smooth muscle ET
B
receptors, nonselective ET
A/B
antagonists could be more or less effective than selective ET
A
antagonists.

Methods and Results
—Two weeks after injection of saline or 60 mg/kg monocrotaline (MCT), rats received 50 mg · kg
−1
· d
−1
of a selective (
LU135252
) or nonselective (BSF420627) antagonist for 3 weeks. This resulted in 4 groups: control (n=15), MCT (n=60), MCT+ET
A
(n=39), and MCT+ET
A/B
(n=40). Five-week survival was 35% in the MCT group; this was increased to 56% in the MCT+ET
A
group (
P
=0.10) and to 67% in the MCT+ET
A/B
group (
P
=0.0015). Drug administration was stopped 48 hours before hemodynamic measurements to evaluate the chronic effects of therapy: PH in the MCT group (RV systolic pressure 87±1 mm Hg) was improved similarly in both MCT+ET
A
and MCT+ET
A/B
groups (72±3 and 70±3 mm Hg, respectively,
P
<0.05). Severe RVH in the MCT group (RV/left ventricle+septum weight ratio 73±1%) was not affected by the selective antagonist (70±2%) but was reduced to 54±2% in the MCT+ET
A/B
group (
P
<0.01). Pulmonary resistive properties, assessed from isolated lung pressure-flow relationships, were improved similarly in survivors from both treated groups.

Conclusions
—Both the nonselective ET
A/B
antagonist BSF420627 and the selective ET
A
antagonist
LU135252
are effective in this model of PH. Similar direct comparative studies in other models of PH and with various dosage regimens are warranted to define the optimal pharmacological approach of PH when ET receptor antagonists are used.
Sudden Cardiac Death, Genes, and Arrhythmogenesis
Authors: Spooner Peter M. , Albert Christine , Benjamin Emelia J. , Boineau Robin , Elston Robert C. , George Alfred L. , Jouven Xavier , Kuller Lewis H. , MacCluer Jean W. , Marbán Eduardo , Muller James E. , Schwartz Peter J. , Siscovick David S. , Tracy Russell P. , Zareba Wojciech , Zipes Douglas P.
Published: June 2012

Abstract
—This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.
Adenovirus-Mediated Gene Transfer of Human Platelet-Activating Factor–Acetylhydrolase Prevents Injury-Induced Neointima Formation and Reduces Spontaneous Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Quarck Rozenn , De Geest Bart , Stengel Dominique , Mertens Ann , Lox Marleen , Theilmeier Gregor , Michiels Carine , Raes Martine , Bult Hidde , Collen Désiré , Van Veldhoven Paul , Ninio Ewa , Holvoet Paul
Published: June 2012

Background
—Atherosclerosis is characterized by an early inflammatory response involving proinflammatory mediators such as platelet-activating factor (PAF)-like phospholipids, which are inactivated by PAF-acetylhydrolase (PAF-AH). The effect of adenovirus-mediated expression of PAF-AH on injury-induced neointima formation and spontaneous atherosclerosis was studied in apolipoprotein E–deficient mice.

Methods and Results
—Intravenous administration of an adenovirus (5×10
8
plaque-forming units) directing liver-specific expression of human PAF-AH resulted in a 3.5-fold increase of plasma PAF-AH activity at day 7 (
P
<0.001); this was associated with a 2.4- and 2.3-fold decrease in malondialdehyde-modified LDL autoantibodies and the lysophosphatidylcholine/phosphatidylcholine ratio, respectively (
P
<0.001 for both). Non-HDL and HDL cholesterol levels in
PAF-AH
–treated mice were similar to those of control virus-treated mice. Seven days after virus injection, endothelial denudation of the common left carotid artery was induced with a guidewire. Neointima formation was assessed 18 days later.
PAF-AH
gene transfer reduced oxidized lipoproteins by 82% (
P
<0.001), macrophages by 69% (
P
=0.006), and smooth muscle cells by 84% (
P
=0.002) in the arterial wall. This resulted in a 77% reduction (
P
<0.001) of neointimal area. Six weeks after adenovirus-mediated gene transfer, spontaneous atherosclerotic lesions in the aortic root were analyzed.
PAF-AH
gene transfer reduced atherosclerotic lesions by 42% (
P
=0.02) in male mice, whereas a nonsignificant 14% reduction was observed in female mice. Basal and PAF-AH activity after gene transfer were higher in male mice than in female mice (
P
=0.01 and
P
=0.04, respectively).

