bluuebunny/crossref_metadata_2025 huggingface dataset:
Power-Law Relationship of Heart Rate Variability as a Predictor of Mortality in the Elderly
Authors: Huikuri Heikki V. , Mäkikallio Timo H. , Airaksinen K. E. Juhani , Seppänen Tapio , Puukka Pauli , Räihä Ismo J. , Sourander Leif B.
Published: June 2012

Background
—The prognostic role of heart rate (HR) variability analyzed from 24-hour ECG recordings in the general population is not well known. We studied whether analysis of 24-hour HR behavior is able to predict mortality in a random population of elderly subjects.

Methods and Results
—A random sample of 347 subjects of ≥65 years of age (mean, 73±6 years) underwent a comprehensive clinical evaluation, laboratory tests, and 24-hour ECG recordings and were subsequently followed up for 10 years. Various spectral and nonspectral measures of HR variability were analyzed from the baseline 24-hour ECG recordings. Risk factors for all-cause, cardiac, cerebrovascular, cancer, and other causes of death were assessed. By the end of 10-year follow-up, 184 subjects (53%) had died and 163 (47%) were still alive. Seventy-four subjects (21%) had died of cardiac disease, 37 of cancer (11%), 25 of cerebrovascular disease (7%), and 48 (14%) of various other causes. Among all analyzed variables, a steep slope of the power-law regression line of HR variability (<−1.50) was the best univariate predictor of all-cause mortality (odds ratio, 7.9; 95% confidence interval [CI], 3.7 to 17.0;
P
<.0001). After adjusting for age and sex and including all univariate predictors of mortality in the proportional hazards analysis, ie, measures of HR variability, history of heart disease, functional class, smoking, medication, and blood cholesterol and glucose concentrations, all-cause mortality was predicted only by the slope of HR variability (adjusted relative risk, 1.74; 95% CI, 1.42 to 2.13;
P
<.0001) and a history of congestive heart failure (adjusted relative risk, 1.70;
P
=.0002). The slope of HR variability predicted both cardiac (adjusted relative risk, 2.05;
P
=.0002) and cerebrovascular death (adjusted relative risk, 2.84;
P
=.0001) but not cancer or other causes of death.

Conclusions
—Power-law relationship of 24-hour HR variability is a more powerful predictor of death than the traditional risk markers in elderly subjects. Altered long-term behavior of HR implies an increased risk of vascular causes of death rather than being a marker of any disease or frailty leading to death.
Nitric Oxide–Induced Downregulation of Cdk2 Activity and Cyclin A Gene Transcription in Vascular Smooth Muscle Cells
Authors: Guo Kun , Andrés Vicente , Walsh Kenneth
Published: June 2012

Background
—Nitric oxide (NO) inhibits vascular smooth muscle cell (VSMC) proliferation and neointima formation after balloon injury. However, the molecular mechanisms underlying NO-mediated growth arrest are poorly understood. In the present study, we examined the effects of the NO donors sodium nitroprusside (SNP) and
S
-nitroso-
N
-acetylpenicillamine (SNAP) on cell cycle activity in VSMCs.

Methods and Results
—Stimulation of quiescent rat VSMCs with serum leads to an increase in cyclin-dependent kinase (cdk)2 kinase activity that correlates with a marked induction of cyclin A protein expression. The addition of SNP or SNAP to VSMC cultures at the time of serum stimulation abrogates the induction of cdk2 activity without suppressing protein levels of cdk2 or cyclin E. These NO donors block serum-stimulated upregulation of cyclin A mRNA and protein and repress the serum induction of cyclin A promoter activity in VSMCs.

Conclusions
—The addition of the nitric oxide donors SNP or SNAP to mitogen-stimulated VSMCs prevents activation of cdk2, a key regulator of the G
1
and S phases of the cell cycle. These NO donors do not affect the expression of cdk2 protein but block the mitogen-induced expression of cyclin A, an activating subunit of cdk2. SNP and SNAP also repress the mitogen-stimulated activation of the cyclin A promoter. These data suggest that the antiproliferative effect of NO on VSMCs results, at least in part, from the repression of cyclin A gene transcription.
Effect of Risk Factors on the Mechanism of Acute Thrombosis and Sudden Coronary Death in Women
Authors: Burke Allen P. , Farb Andrew , Malcom Gray T. , Liang You-hui , Smialek John , Virmani Renu
Published: June 2012

Background
—Traditional risk factors have been linked to atherosclerotic heart disease in women. However, the effect of risk factors and menopausal status on the mechanism of sudden coronary death is unknown.

Methods and Results
—We examined 51 cases of sudden coronary death and 15 hearts from women who died of trauma. Coronary deaths were divided into four mechanisms of death: ruptured plaque with acute thrombus (n=8), eroded plaque with acute thrombus (n=18), stable plaque with healed infarct (n=18), and stable plaque without infarction (n=7). Vulnerable plaques prone to rupture were defined as those with a thin, fibrous cap infiltrated by macrophages and were quantitated in coronary deaths and control subjects. Total cholesterol (TC), HDL cholesterol, glycosylated hemoglobin, cigarette smoking, and hypertension were determined in each case. Compared with control subjects, women with plaque ruptures had elevated TC (270±55 versus 194±44 mg/dL,
P
=0.002), and those with erosions were more likely to be smokers (78% versus 33%,
P
=0.01). Women with stable plaque and healed infarct had elevated glycosylated hemoglobin (10.2±5.0% versus 6.4±0.4% in control subjects,
P
=0.001) and were more likely to be hypertensive (50% versus 15% in control subjects,
P
=0.03). By multivariate analysis, cigarette smoking was associated with plaque erosion (
P
=0.03, odds ratio [OR] 21), glycoslyated hemoglobin with stable plaque and healed infarct (
P
=0.03, OR 41), TC with plaque rupture (
P
=0.02, OR 7), and hypertension with stable plaque with healed infarct (
P
=0.02, OR 15). Seven of 8 plaque ruptures occurred in women >50 years of age versus 3 of 18 erosions (
P
=0.001). In cases of coronary death, vulnerable plaques were associated with elevated cholesterol (
P
=0.002) and age >50 years (
P
=0.002), independent of other risk factors.

