bluuebunny/crossref_metadata_2025 huggingface dataset:
Atrioventricular Node Modification in Patients With Chronic Atrial Fibrillation
Authors: Rokas Stelios , Gaitanidou Styliani , Chatzidou Sofia , Pamboucas Costas , Achtipis Dennis , Stamatelopoulos Stamatios
Published: June 2012

Background
—This study evaluates the role of RR interval distribution pattern as an outcome predictor of radiofrequency (RF) modification of atrioventricular (AV) node in chronic atrial fibrillation (AF) and attempts to elucidate the likely mechanism of rate control.

Methods and Results
—Sixty-five patients with chronic AF underwent AV node modification. The RR interval distribution pattern was derived from 24-hour ECG recordings obtained before and after the procedure. The preablation pattern was bimodal (B) in 36 patients (55%) and unimodal (U) in 29 patients (45%). After the modification procedure, the B pattern shifted to U (78%) or became modified B (22%). The mean number of RF pulses delivered and the fluoroscopy time were n=8±5 and 24±11 minutes, respectively, in patients with B pattern versus n=18±7 and 45±17 minutes in patients with U pattern (
P
<0.001 for both). The location of successful ablation was posteroseptal and lower midseptal in 26 patients (81%) with B pattern versus 2 (13%) with U pattern (
P
<0.001). Mean and maximal ventricular rates and heart rate at peak exercise were reduced after the procedure in both groups (
P
<0.001 for all). Long-term success rate, AV block incidence, and pacemaker implantation rate were 89%, 0%, and 8%, respectively, in patients with B pattern versus 52% (
P
<0.001), 21% (
P
=0.006), and 48% (
P
<0.001) in patients with U pattern.

Conclusions
—RF modification of the AV node is expected to be more effective, safe, and expeditious in patients with chronic AF and B RR interval distribution pattern. Posterior atrionodal input ablation may be the prevailing mechanism of rate control in these patients, whereas U-pattern patients may benefit from partial injury to the AV node.
Differential Effects of Nifedipine and Co-Amilozide on the Progression of Early Carotid Wall Changes
Authors: Simon Alain , Gariépy Jérome , Moyse Dominique , Levenson Jaime
Published: June 2012

Background
—Common carotid artery intima-media thickness (IMT) progression was compared between 4 years of treatment with nifedipine and diuretic.

Methods and Results
—This study, ancillary to the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), involved nifedipine 30 mg or co-amilozide (hydrochlorothiazide 25 mg and amiloride 2.5 mg) with optional subsequent titration. Among 439 randomized hypertensive patients, 324 had ≥1 year of follow-up (intent-to-treat group), and 242 completed follow-up (until-end-of-study group). Ultrasonography was performed at baseline, 4 months later, and then every year. Central computerized reading provided far-wall IMT, diameter, and cross-sectional area IMT (CSA-IMT). The primary outcome was IMT progression rate (slope of IMT-time regression). Secondary outcomes were changes from baseline (Δ) in IMT, diameter, and CSA-IMT. In the until-end-of-study population, between-treatment differences existed in IMT progression rate (
P
=0.002), Δ IMT (
P
=0.001), and Δ CSA-IMT (
P
=0.006), because IMT progressed on co-amilozide but not on nifedipine. In the intent-to-treat population, treatment differences existed in Δ IMT (
P
=0.004) and Δ CSA-IMT (
P
=0.04) but not in IMT progression rate (
P
=0.09). Patients with ≥2, 3, or 4 years of follow-up showed treatment differences in IMT progression rate (
P
=0.04, 0.004, 0.007, respectively), Δ IMT (
P
=0.005, 0.001, 0.005), and Δ CSA-IMT (
P
=0.025, 0.013, 0.015). Diameter decreased more on co-amilozide than on nifedipine in the intent-to-treat population (
P
<0.05), whereas blood pressure decreased similarly on both treatments.