Conclusions
—Gene transfer of
PAF-AH
inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E–deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.
Acute Cardiac Allograft Rejection in Nitric Oxide Synthase-2
−/−
and Nitric Oxide Synthase-2
+/+
Mice
Authors: Szabolcs Matthias J. , Ma Ninsheng , Athan Eleni , Zhong Jing , Ming Ming , Sciacca Robert R. , Husemann Jens , Albala Arline , Cannon Paul J.
Published: June 2012

Background
—The contribution of nitric oxide synthase (NOS)-2 to myocardial inflammation and cardiomyocyte necrosis and apoptosis during allograft rejection was investigated through heterotopic cardiac transplantation in mice.

Methods and Results
—In the first experiments, hearts from C3H donor mice were transplanted into NOS-2
−/−
and NOS-2
+/+
C57BL/6J.129J recipients. A second series of experiments included NOS-2
−/−
donor hearts transplanted into NOS-2
−/−
recipients and wild-type NOS-2
+/+
donor hearts transplanted into wild-type NOS-2
+/+
recipients. (All donors were C57BL/6J and recipients were C57BL/6J.129J.) In the first series of experiments, no significant differences were observed in allograft survival, rejection score, total number of apoptotic nuclei (TUNEL), total number of apoptotic cardiomyocytes, or graft NOS-2 mRNA and protein. Positive NOS-2 immunostaining occurred in endothelial cells and cardiomyocytes in the allografts; the inflammatory infiltrate was NOS-2 positive only when recipients were NOS-2
+/+
. In the second series of experiments, cardiac allograft survival was significantly increased in the NOS-2
−/−
mice (26±13 versus 17±8 days,
P
<0.05), along with significant reductions in inflammatory infiltrate, rejection score, and total number of apoptotic nuclei (23.5±9.5 versus 56.4±15.3,
P
<0.01) and of apoptotic cardiomyocytes (2.9±1.6 versus 6.9±2.7,
P
<0.05). No NOS-2 or nitrotyrosine, a marker of peroxynitrite exposure, was detected in NOS-2
−/−
allografts transplanted into NOS-2
−/−
recipients.

Conclusions
—The data suggest that NO derived from NOS-2 contributes to the inflammatory response and to cardiomyocyte damage and apoptosis during acute cardiac allograft rejection.
Noninvasive Quantification of Coronary Blood Flow Reserve in Humans Using Myocardial Contrast Echocardiography
Authors: Wei Kevin , Ragosta Michael , Thorpe Jerrel , Coggins Matthew , Moos Sally , Kaul Sanjiv
Published: June 2012

Background
—We hypothesized that coronary blood flow (CBF) reserve could be quantified noninvasively in humans using myocardial contrast echocardiography (MCE).

Methods and Results
—Eleven patients with normal epicardial coronary arteries (group I) and 19 with single-vessel coronary stenosis (group II) underwent quantitative coronary angiography, MCE, and CBF velocity measurements at rest and during intravenous adenosine infusion. In group I patients, MCE-derived myocardial blood flow (MBF) velocity reserve (2.4±0.08) was similar to CBF velocity reserve using a Doppler flow wire (2.4±1.1). Patients with a single risk factor had a significantly higher MBF reserve (3.0±0.89) than those with ≥2 risk factors (1.7±0.22). In group II patients, significant differences were found in MBF velocity reserve in patients with mild (<50%), moderate (50% to 75%), or severe (>75%) stenoses (2.2±0.40, 1.6±0.65, and 0.55±0.19, respectively;
P
=0.005). A linear relation was found between flow velocity reserve determined using the 2 methods (
r
=0.76,
P
<0.001), and a curvilinear relation was noted between the percent coronary stenosis measured using quantitative coronary angiography and velocity reserve using both methods.