Conclusions
—In women, traditional risk factors have distinct effects on the mechanisms of sudden coronary death, which vary by menopausal status. Effective risk factor modification may therefore differ between younger and older women and may be targeting different mechanisms of plaque instability.
Independent Prognostic Significance of Ischemic ST-Segment Response Limited to Recovery From Treadmill Exercise in Asymptomatic Subjects
Authors: Rywik Tomasz M. , Zink Richard C. , Gittings Neil S. , Khan Akbar A. , Wright Jeanette G. , O’Connor Frances C. , Fleg Jerome L.
Published: June 2012

Background
—Although exercise-induced ST depression is an independent predictor of future coronary events in asymptomatic populations, the predictive value of ST depression beginning after exercise cessation is unknown.

Methods and Results
—We analyzed the treadmill exercise tests of 825 healthy volunteers who were 22 to 89 years of age from the Baltimore Longitudinal Study of Aging. All subjects were free from coronary heart disease by history, physical examination, and resting ECG. From 825 participants, 611 (group 0) had no ischemic ST-segment changes during or after treadmill exercise, while 214 subjects developed ≥1-mm flat or downsloping ST depression: 151 (group 1) had ST changes starting during exercise, and 63 (group 2) had changes limited to recovery. Groups 1 and 2 were similar in age, sex, smoking status, hypertension prevalence, fasting plasma glucose, and serum cholesterol (CHOL). However, both groups were older and had higher CHOL and prevalence of hypertension than group 0. Treadmill exercise duration, peak oxygen consumption, and maximal heart rate were similar between groups 1 and 2 but were lower than in group 0 (each
P
<0.05). During a mean follow-up time of 9 years, 55 subjects developed coronary events (angina pectoris, myocardial infarction, or coronary death): 21 of 611 (3.4%) in group 0, 22 of 151 (14.6%) in group 1, and 12 of 63 (19%) in group 2 (
P
=0.001). By survival analysis, the risk of coronary events was similar in groups 1 and 2 but significantly higher than in group 0 (
P
<0.0001). Multiple logistic regression showed that age (odds ratio [OR]=1.07 per year,
P
=0.00001), CHOL (OR=1.02 per 1 mg,
P
=0.0001), and presence of ST-segment depression (OR=2.59,
P
=0.007 and OR=2.38,
P
=0.04 for groups 1 and 2, respectively) were independent predictors of events.

Conclusions
—Thus, ischemic ST-segment changes developing during recovery from treadmill exercise in apparently healthy individuals have adverse prognostic significance similar to those appearing during exercise.
Sleep Apnea in 81 Ambulatory Male Patients With Stable Heart Failure
Authors: Javaheri S. , Parker T. J. , Liming J. D. , Corbett W. S. , Nishiyama H. , Wexler L. , Roselle G. A.
Published: June 2012

Background
—Heart failure is a highly prevalent disorder that continues to be associated with repeated hospitalizations, high morbidity, and high mortality. Sleep-related breathing disorders with repetitive episodes of asphyxia may adversely affect heart function. The main aims of this study were to determine the prevalence, consequences, and differences in various sleep-related breathing disorders in ambulatory male patients with stable heart failure.

Methods and Results
—This article reports the results of a prospective study of 81 of 92 eligible patients with heart failure and a left ventricular ejection fraction <45%. There were 40 patients without (hourly rate of apnea/hypopnea, 4±4; group 1) and 41 patients with (51% of all patients; hourly rate of apnea/hypopnea, 44±19; group 2) sleep apnea. Sleep disruption and arterial oxyhemoglobin desaturation were significantly more severe and the prevalence of atrial fibrillation (22% versus 5%) and ventricular arrhythmias were greater in group 2 than in group 1. Forty percent of all patients had central sleep apnea, and 11% had obstructive sleep apnea. The latter patients had significantly greater mean body weight (112±30 versus 75±16 kg) and prevalence of habitual snoring (78% versus 28%). However, the hourly rate of episodes of apnea and hypopnea (36±10 versus 47±21), episodes of arousal (20±14 versus 23±11), and desaturation (lowest saturation, 72±11% versus 78±12%) were similar in patients with these different types of apnea.

