bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Stenting Versus Balloon Angioplasty in Occluded Coronary Arteries
Authors: Buller Christopher E. , Dzavik Vladimir , Carere Ronald G. , Mancini G. B. John , Barbeau Gerald , Lazzam Charles , Anderson Todd J. , Knudtson Merril L. , Marquis Jean-Francois , Suzuki Takahiko , Cohen Eric A. , Fox Rebecca S. , Teo Koon K.
Published: June 2012

Background
—Balloon angioplasty (PTCA) of occluded coronary arteries is limited by high rates of restenosis and reocclusion. Although stenting improves results in anatomically simple occlusions, its effect on patency and clinical outcome in a broadly selected population with occluded coronary arteries is unknown.

Methods and Results
—Eighteen centers randomized 410 patients with nonacute native coronary occlusions to PTCA or primary stenting with the heparin-coated Palmaz-Schatz stent. The primary end point, failure of sustained patency, was determined at 6-month angiography. Repeat target-vessel revascularization, adverse cardiovascular events, and angiographic restenosis (>50% diameter stenosis) constituted secondary end points. Sixty percent of patients had occlusions of >6 weeks’ duration, baseline flow was TIMI grade 0 in 64%, and median treated segment length was 30.5 mm. With 95.6% angiographic follow-up, primary stenting resulted in a 44% reduction in failed patency (10.9% versus 19.5%,
P
=0.024) and a 45% reduction in clinically driven target-vessel revascularization at 6 months (15.4% versus 8.4%,
P
=0.03). The incidence of adverse cardiovascular events was similar for both strategies (PTCA, 23.6%; stent, 23.3%;
P
=NS). Stenting resulted in a larger mean 6-month minimum lumen dimension (1.48 versus 1.23 mm,
P
<0.01) and a reduced binary restenosis rate (55% versus 70%,
P
<0.01).

Conclusions
—Primary stenting of broadly selected nonacute coronary occlusions is superior to PTCA alone, improving late patency and reducing restenosis and target-vessel revascularization.
Seasonal Variation in Chronic Heart Failure Hospitalizations and Mortality in France
Authors: Boulay Fabrice , Berthier Frédéric , Sisteron Olivier , Gendreike Yves , Gibelin Pierre
Published: June 2012

Background
—Circannual variation in blood pressure and in the incidence of acute myocardial infarction is well known but has not been investigated in chronic heart failure. This report describes and compares the seasonal variation of chronic heart failure hospitalizations and mortality in the French population.

Methods and Results
—All deaths that occurred among French adults over the period 1992 to 1996 (n=138 602) and all discharges by adults in French public hospitals for chronic heart failure over the period 1995 to 1997 (n=324 013) were examined retrospectively. First, chronic heart failure deaths in France occurred with a striking annual periodicity and peaked in winter (December through January), both in the overall population and in subgroups defined by age (>44 years old) and sex. The distribution of cumulative monthly deaths differed by nearly 35%, ranging from a peak of 20% above average in January to 15% below average in August (Roger’s test:
P
<0.001). Second, hospitalizations for chronic heart failure in French public hospitals followed a similar seasonal pattern (
P
<0.001), with a winter-spring predominance (+7% to +10% from December through April). Third, for persons ≥85 years old, excess hospitalizations occurred earlier in the year, with marked synchronized peaks in January for both mortality and hospitalizations (
P
<0.001).

Conclusions
—Clear seasonal variations in adult chronic heart failure hospitalizations and deaths were identified. The considerable economic impact on health care services warrants further epidemiological investigations and a more comprehensive approach to disease management.
α- and β-Adrenergic Pathways Differentially Regulate Cell Type–Specific Apoptosis in Rat Cardiac Myocytes
Authors: Iwai-Kanai Eri , Hasegawa Koji , Araki Makoto , Kakita Tsuyoshi , Morimoto Tatsuya , Sasayama Shigetake
Published: June 2012

Background
—The apoptosis of cardiac myocytes may play a role in the development of heart failure. Norepinephrine is one of the factors activated in heart failure and can induce myocardial cell apoptosis in culture. However, it is unknown if α- and β-adrenergic pathways coordinately or differentially regulate apoptosis and if this apoptotic pathway uses common or cell type–specific apoptotic signals.

Methods and Results
—We stimulated cultured neonatal rat cardiac myocytes with an α
1
-adrenergic agonist (PE, phenylephrine), a β-adrenergic agonist (isoproterenol [Iso]) or a membrane-permeable cAMP analogue (8-Br-cAMP) in serum-free conditions for 48 hours. Iso and 8-Br-cAMP markedly increased the number of TUNEL-positive cells (%TUNEL-positive nuclei >40%) compared with saline stimulation (<10%). DNA fragmentation was also confirmed by ladder formation in agarose gels. Apoptotic myocytes were characterized by cell shrinkage and nuclear condensation, consistent with morphological features of apoptosis. The Iso-induced apoptosis was almost completely inhibited by the protein kinase A–specific inhibitor KT5720. In contrast, PE inhibited 8-Br-cAMP–induced myocardial cell apoptosis. The apoptosis-inhibitory effect by PE was negated by the α
1
-adrenergic receptor antagonist prazosin and the MEK-1–specific inhibitor PD098059. Interestingly, although 8-Br-cAMP markedly induced apoptosis in cardiac myocytes, it completely blocked serum depletion–induced apoptosis in PC12 cells, a rat pheochromocytoma cell line.