Conclusions
—CBF reserve can be measured in humans using MCE. This method may allow the noninvasive assessment of coronary stenosis severity and the detection of microvascular dysfunction.
Point-of-Care Measured Platelet Inhibition Correlates With a Reduced Risk of an Adverse Cardiac Event After Percutaneous Coronary Intervention
Authors: Steinhubl Steven R. , Talley J. David , Braden Gregory A. , Tcheng James E. , Casterella Peter J. , Moliterno David J. , Navetta Frank I. , Berger Peter B. , Popma Jeffrey J. , Dangas George , Gallo Richard , Sane David C. , Saucedo Jorge F. , Jia Gang , Lincoff A. Michael , Theroux Pierre , Holmes David R. , Teirstein Paul S. , Kereiakes Dean J.
Published: June 2012

Background
—The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown.

Methods and Results
—Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACEs: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve ≥95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%,
P
=0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those ≥70% inhibited (
P
=0.009). By multivariate analysis, platelet function inhibition ≥95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96,
P
=0.04).

Conclusions
—Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.
Glycemic Control and Heart Failure Among Adult Patients With Diabetes
Authors: Iribarren Carlos , Karter Andrew J. , Go Alan S. , Ferrara Assiamira , Liu Jennifer Y. , Sidney Stephen , Selby Joseph V.
Published: June 2012

Background
—Glycemic control is associated with microvascular events, but its effect on the risk of heart failure is not well understood. We examined the association between hemoglobin (Hb) A
Ic
and the risk of heart failure hospitalization and/or death in a population-based sample of adult patients with diabetes and assessed whether this association differed by patient sex, heart failure pathogenesis, and hypertension status.

Methods and Results
—A cohort design was used with baseline between January 1, 1995, and June 30, 1996, and follow-up through December 31, 1997 (median 2.2 years). Participants were 25 958 men and 22 900 women with (predominantly type 2) diabetes, ≥19 years old, with no known history of heart failure. There were a total of 935 events (516 among men; 419 among women). After adjustment for age, sex, race/ethnicity, education level, cigarette smoking, alcohol consumption, hypertension, obesity, use of β-blockers and ACE inhibitors, type and duration of diabetes, and incidence of interim myocardial infarction, each 1% increase in Hb A
Ic
was associated with an 8% increased risk of heart failure (95% CI 5% to 12%). An Hb A
Ic
≥10, relative to Hb A
Ic
<7, was associated with 1.56-fold (95% CI 1.26 to 1.93) greater risk of heart failure. Although the association was stronger in men than in women, no differences existed by heart failure pathogenesis or hypertension status.

Conclusions
—These results confirm previous evidence that poor glycemic control may be associated with an increased risk of heart failure among adult patients with diabetes.
Unrecognized Pulmonary Venous Desaturation Early After Norwood Palliation Confounds Q̇p:Q̇s Assessment and Compromises Oxygen Delivery
Authors: Taeed Roozbeh , Schwartz Steven M. , Pearl Jeffrey M. , Raake Jenni L. , Beekman Robert H. , Manning Peter B. , Nelson David P.
Published: June 2012

Background
—Hemodynamic stability after Norwood palliation often requires manipulation of pulmonary vascular resistance to alter the pulmonary-to-systemic blood flow ratio (Q̇p:Q̇s). Q̇p:Q̇s is often estimated from arterial saturation (Sa
o
2
), a practice based on 2 untested assumptions: constant systemic arteriovenous O
2
difference and normal pulmonary venous saturation.