Conclusions
—Fifty-one percent of male patients with stable heart failure suffer from sleep-related breathing disorders: 40% from central and 11% from obstructive sleep apnea. Both obstructive and central types of sleep apnea result in sleep disruption and arterial oxyhemoglobin desaturation. Patients with sleep apnea have a high prevalence of atrial fibrillation and ventricular arrhythmias.
Endothelin
A
Receptor Blockade Improves Nitric Oxide–Mediated Vasodilation in Monocrotaline-Induced Pulmonary Hypertension
Authors: Prié Stéphane , Stewart Duncan J. , Dupuis Jocelyn
Published: June 2012

Background
—Nitric oxide (NO) and endothelin (ET) have been implicated in the pathogenesis of pulmonary hypertension (PH). Chronic ET
A
antagonist therapy reduces PH in monocrotaline (MCT)-treated rats. Interactions between the
l
-arginine–NO pathway and the ET system have been described. We therefore studied the effect of long-term treatment with an oral ET
A
antagonist (LU 135252) on NO-related vasodilation in isolated lungs from control rats and rats with MCT-induced PH.

Methods and Results
—Three weeks after MCT injection, PH was associated with an increase in right ventricular pressure (from 27.4±0.9 to 66.6±4.1 mm Hg) and a decrease in endothelium-independent vasodilation in response to sodium nitroprusside (10
−10
to 10
−5
mol/
l
ΔE
max
, from 11.1±0.9 to 2.7±0.3 mm Hg). Endothelium-dependent vasodilation in response to acetylcholine (10
−9
to 10
−4
mol/
l
) and the calcium ionophore A23187 (10
−9
to 10
−7
mol/
l
) remained unaffected. Treatment with LU 135252 did not significantly affect the endothelium-dependent and -independent vasodilations in control rats. However, in MCT-treated rats, LU 135252 therapy significantly reduced right ventricular pressure (39.7±2.1 mm Hg), potentiated acetylcholine-induced vasodilatation (ΔE
max
, from 1.6±0.2 to 3.7±0.4 mm Hg), and improved the responses to sodium nitroprusside (ΔE
max
, from 2.7±0.3 to 5.6±0.6 mm Hg). LU 135252 did not significantly alter the non–receptor-mediated endothelium-dependent vasodilation to A23187 or pulmonary constitutive NO synthase activity.

Conclusions
—MCT PH is associated with a reduced smooth muscle responsiveness to NO but a maintained endothelium-dependent vasodilatory potency. Long-term ET
A
antagonist therapy not only restores smooth muscle responsiveness to NO but also increases endothelium-dependent dilation in response to acetylcholine. This mechanism may contribute to the therapeutic benefit of ET
A
antagonists in PH.
Increased Plasminogen Activator Inhibitor Type 1 in Coronary Artery Atherectomy Specimens From Type 2 Diabetic Compared With Nondiabetic Patients
Authors: Sobel Burton E. , Woodcock-Mitchell Janet , Schneider David J. , Holt Robert E. , Marutsuka Kousuke , Gold Herman
Published: June 2012

Background
—Inhibition of fibrinolysis attributable to elevated concentrations of plasminogen activator inhibitor type 1 (PAI-1) in blood is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes mellitus. Because we have shown that insulin can stimulate PAI-1 synthesis in vivo and because accelerated vascular disease is common in such patients as well, we hypothesized that increased PAI-1, potentially predisposing to thrombosis, acute occlusion, and accelerating atherosclerosis because of thrombus-associated mitogens, would be present in excess in atheroma from type 2 diabetic subjects.

Methods and Results
—Samples acquired by directional coronary atherectomy from 25 patients with type 2 diabetes and 18 patients without diabetes were characterized qualitatively histologically for cellularity and by immunohistochemistry visually and qualitatively and by quantitative image analysis for assessment of urokinase-type plasminogen activator (u-PA) and PAI-1. Patients with and without diabetes were similar with respect to demographic features and the distribution and severity of coronary artery disease. Substantially more PAI-1 and substantially less u-PA were present in the atherectomy samples from subjects with diabetes.

Conclusions
—The disproportionate elevation of PAI-1 compared with u-PA observed in atheromatous material extracted from vessels of diabetic subjects is consistent with increased gene expression of PAI-1 in vessels as well as the known increase of PAI-1 in blood, presumably reflecting increased synthesis. The increased PAI-1 detected in the atheroma may contribute in vivo to accelerated or persistent thrombosis underlying acute occlusion and to vasculopathy exacerbated by clot-associated mitogens in the vessel wall. Because the changes were observed to be associated with insulin resistance and type 2 diabetes mellitus, they may be modifiable by reduction of insulin resistance with insulin sensitizers and stringent control of hyperglycemia.
Clinical Features and Prognostic Implications of Familial Hypertrophic Cardiomyopathy Related to the Cardiac Myosin-Binding Protein C Gene
Authors: Charron Philippe , Dubourg Olivier , Desnos Michel , Bennaceur Mohammed , Carrier Lucie , Camproux Anne-Claude , Isnard Richard , Hagege Albert , Langlard Jean Marc , Bonne Gisele , Richard Pascale , Hainque Bernard , Bouhour Jean-Brieuc , Schwartz Ketty , Komajda Michel
Published: June 2012

Background
—Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (
MYBPC3
) gene. The aim of this study was to perform this type of analysis.

Methods and Results
—We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the
MYBPC3
gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the
MYBPC3
group to seven mutations in the β-myosin heavy-chain gene (β
-MHC
) group (n=52). There was no significant phenotypic difference among the different mutations in the
MYBPC3
gene. However, in the
MYBPC3
group compared with the β
-MHC
group, (1) prognosis was significantly better (
P
<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41±19 versus 35±17 years,
P
<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12±4 versus 16±7 mm,
P
<0.03), and abnormal T waves less frequent (9% versus 45%,
P
<0.02).