Conclusions
—A difference in early carotid wall changes is shown between 2 equally effective antihypertensive treatments.
Role for p27
Kip1
in Vascular Smooth Muscle Cell Migration
Authors: Sun Ji , Marx Steven O. , Chen Hong-Jun , Poon Michael , Marks Andrew R. , Rabbani LeRoy E.
Published: June 2012

Background
—Rapamycin is a potent inhibitor of smooth muscle cell (SMC) proliferation and migration. Rapamycin-mediated inhibition of SMC proliferation is associated with upregulation of the cyclin-dependent kinase inhibitor p27
Kip1
. Previously, we showed that mixed embryonic fibroblasts obtained from p27
Kip1
(−/−) mice were relatively rapamycin-resistant, suggesting that p27
Kip1
plays an integral role in modulating the antiproliferative effects of rapamycin. We hypothesized that the antimigratory effect of rapamycin may also be mediated by p27
Kip1
.

Methods and Results
—Rapamycin (1 to 10 nmol/L) inhibited basic fibroblast growth factor–induced migration of wild-type (WT) but not p27
Kip1
(−/−) SMCs in a dose-dependent manner (
P
<0.05) in a modified Boyden chamber. The effects of rapamycin on aortic SMC explant migration were also studied with WT, p27(+/−), and p27(−/−) mice. Rapamycin 4 mg · kg
−1
· d
−1
IP for 5 days inhibited SMC migration by 90% in the WT and p27
Kip1
(+/−) (
P
<0.05) but not p27
Kip1
(−/−) animals.

Conclusions
—Lack of p27
Kip1
reduces rapamycin-mediated inhibition of SMC migration. These novel findings suggest a role for p27
Kip1
in the signaling pathway(s) that regulates SMC migration.
Biological Profiles in Subjects With Recurrent Acute Coronary Events Compared With Subjects With Long-Standing Stable Angina
Authors: Bogaty Peter , Poirier Paul , Simard Serge , Boyer Luce , Solymoss Susan , Dagenais Gilles R.
Published: June 2012

Background
—At one end of the clinical spectrum of coronary artery disease (CAD) are subjects who have had repeated acute ischemic events, and at the other end are those with long-standing angina who have never been unstable. This study tests the hypothesis that a specific biological profile can distinguish these 2 extreme groups and predict acute coronary events.

Methods and Results
—Blood levels of lipoprotein(a), homocysteine, tissue plasminogen activator, plasminogen activator inhibitor-1, C-reactive protein (CRP), fibrinogen, and von Willebrand factor were compared in 3 groups of 50 subjects each: (1) those with previous multiple acute coronary events, (2) age-matched subjects with ≥3 years of stable angina and no prior acute coronary events, and (3) matched controls without evidence of atherosclerotic disease and a normal coronary angiogram. All subjects were followed for 4.0 years. Lipoprotein(a), homocysteine, tissue plasminogen activator, and plasminogen activator inhibitor-1 were similar in both CAD groups and significantly higher than in the control group. However, compared with subjects with long-standing stable angina, those with previous multiple coronary events had higher values of CRP (5.7±5.4 versus 3.0±5.2 mg/L,
P
=0.012), fibrinogen (3.38±0.75 versus 2.92±0.64 g/L,
P
=0.001), and von Willebrand factor (1.60±0.55 versus 1.25±0.36 U/mL,
P
=0.0003). On follow-up, myocardial infarction and unstable angina occurred in 42% of the group with multiple events, 4% of the stable angina group (
P
<0.0001), and none of the control subjects. In the 100 patients with CAD, CRP was 4.9 mg/L in those with and 1.8 mg/L in those without new instability (
P
<0.0001). In a multivariate analysis, only CRP distinguished those with follow-up acute coronary events (adjusted odds ratio 5.9, 95% CI 2.0 to 17.9;
P
=0.002). A baseline CRP >3.5 mg/L had a relative risk of 7.6 (2.6 to 21.7,
P
=0.0002) for subsequent acute events.

Conclusions
—An inflammatory biological profile distinguished patients with previous multiple acute coronary events from those with long-standing stable angina and predicted acute coronary instability.
Occurrence and Prognostic Significance of Ventricular Arrhythmia Is Related to Pulmonary Function
Authors: Engström Gunnar , Wollmer Per , Hedblad Bo , Juul-Möller Steen , Valind Sven , Janzon Lars
Published: June 2012

Background
—Reduced lung function has been associated with increased rates of myocardial infarction. Whether the occurrence and prognostic significance of ventricular arrhythmia is related to lung function is largely unknown.