Conclusions
—These findings indicate that α- and β-adrenergic pathways differentially regulate myocardial cell apoptosis. The results also suggest that a cAMP– protein kinase A pathway is necessary and sufficient for β-adrenergic agonist–induced apoptosis and that this apoptotic pathway is not functional in other cell types, for example, PC12 cells.
Trandolapril Reduces the Incidence of Atrial Fibrillation After Acute Myocardial Infarction in Patients With Left Ventricular Dysfunction
Authors: Pedersen Ole Dyg , Bagger Henning , Køber Lars , Torp-Pedersen Christian
Published: June 2012

Background
—Studies have suggested that ACE inhibitors have an antiarrhythmic effect on ventricular arrhythmias. Whether they have an effect on atrial fibrillation is unknown.

Methods and Results
—We investigated the effect of ACE inhibition with trandolapril on the incidence of atrial fibrillation in patients with reduced left ventricular function secondary to acute myocardial infarction. The patients in this study were those who qualified for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study, a randomized double-blind placebo-controlled study and who had sinus rhythm on the ECG obtained at randomization. Patients who fulfilled the criteria for inclusion were randomized to treatment with the ACE inhibitor trandolapril or placebo and were followed up for 2 to 4 years. Development and time to occurrence of atrial fibrillation in one 12-lead ECG recorded at the outpatient visits was the primary end point of this investigation. Of the 1749 patients included in the TRACE study, 1577 had sinus rhythm on the ECG recorded at randomization. Of these patients, 790 were randomized to trandolapril treatment and 787 to placebo treatment. The groups differed only slightly with respect to baseline characteristics. A total of 64 patients developed atrial fibrillation during the 2- to 4-year follow-up period. Significantly more patients developed atrial fibrillation in the placebo group than in the trandolapril group, 5.3% (n=42) versus 2.8% (n=22), respectively,
P
<0.05. Cox multivariable regression analysis, adjusting for important baseline characteristics, revealed that trandolapril treatment significantly reduced the risk of developing atrial fibrillation (RR, 0.45; 95% CI, 0.26 to 0.76;
P
<0.01).

Conclusions
—The results from the present study demonstrate that trandolapril treatment reduces the incidence of atrial fibrillation in patients with left ventricular dysfunction after acute myocardial infarction.
Cardiac Interbeat Interval Dynamics From Childhood to Senescence
Authors: Pikkujämsä Sirkku M. , Mäkikallio Timo H. , Sourander Leif B. , Räihä Ismo J. , Puukka Pauli , Skyttä Jarmo , Peng Chung-Kang , Goldberger Ary L. , Huikuri Heikki V.
Published: June 2012

Background
—New methods of R-R interval variability based on fractal scaling and nonlinear dynamics (“chaos theory”) may give new insights into heart rate dynamics. The aims of this study were to (1) systematically characterize and quantify the effects of aging from early childhood to advanced age on 24-hour heart rate dynamics in healthy subjects; (2) compare age-related changes in conventional time- and frequency-domain measures with changes in newly derived measures based on fractal scaling and complexity (chaos) theory; and (3) further test the hypothesis that there is loss of complexity and altered fractal scaling of heart rate dynamics with advanced age.

Methods and Results
—The relationship between age and cardiac interbeat (R-R) interval dynamics from childhood to senescence was studied in 114 healthy subjects (age range, 1 to 82 years) by measurement of the slope, β, of the power-law regression line (log power−log frequency) of R-R interval variability (10
−4
to 10
−2
Hz), approximate entropy (ApEn), short-term (α
1
) and intermediate-term (α
2
) fractal scaling exponents obtained by detrended fluctuation analysis, and traditional time- and frequency-domain measures from 24-hour ECG recordings. Compared with young adults (<40 years old, n=29), children (<15 years old, n=27) showed similar complexity (ApEn) and fractal correlation properties (α
1
, α
2
, β) of R-R interval dynamics despite lower spectral and time-domain measures. Progressive loss of complexity (decreased ApEn,
r
=−0.69,
P
<0.001) and alterations of long-term fractal-like heart rate behavior (increased α
2
,
r
=0.63, decreased β,
r
=−0.60,
P
<0.001 for both) were observed thereafter from middle age (40 to 60 years, n=29) to old age (>60 years, n=29).

Conclusions
—Cardiac interbeat interval dynamics change markedly from childhood to old age in healthy subjects. Children show complexity and fractal correlation properties of R-R interval time series comparable to those of young adults, despite lower overall heart rate variability. Healthy aging is associated with R-R interval dynamics showing higher regularity and altered fractal scaling consistent with a loss of complex variability.
Matrix Metalloproteinase Inhibitor Prevents Acute Lung Injury After Cardiopulmonary Bypass
Authors: Carney David E. , Lutz Charles J. , Picone Anthony L. , Gatto Louis A. , Ramamurthy N. S. , Golub Lorne M. , Simon Sanford R. , Searles Bruce , Paskanik Andrew , Snyder Kathy , Finck Christine , Schiller Henry J. , Nieman Gary F.
Published: June 2012

Background
—Acute lung injury (ALI) after cardiopulmonary bypass (CPB) results from sequential priming and activation of neutrophils. Activated neutrophils release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen radical species, which damage alveolar-capillary basement membranes and the extracellular matrix, resulting in an ALI clinically defined as adult respiratory distress syndrome (ARDS). We hypothesized that treatment with a potent MMP and elastase inhibitor, a chemically modified tetracycline (CMT-3), would prevent ALI in our sequential insult model of ALI after CPB.