Conclusions
—These results are consistent with specific clinical features related to the
MYBPC3
gene: onset of the disease appears delayed and the prognosis is better than that associated with the β
-MHC
gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy.
Age- and Sex-Related Differences in Clinical Manifestations in Patients With Congenital Long-QT Syndrome
Authors: Locati Emanuela H. , Zareba Wojciech , Moss Arthur J. , Schwartz Peter J. , Vincent G. Michael , Lehmann Michael H. , Towbin Jeffrey A. , Priori Silvia G. , Napolitano Carlo , Robinson Jennifer L. , Andrews Mark , Timothy Katherine , Hall W. Jackson
Published: June 2012

Background
—Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry.

Methods and Results
—Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QT
c
>440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers (
KVLQT1
on 11p15.5), 62 LQT2 carriers (
HERG
on 7q35-36), and 31 LQT3 carriers (
SCN5A
on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8±7 versus 14±10 years,
P
<0.0001) and had higher event rates by age 15 years than females (74% versus 51%,
P
<0.0001). Affected family members had similar findings. By Cox analysis adjusting for QT
c
duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 (
P
<0.001), and it was 1.87 (
P
=0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 (
P
<0.001) by age 15 years, and it was 3.25 (
P
<0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%,
P
=0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers.

Conclusions
—Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.
Myocardial Infarction and Apoptosis After Myocardial Ischemia and Reperfusion
Authors: Vakeva Antti P. , Agah Azin , Rollins Scott A. , Matis Louis A. , Li Lan , Stahl Gregory L.
Published: June 2012

Background
—Myocardial ischemia and reperfusion (MI/R)–induced tissue injury involves necrosis and apoptosis. However, the precise contribution of apoptosis to cell death, as well as the mechanism of apoptosis induction, has not been delineated. In this study, we sought to define the contribution of the activated terminal complement components to apoptosis and necrosis in a rat model of MI/R injury.

Methods and Results
—Monoclonal antibodies (mAbs; 18A and 16C) raised against the rat C5 complement component bound to purified rat C5 (ELISA). 18A effectively blocked C5b-9–mediated cell lysis and C5a-induced chemotaxis of rat polymorphonuclear leukocytes (PMNs), whereas 16C had no complement inhibitor activity. A single dose (20 mg/kg IV) of 18A blocked >80% of serum hemolytic activity for >4 hours. Administration of 18A before myocardial ischemia (30 minutes) and reperfusion (4 hours) significantly reduced (91%) left ventricular free wall PMN infiltration compared with 16C treatment. Treatment with 18A 1 hour before ischemia or 5 minutes before reperfusion significantly reduced infarct size compared with 16C treatment. A significant reduction in infarct size (42%) was also observed in 18A-treated rats after 30 minutes of ischemia and 7 days of reperfusion. DNA ladders and DNA labeling (eg, TUNEL assay) demonstrated a dramatic reduction in MI/R-induced apoptosis in 18A-treated compared with 16C-treated rats.

Conclusions
—Anti-C5 therapy in the setting of MI/R significantly inhibits cell apoptosis, necrosis, and PMN infiltration in the rat despite C3 deposition. We conclude that the terminal complement components C5a and C5b-9 are key mediators of tissue injury in MI/R.
Tachycardia-Induced Change of Atrial Refractory Period in Humans
Authors: Yu Wen-Chung , Chen Shih-Ann , Lee Shih-Huang , Tai Ching-Tai , Feng An-Ning , Kuo Benjamin Ing-Tiau , Ding Yu-An , Chang Mau-Song
Published: June 2012

Background
—Atrial fibrillation (AF) has been shown to shorten the atrial effective refractory period (ERP) and make the atrium more vulnerable to AF. This study investigated the effect of atrial rate and antiarrhythmic drugs on ERP shortening induced by tachycardia.

Methods and Results
—Seventy adult patients without structural heart disease were included. For the first part of the study, right atrial ERP was measured with a drive cycle length of 500 ms before and after 10 minutes of rapid atrial pacing using five pacing cycle lengths (450, 400, 350, 300, and 250 ms) in 10 patients. For the second part of the study, the remaining 60 patients were included to study the effects of antiarrhythmic drugs on changes in atrial ERP induced by AF. Atrial ERP was measured with a drive cycle of 500 ms before and after an episode of pacing-induced AF. After the patients were randomized to receive one of six antiarrhythmic drugs (procainamide, propafenone, propranolol,
dl
-sotalol, amiodarone, and verapamil), atrial ERP was measured before and after another episode of pacing-induced AF. In the first part of the study, atrial ERP shortened significantly after 10 minutes of rapid atrial pacing, and the degree of shortening was correlated with pacing cycle length. The second part of the study showed that atrial ERP shortened after conversion of AF (172±15 versus 202±14 ms,
P
<0.0001) and that ERP shortening was attenuated after verapamil infusion (−4.6±1.2% versus −15.1±3.4%,
P
<0.001) but was unchanged after infusion of the other antiarrhythmic drugs. Furthermore, all of these antiarrhythmic drugs could decrease the incidence and duration of secondary AF.