Methods and Results
—We performed a population-based study of 68-year-old men without a history of stroke or myocardial infarction; 402 men participated. Mortality and coronary events (fatal or nonfatal) were studied in relation to ventricular arrhythmia during 24 hours, percentage of the predicted forced expiratory volume (FEV1
%pred
), vital capacity (VC
%pred
), and the FEV/VC ratio. During 14 years of follow-up, 181 men died and 87 experienced a coronary event. Occurrence of frequent or complex ventricular arrhythmia (Lown class 2 to 5) was significantly and inversely associated with FEV1
%pred
. Men with Lown class 2 to 5 and a low FEV1
%pred
(below median) had significantly higher mortality (71.5 versus 26.8 per 1000 person-years;
P
<0.0001) and coronary event rates (37.7 versus 18.0;
P
=0.02) than men with Lown class 2 to 5 and a high FEV1
%pred
. These associations remained significant after adjustments for potential confounders (mortality: relative risk [RR], 2.91; 95% CI,1.68 to 5.04; coronary events: RR, 2.16; 95% CI, 1.07 to 4.37). In men without frequent or complex arrhythmia (Lown 0 to 1), a low FEV1
%pred
was not significantly associated with mortality (RR, 1.37; 95% CI, 0.92 to 2.05) or coronary events (RR, 1.24; 95% CI, 0.67 to 2.27) after adjustments for confounders. The FEV/VC ratio showed similar associations with arrhythmia, mortality, and coronary events.

Conclusions
—Lung function is inversely associated with the occurrence of ventricular arrhythmia. The increased incidence of myocardial infarction and death associated with arrhythmia was mainly limited to men with a low FEV1
%pred
or FEV/VC. We suggest that lung function should be considered when assessing the prognostic significance of ventricular arrhythmia.
Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice
Authors: Kuhlencordt Peter J. , Chen Jiqiu , Han Fred , Astern Joshua , Huang Paul L.
Published: June 2012

Background
—Inducible nitric oxide synthase (iNOS) is expressed by leukocytes and smooth muscle cells in atherosclerotic lesions. To test whether NO produced by iNOS deficiency affects atherosclerosis, we studied apoE/iNOS–double knockout (dKO) and apoE-knockout (KO) control animals fed a “Western-type” diet.

Methods and Results
—After 16 weeks of Western-type diet, the aortic lesion area in apoE/iNOS-dKO males and females was significantly reduced, by 22% and 21%, respectively, compared with apoE-KO males and females. This effect was more pronounced after 24 weeks of Western-type diet, after which lesion formation in male and female dKO mice was reduced by 38% and 40%, respectively. Plasma levels of lipoperoxides in apoE/iNOS-dKO mice (2.0±0.23 μmol/L) were significantly lower than in apoE-KO control animals (3.2±0.44 μmol/L;
P
=0.02). To test whether substrate deficiency plays a role in the proatherogenic actions of iNOS, we administered
l
-arginine to apoE-KO animals for 16 and 24 weeks.
l
-Arginine treatment did not affect lesion formation in apoE-KO animals fed a Western-type diet.

Conclusions
—Genetic deficiency of iNOS decreases diet-induced atherosclerosis and lowers plasma levels of lipoperoxides, a marker for oxidative stress, in apoE-KO animals. Reduction in iNOS-mediated oxidative stress could partly explain protection from lesion formation in dKO animals.
l
-Arginine supplementation did not change lesion area in apoE-KO mice, indicating that substrate deficiency is not a likely cause for iNOS-mediated injury in this model of atherosclerosis.
Plasminogen Activator Inhibitor Type 1 Enhances Neointima Formation After Oxidative Vascular Injury in Atherosclerosis-Prone Mice
Authors: Zhu Yanhong , Farrehi Peter M. , Fay William P.
Published: June 2012

Background
—Plasminogen activator inhibitor type 1 (PAI-1) inhibits neointima formation after vascular injury. Hyperlipidemia modulates the expression of multiple genes, however, and the effects of PAI-1 on the arterial response to injury under hyperlipidemic conditions are unknown. The purpose of this study was to examine the impact of PAI-1 on intimal hyperplasia and other vascular changes that develop after arterial injury in apolipoprotein E–deficient (apoE
−/−
) mice.