Methods and Results
—Anesthetized Yorkshire pigs were randomized to 1 of 5 groups: control (n=3); CPB (n=5), femoral-femoral hypothermic bypass for 1 hour; LPS (n=7), sham bypass followed by infusion of low-dose
Escherichia coli
lipopolysaccharide (LPS; 1 μg/kg); CPB+LPS (n=6), both insults; and CPB+LPS+CMT-3 (n=5), both insults plus intravenous CMT-3 dosed to obtain a 25-μmol/L blood concentration. CPB+LPS caused severe lung injury, as demonstrated by a significant fall in Pa
o
2
and an increase in intrapulmonary shunt compared with all groups (
P
<0.05). These changes were associated with significant pulmonary infiltration of neutrophils and an increase in elastase and MMP-9 activity.

Conclusions
—All pathological changes typical of ALI after CPB were prevented by CMT-3. Prevention of lung dysfunction followed an attenuation of both elastase and MMP-2 activity. This study suggests that strategies to combat ARDS should target terminal neutrophil effectors.
Neuregulin in Cardiac Hypertrophy in Rats With Aortic Stenosis
Authors: Rohrbach Susanne , Yan Xinhua , Weinberg Ellen O. , Hasan Faisal , Bartunek Jozef , Marchionni Mark A. , Lorell Beverly H.
Published: June 2012

Background
—Neuregulins are a family of peptide growth factors that promote cell growth and viability. The potential role of neuregulin-erbB signaling in hypertrophic growth and later failure in the adult heart in vivo is not known.

Methods and Results
—We used ribonuclease protection assays to quantify mRNA levels of neuregulin, erbB2, and erbB4 in left ventricular (LV) tissue and myocytes of normal rats and rats with aortic stenosis with pressure-overload hypertrophy 6 and 22 weeks after banding. At both stages of hypertrophy, Northern blot analyses of mRNA from LV myocytes showed upregulation of atrial natriuretic peptide, a molecular marker of hypertrophy (
P
<0.05). LV tissue neuregulin message levels were similar in animals with aortic stenosis compared with controls (
P
=NS) and were not detectable in myocytes. LV erbB2 and erbB4 message levels in LV tissue and myocytes were maintained during early compensatory hypertrophy in 6-week aortic stenosis animals compared with age-matched controls; in contrast, erbB2 and erbB4 message levels were depressed in 22-week aortic stenosis animals at the stage of early failure (both
P
<0.01 vs age-matched controls). Immunoblotting of erbB2 and erbB4 also showed normal protein levels in 6-week aortic stenosis animals compared with controls; however, erbB2 and erbB4 protein levels were depressed in 22-week aortic stenosis animals (48% decrease in erbB2,
P
<0.05, and 43% decrease in erbB4,
P
<0.01) relative to age-matched controls.

Conclusions
—The neuregulin receptors erbB2 and erbB4 are downregulated at both the message and protein levels at the stage of early failure in animals with chronic hypertrophy secondary to aortic stenosis. These data suggest a role for disabled erbB receptor signaling in the transition from compensatory hypertrophy to failure.
Selective Activation of the K
+
ATP
Channel Is a Mechanism by Which Sudden Death Is Produced by Low-Energy Chest-Wall Impact (Commotio Cordis)
Authors: Link Mark S. , Wang Paul J. , VanderBrink Brian A. , Avelar Erick , Pandian Natesa G. , Maron Barry J. , Estes N. A. Mark
Published: June 2012

Background
—Sudden death due to relatively innocent chest-wall impact has been described in young individuals (commotio cordis). In our previously reported swine model of commotio cordis, ventricular fibrillation (with T-wave strikes) and ST-segment elevation (with QRS strikes) were produced by 30-mph baseball impacts to the precordium. Because activation of the K
+
ATP
channel has been implicated in the pathogenesis of ST elevation and ventricular fibrillation in myocardial ischemia, we hypothesized that this channel could be responsible for the electrophysiologic findings in our experimental model and in victims of commotio cordis.

Methods and Results
—In the initial experiment, 6 juvenile swine were given 0.5 mg/kg IV glibenclamide, a selective inhibitor of the K
+
ATP
channel, and chest impact was given on the QRS. The results of these strikes were compared with animals in which no glibenclamide was given. In the second phase, 20 swine were randomized to receive glibenclamide or a control vehicle (in a double-blind fashion), with chest impact delivered just before the T-wave peak. With QRS impacts, the maximal ST elevation was significantly less in those animals given glibenclamide (0.16±0.10 mV) than in controls (0.35±0.20 mV;
P
=0.004). With T-wave impacts, the animals that received glibenclamide had significantly fewer occurrences of ventricular fibrillation (1 episode in 27 impacts; 4%) than controls (6 episodes in 18 impacts; 33%;
P
=0.01).

Conclusions
—In this experimental model of commotio cordis, blockade of the K
+
ATP
channel reduced the incidence of ventricular fibrillation and the magnitude of ST-segment elevation. Therefore, selective K
+
ATP
channel activation may be a pivotal mechanism in sudden death resulting from low-energy chest-wall trauma in young people during sporting activities.
Infection and Atherosclerosis
Authors: Epstein Stephen E. , Zhou Yi Fu , Zhu Jianhui
Published: June 2012