Conclusions
—The atrial ERP shortening induced by tachycardia was a rate-dependent response. Verapamil, but not other antiarrhythmic drugs, could markedly attenuate this effect. However, verapamil and the other drugs could decrease the incidence and duration of secondary AF.
Role of Endogenous Endothelin in the Development of Graft Arteriosclerosis in Rat Cardiac Allografts
Authors: Okada Kenji , Nishida Yasuhiro , Murakami Hiroshi , Sugimoto Isao , Kosaka Hiroaki , Morita Hironobu , Yamashita Chojiro , Okada Masayoshi
Published: June 2012

Background
—The purpose of this study was to determine whether endothelin-1 (ET-1) contributes to the development of graft arteriosclerosis and whether the orally active nonpeptide endothelin receptor antagonist bosentan, which blocks both ET
A
and ET
B
receptors, can protect against this pathologic damage.

Methods and Results
—Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days. All recipients were given cyclosporine and were euthanized at examination 120 days after transplantation. Plasma ET-1 levels were significantly higher in group 2 than in group 1 (6.99±0.91 and 4.15±0.83 pg/mL, respectively). Strong ET-1 immunoreactivity was seen in both the thickened neointima and the media of the coronary arteries in group 2 but not in group 1. The mean ratio of the coronary luminal area to the total vascular area in group 2 (19.0±11.7%) was significantly lower than that in group 1 (34.2±9.9%) and was significantly increased in group 3 (33.2±9.2%).

Conclusions
—These results show that local upregulation of ET-1, mainly in the thickened neointima and the media of the coronary arteries, may play an important role in the pathogenesis of graft arteriosclerosis by stimulating ET
A
receptors, ET
B
receptors, or both. Orally active bosentan might be a useful agent for the clinical prevention of graft arteriosclerosis.
Sympathetic Denervation and Reinnervation After Arterial Switch Operation for Complete Transposition
Authors: Kondo Chisato , Nakazawa Makoto , Momma Kazuo , Kusakabe Kiyoko
Published: June 2012

Background
—Sympathetic cardiopulmonary nerves arise from the cervical sympathetic trunks and the stellate ganglia and subsequently course along the origin of the great arteries and the coronary arteries to innervate the ventricles. Therefore, the sympathetic nerves may be obligatorily interrupted by the arterial switch operation (ASO) for complete transposition of the great arteries.

Methods and Results
—To demonstrate and characterize the possible sympathetic denervation, 51 patients after ASO, 4.8 years old (range, 1 month to 10.1 years), underwent [
123
I]metaiodobenzylguanidine (MIBG) imaging of the sympathetic nerve terminal. MIBG uptake to the heart was graded by quantitative analysis using the heart-to-mediastinum (H/M) ratio of MIBG uptake. A quantitative criterion for absent uptake of MIBG was set to 1.48 in the H/M ratio. Four patients <1 month after ASO showed complete absence of MIBG uptake, which had been observed preoperatively. In contrast, 47 patients late after ASO (range, 15 months to 10.1 years) showed various degrees of uptake of MIBG. Patients operated on at ≤55 days of age showed positive MIBG uptake much more frequently than those operated on at later ages. Heart rate and rate-pressure product at peak exercise on a treadmill exercise test were significantly greater in patients with positive uptake than in those with absent uptake of MIBG.

Conclusions
—Cardiac sympathetic nerves were denervated early after and reinnervated late after ASO. Neonatal ASO may be favorable to facilitate sympathetic reinnervation, which may affect exercise tolerance late after surgery.
N
-Acetyl-Cysteine Decreases the Matrix-Degrading Capacity of Macrophage-Derived Foam Cells
Authors: Galis Zorina S. , Asanuma Kazuhiko , Godin Denis , Meng Xiaoping
Published: June 2012

Background
—Atherosclerotic plaque destabilization triggers clinical cardiovascular disease and thus represents an attractive therapeutic target. Weakening of tissue through the action of matrix-degrading enzymes, called matrix metalloproteinases (MMPs), released by resident macrophages was previously implicated in unstable vascular syndromes.

Methods and Results
—We used a hypercholesterolemic rabbit model of atherosclerosis to investigate the gelatinolytic activity associated with macrophage-derived foam cells (FCs). Gelatinolytic activity and expression of MMP-9 but not of MMP-2 cosegregated with macrophage FCs in aortic lesions. Macrophage-derived gelatinases were further investigated in vitro. MMP-9 was identified as the main macrophage-derived gelatinase in cells isolated from aortic lesions and from granuloma induced in the same rabbits to increase cell yield. Importantly, detection of activated MMP-9 in the FC culture medium supports the notion that these cells can independently initiate processing of secreted MMP zymogens to active enzymes. We further examined whether FC gelatinolytic activity is dependent on the presence of reactive oxygen species (ROS). We found that treatment (1 to 5 days) with 1 to 10 mmol/L
N
-acetyl-
l
-cysteine (NAC), an ROS scavenger, decreased not only gelatinolytic activity but also gelatinase expression by FCs. Similarly, NAC treatment of explanted lesions abolished in situ gelatinolytic activity and MMP-9 expression.

Conclusions
—Macrophage FCs are an abundant source of gelatinolytic activity that can be inhibited in vitro and in situ by NAC. This newly described action of antioxidant therapy might prove useful to inhibit matrix degradation and to improve vascular stability.
Randomized Comparison of Coronary Stenting With Balloon Angioplasty in Selected Patients With Acute Myocardial Infarction
Authors: Suryapranata Harry , van’t Hof Arnoud W. J. , Hoorntje Jan C. A. , de Boer Menko-Jan , Zijlstra Felix
Published: June 2012

Background
—Although the benefits of primary angioplasty in acute myocardial infarction have been demonstrated, several areas for improvement remain. Therefore, a prospective randomized trial comparing primary stenting with balloon angioplasty in patients with acute myocardial infarction was conducted.