Methods and Results
—Ferric chloride injury of the midportion of the common carotid arteries of apoE
−/−
mice (n=22) induced formation of a neointima that contained smooth muscle cells, foam cells, neutral lipid, tissue factor, and von Willebrand factor. Interactions between vascular injury and apolipoprotein E deficiency were strongly synergistic; either stimulus alone was insufficient to induce significant neointima formation. Mean intima/media ratios were significantly greater (
P
<0.03) in apoE
−/−
, PAI-1
+/+
mice (5.6±1.8, n=12) than in apoE
−/−
, PAI-1
−/−
mice (1.2±0.55, n=12), as were the percentages of bromodeoxyuridine-positive cells in the intima and media (
P
<0.03). Transiently occlusive (<48 hours) and nonocclusive mural thrombi persisted longer in apoE
−/−
, PAI-1
+/+
mice than in apoE
−/−
, PAI-1
−/−
mice.

Conclusions
—In atherosclerosis-prone mice, PAI-1 promotes neointima formation after oxidative vascular injury. The apparent hyperlipidemia-dependent effect of PAI-1 may be mediated by its capacity to inhibit the clearance of platelet-fibrin thrombi that can deliver growth factors to the blood vessel wall or be incorporated into developing vascular lesions. Alternatively, hyperlipidemia may alter the pattern of gene expression in the blood vessel wall to enhance potential effects of PAI-1 on antiproliferative processes, such as transforming growth factor-β activation and apoptosis.
Chlamydia pneumoniae
Infection in Circulating Human Monocytes Is Refractory to Antibiotic Treatment
Authors: Gieffers Jens , Füllgraf Henriette , Jahn Jürgen , Klinger Matthias , Dalhoff Klaus , Katus Hugo A. , Solbach Werner , Maass Matthias
Published: June 2012

Background
—Recovery of the intracellular bacterium
Chlamydia pneumoniae
from atherosclerotic plaques has initiated large studies on antimicrobial therapy in coronary artery disease. The basic concept that antibiotic therapy may eliminate and prevent vascular infection was evaluated in vitro and in vivo by examining the antibiotic susceptibility of
C pneumoniae
in circulating human monocytes, which are thought to transport chlamydiae from the respiratory tract to the vascular wall.

Methods and Results
—Blood monocytes (CD14+) from 2 healthy volunteers were obtained before and after oral treatment with azithromycin or rifampin and then inoculated with a vascular
C pneumoniae
strain and continuously cultured in the presence of the respective antibiotic. Progress of infection and chlamydial viability was assessed by immunogold-labeling and detection of
C pneumoniae
–specific mRNA transcripts. Circulating monocytes from patients undergoing treatment with experimental azithromycin for coronary artery disease were examined for
C pneumoniae
infection by cell culture. Antibiotics did not inhibit chlamydial growth within monocytes. Electron microscopy showed development of chlamydial inclusion bodies. Reverse transcription–polymerase chain reaction demonstrated continuous synthesis of chlamydial mRNA for 10 days without lysis of the monocytes. The in vivo presence of viable pathogen not eliminated by azithromycin was shown by cultural recovery of
C pneumoniae
from the circulating monocytes of 2 patients with coronary artery disease.

Conclusions
—
C pneumoniae
uses monocytes as a transport system for systemic dissemination and enters a persistent state not covered by an otherwise effective antichlamydial treatment. Prevention of vascular infection by antichlamydial treatment may be problematic: circulating monocytes carrying a pathogen with reduced antimicrobial susceptibility might initiate reinfection or promote atherosclerosis by the release of proinflammatory mediators.
Sex Differences in the Prognosis of Congestive Heart Failure
Authors: Simon Tabassome , Mary-Krause Murielle , Funck-Brentano Christian , Jaillon Patrice
Published: June 2012

Background
—Whether female sex is associated with a better prognosis in patients with congestive heart failure (CHF) remains uncertain. The Cardiac Insufficiency Bisoprolol Study (CIBIS) II showed that bisoprolol reduced all-cause mortality and morbidity rates in CHF patients treated with diuretics and ACE inhibitors. We examined whether survival was different in men (n=2132) and women (n=515) enrolled in CIBIS II.