Abstract
—Although definitive proof of a causal role of infection contributing to atherogenesis is lacking, multiple investigations have demonstrated that infectious agents evoke cellular and molecular changes supportive of such a role. Moreover, both
Chlamydia pneumoniae
and cytomegalovirus exacerbate lesion development in animal models of atherosclerosis and restenosis. The fact that multiple pathogens have been associated with atherosclerosis implies that many “atherogenic” pathogens exist, and recent data suggest that the risk of atherosclerosis conveyed by infection relates to the number of atherogenic pathogens with which an individual is infected. It also is evident that variability in host susceptibility to the atherogenic effects of pathogens exists; this variability appears to be related at least in part to whether the host can generate an immune response that successfully controls pathogen inflammatory activity and in part to the specific pattern of immune response—humoral or cellular. The latter may relate to host capacity to control pathogen activity and to a pathogen-induced autoimmune component of the atherogenic process. Additional animal and human studies are necessary to further test the validity of the infection/atherosclerosis link and to provide more insight into the mechanisms by which infection may contribute to atherosclerosis, information critical for devising strategies to reduce or eliminate any contribution to atherosclerosis caused by infection.
Desmin Mutation Responsible for Idiopathic Dilated Cardiomyopathy
Authors: Li Duanxiang , Tapscoft Terry , Gonzalez Oscar , Burch Paula E. , Quiñones Miguel A. , Zoghbi William A. , Hill Rita , Bachinski Linda L. , Mann Douglas L. , Roberts Robert
Published: June 2012

Background
—Idiopathic dilated cardiomyopathy, of which ≈20% of cases are familial (FDCM), is a primary myocardial disorder characterized by ventricular dilatation and impaired systolic function. It is a common cause of heart failure and the need for cardiac transplantation. Although 6 chromosomal loci responsible for autosomal dominant FDCM have been mapped by linkage analysis, none of these genes have been identified. By use of the candidate-gene approach, actin was identified recently as being responsible for dilated cardiomyopathy. Considerable evidence suggests desmin, a muscle-specific intermediate filament, plays a significant role in cardiac growth and development.

Methods and Results
—To determine whether a defect of desmin induces dilated cardiomyopathy, 44 probands with FDCM underwent clinical evaluation and DNA analysis. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of ≥2.7 cm/m
2
with an ejection fraction ≤50% in the absence of other potential causes. After amplification by polymerase chain reaction, the exons of the desmin gene were sequenced. A missense desmin mutation, Ile451Met, which cosegregates with FDCM without clinically evident skeletal muscle abnormalities, was identified in a 4-generation family but was not detected in 460 unrelated healthy individuals.

Conclusions
—A novel missense mutation of desmin, Ile451Met, was identified as the genetic cause of idiopathic dilated cardiomyopathy. This finding is of particular significance because this is the first mutation detected in the desmin tail domain, and the function of the desmin tail remains unknown. Because this mutation leads to a restricted cardiac phenotype in the family studied in the present report, it suggests that the tail of desmin plays an important functional role in cardiac tissue.
Serotonin Is Associated with Coronary Artery Disease and Cardiac Events
Authors: Vikenes Kjell , Farstad Mikael , Nordrehaug Jan Erik
Published: June 2012

Background
—Blood platelets are related to coronary atherogenesis. Platelets secrete serotonin (5-hydroxytryptamine) which has several effects on the vascular wall and promotes thrombogenesis, mitogenesis, and proliferation of smooth muscle cells. Serotonin may therefore be one of the factors involved in the development of coronary artery disease (CAD). We have assessed serotonin among conventional predictors for CAD in patients undergoing coronary angiography for chest pain or clinically suspected angina pectoris.

Methods and Results
—Of 121 consecutive male patients (mean age 65, range 41 to 90 years) undergoing angiography, 96 had coronary artery stenosis and 25 had normal angiograms. Serotonin, blood platelet count, and conventional biochemical risk factors for CAD were determined in the morning the day before the angiography. High serotonin (cut-point 1000 nmol/L) was significantly associated with CAD with an odds ratio (OR) of 3.4 (95% confidence interval 1.2 to 9.8). The corresponding OR for smokers was 4.8 (1.9 to 12.2); hypercholesterolemia (>7 mmol/L), 2.9 (1.1 to 7.6); high platelet count (cut-point 325 10
9
/L), 3.0 (1.0 to 9.5); and family history of heart disease, 2.3 (1.0 to 5.2). After adjustment with conventional risk factors, the OR for CAD was 3.8 (1.1 to 13.1), comparing high and low values of serotonin. The relation between serotonin and CAD was strengthened only when patients <70 years (n=82) were included in the analysis. In this age group, the occurrence of cardiac events during a mean of 3.7 years of follow-up was significantly associated with high serotonin values.

Conclusions
—The study suggests that serotonin is associated with coronary artery disease and occurrence of cardiac events, particularly in younger age groups. This association seems to persist after adjustment for conventional risk factors.
Age-Dependent Association of Apolipoprotein E Genotype With Coronary and Aortic Atherosclerosis in Middle-Aged Men
Authors: Ilveskoski Erkki , Perola Markus , Lehtimäki Terho , Laippala Pekka , Savolainen Vesa , Pajarinen Jarkko , Penttilä Antti , Lalu Kaisa H. , Männikkö Antti , Liesto Kimmo K. , Koivula Timo , Karhunen Pekka J.
Published: June 2012

Background
—Apolipoprotein E (apoE) polymorphism is one of the genetic determinants of serum cholesterol values. The apoE ε4 allele has been associated with advanced coronary heart disease (CHD) diagnosed by angiography, but the role of the apoE genotype in atherosclerosis has not been confirmed at vessel-wall level, nor is any age-dependent effect of the apoE genotype on the development of CHD known.