Methods and Results
—In 12 patients early (≤3 days) after Norwood palliation, simultaneous arterial, superior vena caval (Ssvc
o
2
), and pulmonary venous (Spv
o
2
) oximetry was used to test whether Sa
o
2
accurately predicts Q̇p:Q̇s. Stepwise multiple regression assessed the contributions of Sa
o
2
, Ssvc
o
2
, and Spv
o
2
to Q̇p:Q̇s determination. Sa
o
2
correlated weakly with Q̇p:Q̇s (
R
2
=0.08,
P
<0.05). Inclusion of Ssvc
o
2
and Spv
o
2
improved Q̇p:Q̇s prediction accuracy. Pulmonary venous desaturation (Spv
o
2
<95%) was observed frequently (30%), especially at Fi
o
2
≤0.21, but normalized with higher Fi
o
2
or PEEP in all patients. In 6 patients, Fi
o
2
was increased incrementally from 0.17 to 0.50 to determine whether this was an effective means to manipulate Q̇p:Q̇s. Q̇p:Q̇s failed to change predictably with increased Fi
o
2
. In 5 of 6 patients, however, higher Spv
o
2
and Sa
o
2
enhanced systemic oxygen delivery, as demonstrated by improvement in oxygen extraction.

Conclusions
—Sa
o
2
correlated poorly with Q̇p:Q̇s because of variability in Ssvc
o
2
and Spv
o
2
. A novel observation was that pulmonary venous desaturation occurred frequently early after Norwood palliation but normalized with higher Fi
o
2
or PEEP. Because unrecognized pulmonary venous desaturation confounds Q̇p:Q̇s assessment and compromises Sa
o
2
and oxygen delivery, judicious use of inspired oxygen and PEEP may be beneficial in selected patients early after Norwood palliation.
Artificial Neural Network–Based Method of Screening Heart Murmurs in Children
Authors: DeGroff Curt G. , Bhatikar Sanjay , Hertzberg Jean , Shandas Robin , Valdes-Cruz Lilliam , Mahajan Roop L.
Published: June 2012

Background
—Early recognition of heart disease is an important goal in pediatrics. Efforts in developing an inexpensive screening device that can assist in the differentiation between innocent and pathological heart murmurs have met with limited success. Artificial neural networks (ANNs) are valuable tools used in complex pattern recognition and classification tasks. The aim of the present study was to train an ANN to distinguish between innocent and pathological murmurs effectively.

Methods and Results
—Using an electronic stethoscope, heart sounds were recorded from 69 patients (37 pathological and 32 innocent murmurs). Sound samples were processed using digital signal analysis and fed into a custom ANN. With optimal settings, sensitivities and specificities of 100% were obtained on the data collected with the ANN classification system developed. For future unknowns, our results suggest the generalization would improve with better representation of all classes in the training data.

Conclusion
—We demonstrated that ANNs show significant potential in their use as an accurate diagnostic tool for the classification of heart sound data into innocent and pathological classes. This technology offers great promise for the development of a device for high-volume screening of children for heart disease.
Increased Expression of Isoform 1 of the Sarcoplasmic Reticulum Ca
2+
-Release Channel in Failing Human Heart
Authors: Münch Götz , Bölck Birgit , Sugaru Alina , Brixius Klara , Bloch Wilhelm , Schwinger Robert H.G.
Published: June 2012

Background
—The sarcoplasmic reticulum (SR) Ca
2+
-release channel plays a key role in the excitation-contraction coupling of cardiac myocytes. Because respective alterations have been reported in human heart failure, we investigated isoform expression of the SR Ca
2+
-release channel in human hearts from patients with terminal heart failure (dilated cardiomyopathy [DCM], n=8) and nonfailing organ donors (NF, n=8).

Methods and Results
—Expression of mRNA of SR Ca
2+
-release channel isoforms in isolated human cardiomyocytes and myocardial tissue was analyzed by reverse-transcription polymerase chain reaction. Protein expression was quantified in myocardial tissue with [
3
H]-ryanodine binding and with Western blots, expressed as densitometric units per microgram of protein (DU), and cellular localization was visualized with immunohistochemistry. We found mRNA expression of isoforms 1, 2, and 3 in cardiomyocytes and myocardial tissue both in NF and DCM. Total SR Ca
2+
-release channel protein expression in NF (B
max
2.16±0.43 pmol/mg protein) and in DCM (B
max
2.33±0.22 pmol/mg protein) myocardium was unchanged. Expression of isoform 1 of the SR Ca
2+
-release channel was significantly (
P
=0.0037) increased in DCM myocardium (NF 1.97±0.25 versus DCM 3.37±0.31 DU), whereas protein expression of isoform 2 (NF 14.62±0.87 versus DCM 13.52±0.43 DU) and isoform 3 (NF 1.39±0.13 versus DCM 1.35±0.19 DU) was unchanged. All 3 isoforms of the protein could be localized in human ventricular myocytes with fluorescence immunohistochemistry.