Methods and Results
—Patients with acute myocardial infarction were randomly assigned to undergo either primary stenting (n=112) or balloon angioplasty (n=115). The clinical end points were death, recurrent infarction, subsequent bypass surgery, or repeat angioplasty of the infarct-related vessel. The overall mortality rate at 6 months was 2%. Recurrent infarction occurred in 8 patients (7%) after balloon angioplasty and in 1 (1%) after stenting (
P
=0.036). Subsequent target-vessel revascularization was necessary in 19 (17%) and 4 (4%) patients, respectively (
P
=0.0016). The cardiac event-free survival rate in the stent group was significantly higher than in the balloon angioplasty group (95% versus 80%;
P
=0.012).

Conclusions
—In selected patients with acute myocardial infarction, primary stenting can be applied safely and effectively, resulting in a lower incidence of recurrent infarction and a significant reduction in the need for subsequent target-vessel revascularization compared with balloon angioplasty.
Assessment of QT Dispersion for Prediction of Mortality or Arrhythmic Events After Myocardial Infarction
Authors: Zabel Markus , Klingenheben Thomas , Franz Michael R. , Hohnloser Stefan H.
Published: June 2012

Background
—Risk stratification by means of analysis of QT dispersion (QTD) in the 12-lead surface ECG is under intense investigation in various patient populations. The aim of the present prospective study was to evaluate the prognostic value of QTD and other ECG variables reflecting dispersion of ventricular repolarization in comparison with established risk stratifiers during long-term follow-up in a large cohort of post–myocardial infarction patients treated according to contemporary therapeutic guidelines.

Methods and Results
—In 280 consecutive infarct survivors, the 12-lead ECG was optically scanned and digitized for analysis of QTD (QT
max
−QT
min
) and 25 other repolarization variables, including recently developed and validated parameters such as the T peak–to–T end interval and the area under the T wave. In addition, a variety of established risk stratifiers were assessed. After a mean follow-up period of 32±10 months, 30 patients reached one of the prospectively defined study end points (death, ventricular tachycardia, or resuscitated ventricular fibrillation). Comparisons between event and nonevent patients by means of Kaplan-Meier event probability analyses revealed that none of the ECG dispersion variables were of discriminative value. In contrast, variables such as left ventricular ejection fraction (
P
=0.007), mean 24-hour heart rate (
P
=0.022), or heart rate variability (
P
=0.007) proved to be potentially useful risk stratifiers in this patient population. On multivariate analysis, only LVEF, heart rate variability, and a history of thrombolysis were independent predictors of outcome.

Conclusions
—Determination of QTD from the surface ECG even when performed with the best available methodology failed to predict subsequent risk in this large series of infarct survivors.
Percutaneous Balloon Versus Surgical Closed and Open Mitral Commissurotomy
Authors: Farhat Mohamed Ben , Ayari Mokdad , Maatouk Faouzi , Betbout Fethi , Gamra Habib , Jarrar Mourad , Tiss Mabrouk , Hammami Sonia , Thaalbi Rafik , Addad Faouzi
Published: June 2012

Background
—Percutaneous balloon mitral commissurotomy (BMC) has been proposed as an alternative to surgical closed mitral commissurotomy (CMC) and open mitral commissurotomy (OMC) for the management of rheumatic mitral valve stenosis (MS).

Methods and Results
—We conducted a prospective, randomized trial comparing the results of the 3 procedures in 90 patients (30 patients in each group) with severe pliable MS. Cardiac catheterization was performed in all patients before and at 6 months after each procedure. All patients had clinical and echocardiographic evaluation initially and throughout the 7-year follow-up period. Gorlin mitral valve area (MVA) increased much more after BMC (from 0.9±0.16 to 2.2±0.4 cm
2
) and OMC (from 0.9±0.2 to 2.2±0.4 cm
2
) than after CMC (from 0.9±0.2 to 1.6±0.4 cm
2
). Residual MS (MVA <1.5 cm
2
) was 0% after BMC or OMC and 27% after CMC. There was no early or late mortality or thromboembolism among the three groups. At 7-year follow-up, echocardiographic MVA was similar and greater after BMC and OMC (1.8±0.4 cm
2
) than after CMC (1.3±0.3 cm
2
;
P
<.001). Restenosis (MVA <1.5 cm
2
) rate was 6.6% after BMC or OMC versus 37% after CMC. Residual atrial septal defect was present in 2 patients and severe grade 3 mitral regurgitation was present in 1 patient in the BMC group. Eighty-seven percent of patients after BMC and 90% of patients after OMC were in New York Heart Association functional class I versus 33% (
P
<.0001) after CMC. Freedom from reintervention was 90% after BMC, 93% after OMC, and 50% after CMC.