Methods and Results
—The right and left anterior descending coronary arteries (RCA and LAD) and the aorta from 700 male autopsy cases (Helsinki Sudden Death Study) in 1981-1982 and 1991-1992 (average age 53 years, range 33 to 70 years) were stained for fat, and all areas covered with fatty streaks, fibrotic plaques, and complicated lesions were measured. In the RCA and LAD, the apoE genotype was significantly associated with the area of total atherosclerotic lesions in men <53 years old but not with that in older men (
P
=0.0085 and
P
=0.041, respectively, for age-by-genotype interaction). Men <53 years old with the ε4/3 genotype showed 61% larger total atherosclerotic lesion area in the RCA (
P
=0.0027) and 26% larger area in the LAD (
P
=0.12) than did men with the ε3/3. The apoE ε4/3 was also associated with atherosclerotic lesions in the abdominal (
P
=0.014) and thoracic (
P
=0.12) aorta, but this effect, unlike that of the coronary arteries, was not age-related.

Conclusions
—In men, the apoE ε4 allele is a significant genetic risk factor for coronary atherosclerosis in early middle age. This suggests that at older age, other known risk factors of CHD play a more important role in the atherosclerotic process than apoE polymorphisms.
Electrophysiological Delineation of the Tachycardia Circuit in Atrioventricular Nodal Reentrant Tachycardia
Authors: Yamabe Hiroshige , Misumi Ikuo , Fukushima Hironobu , Ueno Kazuhiro , Kimura Yoshihiro , Hokamura Youichi
Published: June 2012

Background
—The exact boundaries of the reentry circuit in atrioventricular nodal reentrant tachycardia (AVNRT) have not been convincingly defined.

Methods and Results
—To define the tachycardia circuit, single extrastimuli were delivered during AVNRT to 8 sites of the right intra-atrial septum: 3 arbitrarily divided sites of the AV junction extending from the His bundle (HB) site to the coronary sinus ostium (CSOS) (sites S, M, and I) and the superior (S-CSOS), inferior (I-CSOS), posterior (P-CSOS), and posteroinferior (PI-CSOS) portions of the CSOS and the CSOS in 18 patients. The mean tachycardia cycle length (TCL) was 368±52 ms. Retrograde earliest atrial activation was observed at the HB site in all patients. The longest coupling intervals of single extrastimuli that reset AVNRT at sites S, M, I, I-CSOS, CSOS, S-CSOS, P-CSOS, and PI-CSOS were 356±51, 356±51, 355±52, 357±51, 318±47, 305±53, 311±56, and 312±56 ms, respectively, and the following return cycles at these sites were 368±52, 368±53, 367±53, 367±53, 407±66, 431±73, 415±55, and 412±56 ms, respectively. The longest coupling intervals at sites S, M, I, and I-CSOS did not differ from each other and were longer than those at CSOS and S-, P-, and PI-CSOS (
P
<0.0001). The return cycles at sites S, M, I, and I-CSOS did not differ from the TCL, whereas those at CSOS and S-, P-, and PI-CSOS were longer than the TCL (
P
<0.0001).

Conclusions
—The perinodal atrium extending from the HB site to I-CSOS was involved in the tachycardia circuit. I-CSOS was thought to be the entrance of the slow pathway.
Risk Factors for Early or Delayed Stroke After Cardiac Surgery
Authors: Hogue Charles W. , Murphy Suzan F. , Schechtman Kenneth B. , Dávila-Román Victor G.
Published: June 2012

Background
—Stroke after cardiac surgery is a devastating complication that leads to excess mortality and health resource utilization. The purpose of this study was to identify risk factors for perioperative stroke, including strokes detected early after cardiac surgery or postoperatively.

Methods and Results
—Data were obtained from 2972 patients undergoing coronary artery bypass graft and/or valve surgery. Patients ≥65 years old and those with a history of symptomatic neurological disease underwent preoperative carotid artery ultrasound scanning. Intraoperative epiaortic ultrasound to assess for ascending aorta atherosclerosis was performed in all patients. New strokes were considered as a single end point and were categorized with respect to whether they were detected immediately after surgery (early stroke) or after an initial, uneventful neurological recovery from surgery (delayed stroke). Strokes occurred in 48 patients (1.6%); 31 (65%) were delayed strokes. By multivariate analysis, prior neurological event, aortic atherosclerosis, and duration of cardiopulmonary bypass were independently associated with early stroke, whereas predictors of delayed stroke were prior neurological event, diabetes, aortic atherosclerosis, and the combined end points of low cardiac output and atrial fibrillation. Female sex was associated with a 6.9-fold increased risk of early stroke and a 1.7-fold increased risk of delayed stroke. In-hospital mortality of patients with early (41%) and delayed (13%) strokes was higher than that of other patients (3%,
P
=0.0001).

Conclusions
—Most strokes after cardiac surgery occurred after initial uneventful recovery from surgery. Women were at higher risk to suffer early and delayed perioperative strokes. Atrial fibrillation had no impact on postoperative stroke rate unless it was accompanied by low cardiac output syndrome.
Changes in Intra-Abdominal Visceral Fat and Serum Leptin Levels in Patients With Obstructive Sleep Apnea Syndrome Following Nasal Continuous Positive Airway Pressure Therapy
Authors: Chin Kazuo , Shimizu Kouichi , Nakamura Takaya , Narai Noboru , Masuzaki Hiroaki , Ogawa Yoshihiro , Mishima Michiaki , Nakamura Takashi , Nakao Kazuwa , Ohi Motoharu
Published: June 2012

Background
—Obstructive sleep apnea syndrome (OSAS) is a common disorder in obese subjects. Visceral fat accumulation (VFA) is a better predictor of coronary heart disease than body mass index. Leptin is a hormone involved in the control of body weight and fat distribution. The effect of nasal continuous positive airway pressure (NCPAP) treatment on VFA and serum leptin levels in OSAS patients has not been known.