Conclusions
—All 3 isoforms of the SR Ca
2+
-release channel were determined in human ventricular cardiomyocytes. Increased expression of isoform 1 of the SR Ca
2+
-release channel could contribute to impaired excitation-contraction coupling in human heart failure.
Intracoronary Stenting and Angiographic Results
Authors: Kastrati Adnan , Mehilli Julinda , Dirschinger Josef , Dotzer Franz , Schühlen Helmut , Neumann Franz-Josef , Fleckenstein Martin , Pfafferott Conrad , Seyfarth Melchior , Schömig Albert
Published: June 2012

Background
—Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results.

Methods and Results
—A total of 651 patients with coronary lesions situated in native vessels >2.8 mm in diameter were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 μm) and 325 patients to the thick-strut stent (strut thickness of 140 μm). The primary end point was the angiographic restenosis (≥50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the combined rate of death and myocardial infarctions at 1 year. The incidence of angiographic restenosis was 15.0% in the thin-strut group and 25.8% in the thick-strut group (relative risk, 0.58; 95% CI, 0.39 to 0.87;
P
=0.003). Clinical restenosis was also significantly reduced, with a reintervention rate of 8.6% among thin-strut patients and 13.8% among thick-strut patients (relative risk, 0.62; 95% CI, 0.39 to 0.99;
P
=0.03). No difference was observed in the combined 1-year rate of death and myocardial infarction.

Conclusions
—The use of a thinner-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting. These findings may have relevant implications for the currently most widely used percutaneous coronary intervention.
Dysfunctional Regulation of Endothelial Nitric Oxide Synthase (eNOS) Expression in Response to Exercise in Mice Lacking One eNOS Gene
Authors: Kojda Georg , Cheng Yian C. , Burchfield Jana , Harrison David G.
Published: June 2012

Background
—Previous data suggest that 1 endothelial NO synthase (eNOS) gene is sufficient to allow normal expression and function of eNOS under basal conditions. We hypothesized that this might not hold true for conditions known to increase eNOS gene expression, such as exercise.

Methods and Results
—Male mice heterozygous for a disruption of the eNOS gene (eNOS
+/
−
) and normal C56Bl/6J mice (eNOS
+/+
), 3 to 4 months of age, underwent exercise training for 3 weeks. Nontrained mice were exposed to the exercise environment (noise and vibration of the treadmill) without exercise for an identical period. In eNOS
+/+
mice (n=7), exercise increased aortic eNOS protein expression by 3.4±0.4-fold (
P
<0.002). This was associated with a greater vascular cGMP accumulation on stimulation with acetylcholine (
P
<0.05). Furthermore, exercise training increased eNOS mRNA (1.78±0.4-fold) and protein (1.76±0.17-fold) in left ventricular tissue, as determined by competitive reverse transcription–polymerase chain reaction and Western analysis (
P
<0.05 for both). In striking contrast, exercise had no effect on aortic eNOS expression and cGMP accumulation in eNOS
+/
−
mice (
P
>0.05). Thus, although eNOS expression appears to be normal in eNOS
+/
−
mice under basal conditions, these mice are unable to increase eNOS expression during exercise.

Conclusions
—These findings show that regulation of eNOS expression during exercise requires the presence of both alleles of the gene and may have implications for conditions in which polymorphisms of eNOS are present in only 1 allele in humans. These individuals may have a normal vascular reactivity under basal conditions but may be unable to adapt their vascular reactivity in response to exercise training.