Conclusions
—In contrast to surgical CMC, BMC and OMC produce excellent and comparable early hemodynamic improvement and are associated with a lower rate of residual stenosis and restenosis and need for reintervention. However, the good results, lower cost, and elimination of drawbacks of thoracotomy and cardiopulmonary bypass indicate that BMC should be the treatment of choice for patients with tight pliable rheumatic MS.
Reactivity of the Human Fetal Pulmonary Circulation to Maternal Hyperoxygenation Increases During the Second Half of Pregnancy
Authors: Rasanen Juha , Wood Dennis C. , Debbs Robert H. , Cohen Jose , Weiner Stuart , Huhta James C.
Published: June 2012

Background
—The aims of the present study were to determine whether maternal hyperoxygenation affects human fetal pulmonary circulation and whether there is a gestational age-related response in the fetal pulmonary circulation to maternal hyperoxygenation during the second half of gestation.

Methods and Results
—Twenty women between 20 and 26 weeks of gestation and 20 women between 31 and 36 weeks of gestation with normal singleton pregnancies were randomized to receive either 60% humidified oxygen or medical compressed air (room air) by a face mask. Fetal aortic and pulmonary valve; ductus arteriosus (DA); and right (RPA), left (LPA), and distal (DPA) pulmonary artery blood velocity waveforms were obtained by Doppler ultrasound before, during, and after maternal administration of either 60% oxygen or room air. Left and right ventricular cardiac outputs, DA volume blood flow, and RPA and LPA volume blood flows (Q
P
) were calculated. Foramen ovale volume blood flow (left ventricular cardiac output−Q
P
) was estimated. Pulsatility index (PI) values of DA, RPA, LPA, and DPA were calculated. Maternal hyperoxygenation did not change any of the measured fetal parameters between 20 and 26 weeks, whereas between 31 and 36 weeks, the PI values of RPA, LPA, and DPA decreased (
P
<.0001) and the PI of DA increased (
P
<.0001). In addition, Q
P
increased (
P
<.001), and DA volume blood flow (
P
<.01) and foramen ovale volume blood flow (
P
<.03) decreased. Left and right ventricular cardiac outputs were unchanged. All changes returned to baseline after maternal hyperoxygenation was discontinued.

Conclusions
—Reactivity of the human fetal pulmonary circulation to maternal hyperoxygenation increases with advancing gestation; this suggests that fetal pulmonary circulation is under acquired vasoconstriction at least after 31 to 36 weeks of gestation.
Cell-Free and Erythrocytic
S
-Nitrosohemoglobin Inhibits Human Platelet Aggregation
Authors: Pawloski John R. , Swaminathan Rajesh V. , Stamler Jonathan S.
Published: June 2012

Background
—Nitric oxide (NO) and related molecules are thought to inhibit human platelet aggregation by raising levels of cGMP.

Methods and Results
—Both oxidative stress (reactive oxygen species) and hemoglobin (Hb) seem to oppose NO effects. A major fraction of NO in the blood is bound to thiols of Hb, forming
S
-nitrosohemoglobin (SNO-Hb), which releases the NO group on deoxygenation in the microcirculation. Here we show that (1) both cell-free and intraerythrocytic SNO-Hb (SNO-RBC) inhibit platelet aggregation, (2) the oxidation state of the hemes in Hb influences the response—SNO-metHb (which is functionally similar to SNO-deoxyHb) has greater platelet inhibitory effects than SNO-oxyHb, and (3) the mechanism of platelet inhibition by SNO-Hb is cGMP independent.

Conclusions
—We suggest that the RBC has evolved a means to counteract platelet activation in small vessels and the proaggregatory effects of oxidative stress by forming SNO-Hb.
Randomized Trial of an Oral Platelet Glycoprotein IIb/IIIa Antagonist, Sibrafiban, in Patients After an Acute Coronary Syndrome
Authors: Cannon Christopher P. , McCabe Carolyn H. , Borzak Steven , Henry Timothy D. , Tischler Marc D. , Mueller Hiltrud S. , Feldman Robert , Palmeri Sebastian T. , Ault Kenneth , Hamilton Scott A. , Rothman Joel M. , Novotny William F. , Braunwald Eugene
Published: June 2012

Background
—Inhibitors of the platelet glycoprotein IIb/IIIa receptor given intravenously have been shown to be effective in reducing ischemic complications after coronary angioplasty and in unstable angina, making this a promising new class of agents for the treatment and prevention of ischemic events in patients with acute coronary syndromes. Sibrafiban (Ro 48–3657) is an oral, peptidomimetic, selective antagonist of the glycoprotein IIb/IIIa receptor.

Methods and Results
—The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 329 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibition were achieved: mean peak values ranged from 47% to 97% inhibition of 20 μmol/L ADP-induced platelet aggregation on day 28 across the seven doses. Twice-daily dosing provided more sustained platelet inhibition (mean inhibition, 36% to 86% on day 28), whereas platelet inhibition returned to baseline levels by 24 hours with once-daily dosing. Major hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined “minor” bleeding, usually mucocutaneous, occurred in 0% to 32% of patients in the various sibrafiban groups and in none of the patients treated with aspirin. Minor bleeding was related to total daily dose (
P
=.002), once- versus twice-daily dosing (
P
<.0001), renal function (
P
<.0001), and presentation with unstable angina (
P
<.01).