Methods and Results
—VFA and subcutaneous fat accumulation (SFA) were assessed by CT before and after NCPAP treatment in 22 OSAS patients (mean apnea and hypopnea index >50 episodes/h). Serum leptin levels of another 21 OSAS patients were measured before and after 3 to 4 days of NCPAP to gain insight into the mechanism by which NCPAP affects fat distribution. VFA and SFA decreased significantly after 6 months of NCPAP treatment (236±16 to 182±14cm
2
,
P
=0.0003 and 215±21 to 189±18 cm
2
,
P
=0.003, respectively). VFA decreased significantly in the body weight reduction group (n=9,
P
<0.01) and the no body weight reduction group (n=13,
P
<0.03). In contrast, SFA changed significantly in the body weight reduction group only (
P
<0.01). Leptin levels decreased significantly following 3 to 4 days of NCPAP (
P
<0.01), whereas body weight, fasting insulin, and cortisol levels did not change significantly.

Conclusions
—Correction of sleep disordered breathing by NCPAP may be used to reduce VFA in OSAS patients. OSAS may have significant effects on the serum leptin levels.
Effect of Postmenopausal Hormones on Inflammation-Sensitive Proteins
Authors: Cushman Mary , Legault Claudine , Barrett-Connor Elizabeth , Stefanick Marcia L. , Kessler Craig , Judd Howard L. , Sakkinen Pamela A. , Tracy Russell P.
Published: June 2012

Background
—Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events. In contrast, in a recent clinical trial of women with coronary disease, a subgroup analysis demonstrated increased risk during the early months of therapy. Because higher levels of inflammation factors predict vascular disease outcomes, the effect of hormones on these factors is of interest.

Methods and Results
—Four inflammation-sensitive factors, C-reactive protein, soluble E-selectin, von Willebrand factor antigen, and coagulation factor VIIIc were measured at baseline, 12, and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, a randomized, placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors. Compared with placebo, all 4 active preparations resulted in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin (
P
=0.0001). There were no effects of treatment on concentrations of von Willebrand factor or factor VIIIc. There were no differences in effects among treatment arms. Relative to placebo, when combining active treatment arms, final concentrations of C-reactive protein were 85% higher whereas E-selectin was 18% lower compared with baseline.

Conclusions
—Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein. Such an effect may be related to adverse early effects of estrogen therapy. In contrast, hormones reduced the concentration of soluble E-selectin, and this might be considered an anti-inflammatory effect. Because PEPI was not designed to assess clinical endpoints, studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed.
Alimentary Lipemia, Postprandial Triglyceride-Rich Lipoproteins, and Common Carotid Intima-Media Thickness in Healthy, Middle-Aged Men
Authors: Boquist Susanna , Ruotolo Giacomo , Tang Rong , Björkegren Johan , Bond M. Gene , de Faire Ulf , Karpe Fredrik , Hamsten Anders
Published: June 2012

Background
—Alimentary lipemia has been associated with coronary heart disease and common carotid artery intima-media thickness (IMT). This study was designed to investigate the relations of subclasses of postprandial triglyceride-rich lipoproteins (TRLs) with IMT.

Methods and Results
—Ninety-six healthy 50-year-old men with an apolipoprotein (apo) E3/E3 genotype underwent an oral fat tolerance test and B-mode carotid ultrasound examination. The apo B-48 and apo B-100 contents of each fraction of TRLs were determined as a measure of chylomicron remnant and VLDL particle concentrations. In the fasting state, LDL cholesterol (
P
<0.05) and basal proinsulin (
P
<0.05) were significantly related to IMT, whereas HDL cholesterol, plasma triglycerides, and insulin were not. In the postprandial state, plasma triglycerides at 1 to 4 hours (
P
<0.01 at 2 hours), total triglyceride area under the curve (AUC) (
P
<0.05), incremental triglyceride AUC (
P
<0.01), and the large VLDL (Sf 60 to 400 apo B-100) concentration at 3 hours (
P
<0.05) were significantly related to IMT. Multivariate analyses showed that plasma triglycerides at 2 hours, LDL cholesterol, and basal proinsulin were consistently and independently related to IMT when cumulative tobacco consumption, alcohol intake, waist-to-hip circumference ratio, and systolic blood pressure were included as confounders.

Conclusions
—These results provide further evidence for postprandial triglyceridemia as an independent risk factor for early atherosclerosis and also suggest that the postprandial triglyceridemia is a better predictor of IMT than particle concentrations of individual TRLs.
Relation Between Ligament of Marshall and Adrenergic Atrial Tachyarrhythmia
Authors: Doshi Rahul N. , Wu Tsu-Juey , Yashima Masaaki , Kim Young-Hoon , Ong James J. C. , Cao Ji-Min , Hwang Chun , Yashar Payam , Fishbein Michael C. , Karagueuzian Hrayr S. , Chen Peng-Sheng
Published: June 2012

Background
—The mechanism of the adrenergic atrial tachyarrhythmia is unclear. We hypothesize that the ligament of Marshall (LOM) is sensitive to adrenergic stimulation and may serve as a source of the adrenergic atrial tachyarrhythmia.