Methods and Results
—Women differed from men with regard to age, NYHA functional classification, primary cause of CHF, and risk factors such as left bundle-branch block. After adjustment for baseline differences, the probability of all-cause mortality was significantly reduced by 36% in women compared with that in men (hazard ratio 0.64, 95% CI 0.47 to 0.86,
P
=0.003). Women also had a 39% reduction in cardiovascular deaths (hazard ratio 0.64, 95% CI 0.45 to 0.91,
P
=0.01) and a 70% reduction in deaths from pump failure (hazard ratio 0.30, 95% CI 0.13 to 0.70,
P
=0.005) compared with men. Kaplan-Meier survival analysis revealed a significant reduction in all-cause mortality among women treated with bisoprolol compared with men (6% versus 12%
P
=0.01) but not among women treated with placebo (13% versus 18%,
P
=0.10). However, this sex/β-blocker effect was not significant in multivariate analysis.

Conclusions
—These results indicate that regardless of β-blocker treatment and baseline clinical profile, female sex is a significant independent predictor of survival in patients with CHF.
Magnetic Resonance Imaging of Atherosclerotic Plaque With Ultrasmall Superparamagnetic Particles of Iron Oxide in Hyperlipidemic Rabbits
Authors: Ruehm Stefan G. , Corot Claire , Vogt Peter , Kolb Stefan , Debatin Jörg F.
Published: June 2012

Background
—Based on the observation that ultrasmall superparamagnetic particles of iron oxides (USPIOs) are phagocytosed by cells of the mononuclear phagocytic system, the purpose of this study was to evaluate their use as a marker of atherosclerosis-associated inflammatory changes in the vessel wall before luminal narrowing is present.

Methods and Results
—Experiments were conducted on 6 heritable hyperlipidemic and 3 New Zealand White rabbits. 3D MR angiography (MRA) of the thoracic aorta was performed on all rabbits by use of a conventional paramagnetic contrast agent that failed to reveal any abnormalities. One week later, all rabbits except 1 of the hyperlipidemic animals were injected with a USPIO contrast agent (Sinerem, Guerbet) at a dose of 1 mmol Fe/kg. 3D MRA data sets collected over the subsequent 5 days showed increasing signal in the aortic lumen. Whereas the aortic wall of the control rabbits remained smooth and bright, marked susceptibility effects became evident on day 4 within the aortic walls of hyperlipidemic rabbits. Ex vivo imaging of aortic specimens confirmed the in vivo results. Histopathology documented marked Fe uptake in macrophages embedded in atherosclerotic plaque of the hyperlipidemic rabbits. Electron microscopy showed multiple cytoplasmic Fe particles in macrophages. No such changes were seen in control rabbits or in the hyperlipidemic rabbit that had not received Sinerem.

Conclusions
—USPIOs are phagocytosed by macrophages in atherosclerotic plaques of the aortic wall of hyperlipidemic rabbits in a quantity sufficient to cause susceptibility effects detectable by MRI.
Gold-Coated NIR Stents in Porcine Coronary Arteries
Authors: Edelman Elazer R. , Seifert Philip , Groothuis Adam , Morss Alisa , Bornstein Danielle , Rogers Campbell
Published: June 2012

Background
—As endovascular stents are altered to add functionality, eg, by adding radiopaque coatings, biocompatibility may suffer.

Methods and Results
—We examined the vascular response in porcine coronary arteries to stainless steel gold-coated NIR stents (7-cell, Medinol, Inc). Stents, 9 and 16 mm in length, were left bare or coated with a 7-μm layer of gold. Physical and material effects were examined in four different gold-coated stent types, two at each length that either had the coating applied to the standard strut, ie, gold coated thicker than controls, or had the coating applied to thinned struts, ie, gold coated of the same thickness as control struts. Simple gold coating exacerbated intimal hyperplastic and inflammatory reactions over 28 days, but postplating thermal processing smoothed the coating surface and negated the adverse tissue response to gold. The relative amounts of base steel and gold coating and their resistances to expansion and collapse determined the extent of stent recoil.

Conclusions
—Gold coatings enhance the radiopacity of steel stents, but not without effects on vascular repair. Material effects predominate and can be abrogated by heating coated stents to alter surface finish and material purity. Clinical results may suffer unless consideration is given to material and physical effects of gold.
Soluble P-Selectin and the Risk of Future Cardiovascular Events
Authors: Ridker Paul M. , Buring Julie E. , Rifai Nader
Published: June 2012

Background
—P-selectin, a cell-surface adhesion molecule involved in leukocyte rolling and attachment, has been hypothesized to play a role in the initiation of atherosclerosis. However, little clinical data are available evaluating the role of soluble P-selectin in determining vascular risk.