Conclusions
—The oral glycoprotein IIb/IIIa antagonist sibrafiban achieved effective, long-term platelet inhibition with a clear dose-response but at the expense of a relatively high incidence of minor bleeding. Oral IIb/IIIa inhibition deserves further study as a new treatment strategy in patients after acute coronary syndromes.
Potentiated Angiogenic Effect of Scatter Factor/Hepatocyte Growth Factor via Induction of Vascular Endothelial Growth Factor
Authors: Van Belle Eric , Witzenbichler Bernhard , Chen Donghui , Silver Marcy , Chang Ling , Schwall Ralph , Isner Jeffrey M.
Published: June 2012

Background
—Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic growth factor that stimulates proliferation and migration of endothelial cells (ECs) via the c-
Met
receptor, present on ECs as well as other cell types, including smooth muscle cells (SMCs). We studied the effects of recombinant human (rh) SF/HGF in vitro and in vivo in a rabbit model of hindlimb ischemia. We further compared these effects with those of recombinant human vascular endothelial growth factor (rhVEGF
165
), an EC–specific mitogen.

Methods and Results
—In vitro, rhSF/HGF and rhVEGF
165
exhibited similar effects on proliferation and migration of ECs. When both cytokines were administered together, the result was an additive effect on EC proliferation and a synergistic effect on EC migration. Application of rhSF/HGF to cultures of human SMCs resulted in the induction of VEGF mRNA and protein. In vivo, administration of rhSF/HGF (500 μg×3) was associated with significant improvements in collateral formation (
P
<.001) and regional blood flow (
P
<.0005) and with a significant reduction in muscle atrophy (
P
<.0001). These effects were significantly more pronounced than those of rhVEGF
165
administered according to the same protocol (
P
<.05). Neither remote angiogenesis nor other pathological sequelae were observed with either rhSF/HGF or rhVEGF
165
.

Conclusions
—The pleiotropic effects of certain growth factors may potentiate angiogenesis via a combination of direct effects on EC proliferation and migration and indirect effects that result in the generation of other potent EC mitogens from non-EC populations. The synergistic effects demonstrated when SF/HGF and VEGF are administered together in vitro may be reproduced in vivo by SF/HGF-induced upregulation of VEGF in vascular SMCs.
Incremental Prognostic Value of Myocardial Perfusion Single Photon Emission Computed Tomography for the Prediction of Cardiac Death
Authors: Hachamovitch Rory , Berman Daniel S. , Shaw Leslee J. , Kiat Hosen , Cohen Ishac , Cabico J. Arthur , Friedman John , Diamond George A.
Published: June 2012

Background
—The incremental prognostic value of stress single photon emission computed tomography (SPECT) for the prediction of cardiac death as an individual end point and the implications for risk stratification are undefined.

Methods and Results
—We identified 5183 consecutive patients who underwent stress/rest SPECT and were followed up for the occurrence of cardiac death or myocardial infarction. Over a mean follow up of 642±226 days, 119 cardiac deaths and 158 myocardial infarctions occurred (3.0% cardiac death rate, 2.3% myocardial infarction rate). Patients with normal scans were at low risk (≤0.5%/y), and rates of both outcomes increased significantly with worsening scan abnormalities. Patients who underwent exercise stress and had mildly abnormal scans had low rates of cardiac death but higher rates of myocardial infarction (0.7%/y versus 2.6%/y;
P
<.05). After adjustment for prescan information, scan results provided incremental prognostic value toward the prediction of cardiac death. The identification of patients at intermediate risk of nonfatal myocardial infarction and low risk for cardiac death by SPECT may result in significant cost savings when applied to a clinical testing strategy.

Conclusions
—Myocardial perfusion SPECT yields incremental prognostic information toward the identification of cardiac death. Patients with mildly abnormal scans after exercise stress are at low risk for cardiac death but intermediate risk for nonfatal myocardial infarction and thus may benefit from a noninvasive strategy and may not require invasive management.
Thrombin Binds to Soluble Fibrin Degradation Products Where it Is Protected From Inhibition by Heparin-Antithrombin but Susceptible to Inactivation by Antithrombin-Independent Inhibitors
Authors: Weitz Jeffrey I. , Leslie Beverly , Hudoba Monika
Published: June 2012

Background
—Thrombolytic therapy induces a procoagulant state characterized by elevated plasma levels of fibrinopeptide A (FPA), but the responsible mechanism is uncertain.

Methods and Results
—Washed plasma clots were incubated in citrated plasma in the presence or absence of tissue plasminogen activator (t-PA), and FPA generation was monitored as an index of unopposed thrombin activity. FPA levels are almost twofold higher in the presence of t-PA than in its absence. This primarily reflects the action of thrombin bound to soluble fibrin degradation products because (a) there is progressive FPA generation even after clots are removed from t-PA–containing plasma, and (b) clot lysates produce concentration-dependent FPA generation when incubated in citrated plasma. Using thrombin-agarose affinity chromatography, (DD)E and fragment E but not
d
-dimer were identified as the thrombin-binding fibrin fragments, indicating that the thrombin-binding site is located within the E domain. Heparin inhibits thrombin bound to fibrin degradation products less effectively than free thrombin. In contrast, D-Phe-Pro-ArgCH
2
Cl, hirudin and hirugen inhibit free thrombin and thrombin bound to fibrin degradation products equally well.

Conclusions
—Thrombin bound to soluble fibrin degradation products is primarily responsible for the increase in FPA levels that occurs when a clot undergoes t-PA–induced lysis. Like clot-bound thrombin, thrombin bound to fibrin derivatives is protected from inhibition by heparin but susceptible to inactivation by direct thrombin inhibitors. These findings help to explain the superiority of direct thrombin inhibitors over heparin as adjuncts to thrombolytic therapy.