Methods and Results
—We performed computerized mapping studies in isolated-perfused canine left atrial tissues from normal dogs (n=9) and from dogs with chronic atrial fibrillation (AF) induced by 10 to 41 weeks of rapid pacing (n=3). Before isoproterenol, spontaneous activity occurred in only one normal tissue (cycle length, CL >1300 ms). During isoproterenol infusion, automatic rhythm was induced in both normal tissues (CL=578±172 ms) and AF tissues (CL=255±29 ms,
P
<0.05). The origin of spontaneous activity was mapped to the LOM. In the AF tissues, but not the normal tissues, we observed the transition from rapid automatic activity to multiple wavelet AF. Ablation of the LOM terminated the spontaneous activity and prevented AF. Immunocytochemical studies of the LOM revealed muscle tracts surrounded by tyrosine hydroxylase-positive (sympathetic) nerves.

Conclusions
—We conclude that the LOM is richly innervated by sympathetic nerves and serves as a source of isoproterenol-sensitive focal automatic activity in normal canine atrium. The sensitivity to isoproterenol is upregulated after long-term rapid pacing and may contribute to the development of AF in this model.
Ischemic Preconditioning and the β-Adrenergic Signal Transduction Pathway
Authors: Lochner Amanda , Genade Sonia , Tromp Erna , Podzuweit Thomas , Moolman Johan A.
Published: June 2012

Background
—Previous studies from our laboratory showed cyclic increases in tissue cAMP during a multiple-cycle preconditioning (PC) protocol, followed by attenuated cAMP accumulation during sustained ischemia. The aim of this study was to determine whether ischemia-induced activation of the β-adrenergic signaling pathway could act as a trigger in eliciting protection.

Methods and Results
—Isolated perfused rat hearts were preconditioned by 3×5 minutes of global ischemia, interspersed by 5 minutes of reperfusion. β-Adrenergic responsivity was assessed by measurement of tissue cAMP generation after β-adrenergic agonist administration at the end of the PC protocol. Tissue cAMP, adenylyl cyclase, and protein kinase A (PKA) activities and β-adrenergic receptor characteristics were assessed at different times. The role of cAMP generation in eliciting PC was studied by investigation of functional recovery during reperfusion after 25 minutes of global ischemia after (1) cAMP increases in the trigger period were prevented with the β-adrenergic blocker alprenolol 7.5×10
−5
mol/L and (2) increases in cAMP were elicited by administration of forskolin 10
−7
and 10
−6
mol/L or isoproterenol 10
−8
, 10
−7
, and 10
−6
mol/L. Intermittent ischemia resulted in reduced β-adrenergic responsivity at the end of the protocol, although B
max
and
K
d
values of the β-adrenergic receptor population and adenylyl cyclase and PKA activities were increased. Abolishment of cyclic increases in cAMP before sustained ischemia attenuated myocardial protection against ischemia, whereas agonists elicited protection. No clear correlation between protection and β-adrenergic desensitization was observed.

Conclusions
—Ischemia-induced activation of the β-adrenergic signaling pathway during preconditioning should also be considered a trigger in eliciting preconditioning.
Requirement for Protein Kinase C in Reactive Oxygen Species–Induced Apoptosis of Vascular Smooth Muscle Cells
Authors: Li Pei-Feng , Maasch Christian , Haller Hermann , Dietz Rainer , von Harsdorf Rüdiger
Published: June 2012

Background
—Vascular smooth muscle cell (VSMC) apoptosis is a component of a variety of cardiovascular diseases and may be related to reactive oxygen species (ROS). This study was designed to determine the role of protein kinase C (PKC) in ROS-induced VSMC apoptosis.

Methods and Results
—Rat aortic VSMCs were exposed to H
2
O
2
, and the nature of cell death was characterized in the absence or presence of different PKC inhibitors. The results demonstrate that exposure of VSMCs to H
2
O
2
led to a dose-dependent (25 to 100 μmol/L) and time-dependent (peak at 2 minutes) activation of PKC. Among the PKC isoforms α, β, δ, ε, and ζ, only PKC-α and PKC-ε were found to change their intracellular distribution on H
2
O
2
treatment. Apoptosis was the predominant form of cell death when PKC had been activated by H
2
O
2
alone or by H
2
O
2
in the presence of 50 nmol/L phorbol 12-myristate 13-acetate. In contrast, necrosis became the predominant form of cell death when PKC had been downregulated by prolonged exposure to 200 nmol/L phorbol 12,13-dibutyrate or inhibited by 50 nmol/L staurosporine, 100 nmol/L calphostin C, or 30 μmol/L H-7. In addition, caspase-3 was activated in H
2
O
2
-induced VSMC apoptosis but not when PKC was downregulated or inhibited. Inhibition of caspase-3 by 50 μmol/L Ac-DEVD-CHO could significantly attenuate H
2
O
2
-induced apoptosis and was not associated with the induction of necrosis.

Conclusions
—We conclude that in VSMCs, PKC converts the ROS-induced signals from necrotic cell death to the activation of an apoptotic cell death program. These data imply a novel and important role of PKC for the pathogenesis of such vascular diseases as atherosclerosis, restenosis, and hypertension.
Short- and Intermediate-Term Results of
32
P Radioactive β-Emitting Stent Implantation in Patients With Coronary Artery Disease
Authors: Albiero Remo , Adamian Milena , Kobayashi Nobuyuky , Amato Antonio , Vaghetti Marco , Di Mario Carlo , Colombo Antonio
Published: June 2012

Background
—Radioactive
32
P β-emitting stents have been shown to reduce intrastent neointimal hyperplasia in a substantial dose-related manner in the animal model. The aim of this dose-response study was to evaluate, in the clinical setting, the safety and efficacy at 6-month follow-up of this approach to reducing restenosis.

Methods and Results
—A total of 122
32
P radioactive β-emitting stents (initially the Palmaz-Schatz and later the BX Isostent) with an activity level of 0.75 to 3.0 μCi (group 1), 3.0 to 6.0 μCi (group 2), and 6.0 to 12.0 μCi (group 3) were implanted in 91 lesions in 82 patients. There were no procedural events. At 6-month follow-up, no deaths had occurred, and only 1 patient had stent thrombosis. Pure intrastent binary restenosis was 16% in group 1, 3% in group 2, and 0% in group 3. However, intralesion restenosis was 52% in group 1, 41% in group 2, and 50% in group 3.

Conclusions
—The use of
32
P radioactive β-emitting stents in patients with CAD is feasible. At 6-month follow-up, intrastent neointimal hyperplasia was reduced in a dose-related manner. However, in the 3 groups, intralesion restenosis was high because of a high late lumen loss in the reference segments at the stent edges, possibly as a result of a low activity level of radiation at the edges of the stent combined with an aggressive approach to stenting. We called this “edge effect” the “candy wrapper.”
Cardiac Na
+
Channel Dysfunction in Brugada Syndrome Is Aggravated by β
1
-Subunit
Authors: Makita Naomasa , Shirai Nobumasa , Wang Dao W. , Sasaki Koji , George Alfred L. , Kanno Morio , Kitabatake Akira
Published: June 2012

Background
—Mutations in the gene encoding the human cardiac Na
+
channel α-subunit (hH1) are responsible for chromosome 3–linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary β
1
-subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na
+
channels expressed in
Xenopus
oocytes but has little if any functional effect on the cardiac isoform. Here, we characterize the altered effects of a human β
1
-subunit (hβ
1
) on the heterologously expressed hH1 mutation (T1620M) previously associated with IVF.

Methods and Results
—When expressed alone in
Xenopus
oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V
1/2
) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of hβ
1
did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V
1/2
and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal.

Conclusions
—It is suggested that coexpression of hβ
1
exposes a more severe functional defect that results in a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo. One possible explanation for our finding is an altered α-/β
1
-subunit association in the mutant.
Plasminogen Activator Inhibitor 4G Polymorphism Is Associated With Decreased Risk of Cerebrovascular Mortality in Older Women
Authors: Roest Mark , van der Schouw Yvonne T. , Banga Jan Dirk , Tempelman Mariëlle J. , de Groot Philip G. , Sixma Jan J. , Grobbee Diederick E.
Published: June 2012

Background
—A common 4G allele of a 4G/5G polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with increased transcription of the PAI-1 protein, which may lead to decreased fibrinolysis. It has therefore been proposed as a candidate risk factor for myocardial infarction or stroke.

Methods and Results
—We studied the relationship between PAI-1 4G/5G genotype and the risk of cardiovascular mortality in a prospective cohort study among 12 239 women initially aged between 52 and 67 years, with a maximum follow-up time of 18 years (153 732 follow-up years). PAI-1 4G/5G genotype was measured in DNA obtained from urine samples, which were collected at baseline, of 498 women who died of a cardiovascular disease and a random sample of 512 women from the same cohort who did not die of cardiovascular disease. The PAI-1 4G/5G genotype was not associated with risk of myocardial infarction or other cardiovascular mortality. However, PAI-1 4G4G homozygotes had a markedly reduced risk of cerebrovascular mortality compared with PAI-1 5G5G homozygotes: the relative risk was 0.4, with a 95% CI of 0.2 to 0.7, whereas the relative risk of cerebrovascular mortality in PAI-1 4G5G heterozygotes compared with PAI-1 5G5G homozygotes was 0.7, with a 95% CI of 0.4 to 1.1.

Conclusions
—These findings are suggestive of an important contribution of PAI-1 in cerebrovascular pathology, probably via pathways other than fibrinolysis. PAI-1 may protect against destabilization of the atherosclerotic plaque, or it may inhibit neurotoxicity of tissue plasminogen activator in the brain.
β
2
-Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis
Authors: Du Xiao-Jun , Autelitano Dominic J. , Dilley Rodney J. , Wang Binghui , Dart Anthony M. , Woodcock Elizabeth A.
Published: June 2012

Background
—β-Adrenergic signaling is downregulated in the failing heart, and the significance of such change remains unclear.

Methods and Results
—To address the role of β-adrenergic dysfunction in heart failure (HF), aortic stenosis (AS) was induced in wild-type (WT) and transgenic (TG) mice with cardiac targeted overexpression of β
2
-adrenergic receptors (ARs), and animals were studied 9 weeks later. The extents of increase in systolic arterial pressure (
P
<0.01 versus controls), left ventricular (LV) hypertrophy (TG, 94±6 to 175±7 mg; WT, 110±6 to 168±10 mg; both
P
<0.01), and expression of ANP mRNA were similar between TG and WT mice with AS. TG mice had higher incidences of premature death and critical illness due to heart failure (75% versus 23%), pleural effusion (81% versus 45%), and left atrial thrombosis (81% versus 36%, all
P
<0.05). A more extensive focal fibrosis was found in the hypertrophied LV of TG mice (
P
<0.05). These findings indicate a more severe LV dysfunction in TG mice. In sham-operated mice, LV dP/dt
max
and heart rate were markedly higher in TG than WT mice (both
P
<0.01). dP/dt
max
was lower in both AS groups than in sham-operated controls, and this tended to be more pronounced in TG than WT mice (−32±5% versus −16±6%,
P
=0.059), although dP/dt
max
remained higher in TG than WT groups (
P
<0.05).

Conclusions
—Elevated cardiac β-adrenergic activity by β
2
-AR overexpression leads to functional deterioration after pressure overload.