Methods and Results
—In a large-scale prospective study of apparently healthy women, we measured baseline plasma concentration of soluble P-selectin among 115 participants who subsequently developed cardiovascular events and among 230 age- and smoking-matched participants who remained free of disease during 3.5 years of follow-up. Overall, mean levels of soluble P-selectin were significantly higher at baseline among women who subsequently experienced cardiovascular events compared with those who did not (83.2 versus 69.3 ng/mL;
P
=0.003). The risk of future cardiovascular events increased with increasing quartiles of soluble P-selectin (
P
=0.02), such that women in the highest quartile at study entry had an age- and smoking-matched relative risk 2.2 times higher than those in the lowest quartile (95% confidence interval, 1.2 to 4.2;
P
=0.01). This effect was independent of traditional risk factors. For each quartile increase in soluble P-selectin, the risk of future cardiovascular events increased 28% (
P
=0.03) after additional adjustment for obesity, hypertension, hyperlipidemia, diabetes, and exercise frequency. The highest risks were observed among women with the very highest levels of P-selectin (>137.3 ng/mL, the 95th percentile cut point of the control distribution).

Conclusions
—Soluble P-selectin levels are elevated among apparently healthy women at risk for future vascular events.
High Prevalence of Myocardial Perfusion Abnormalities on Positron Emission Tomography in Asymptomatic Persons With a Parent or Sibling With Coronary Artery Disease
Authors: Sdringola Stefano , Patel Dhaval , Gould K. Lance
Published: June 2012

Background
—We hypothesized that asymptomatic persons with a parent or sibling with coronary artery disease (CAD) have myocardial perfusion defects on positron emission tomography (PET) as markers of early CAD.

Methods and Results
—After medical and family histories were recorded, 90 subjects underwent rest-dipyridamole cardiac PET perfusion imaging, including 18 index cases (a subject with CAD documented by PET and arteriography), 32 asymptomatic adults without known CAD who had a parent or sibling with CAD among these index cases, 30 asymptomatic subjects with comparable coronary risk factors without CAD or a family history of CAD, and 10 volunteer control subjects with no risk factors and no family history. PET perfusion images were quantified with automated software for size of abnormalities as percent of the cardiac image outside 95% CIs of normal controls and for severity as the lowest quadrant average relative activity. Of asymptomatic subjects with a parent or sibling with CAD (first-degree relatives), 50% had dipyridamole-induced myocardial perfusion defects that involved ≥5% of the cardiac image outside normal 95% CIs with or without other risk factors. The size of perfusion defects was larger in first-degree relatives than in control subjects (11±13% versus 1±1%,
P
=0.02) and larger than in asymptomatic subjects with comparable risk factors but no family history of CAD (11±13% versus 5±6%,
P
=0.02).

Conclusions
—This study documents the presence of quantitative, statistically significant, dipyridamole-induced myocardial perfusion abnormalities on PET in 50% of asymptomatic persons with a parent or sibling with CAD, independent of other risk factors, indicating preclinical coronary atherosclerosis.
Hyperinsulinemia and Autonomic Nervous System Dysfunction in Obesity
Authors: Emdin Michele , Gastaldelli Amalia , Muscelli Elza , Macerata Alberto , Natali Andrea , Camastra Stefania , Ferrannini Ele
Published: June 2012

Background
—Because hyperinsulinemia acutely stimulates adrenergic activity, it has been postulated that chronic hyperinsulinemia may lead to enhanced sympathetic tone and cardiovascular risk.

Methods and Results
—In 21 obese (body mass index, 35±1 kg/m
2
) and 17 lean subjects, we measured resting cardiac output (by 2-dimensional echocardiography), plasma concentrations and timed (diurnal versus nocturnal) urinary excretion of catecholamines, and 24-hour heart rate variability (by spectral analysis of ECG). In the obese versus lean subjects, cardiac output was increased by 22% (
P
<0.03), and the nocturnal drop in urinary norepinephrine output was blunted (
P
=0.01). Spectral power in the low-frequency range was depressed throughout 24 hours (
P
<0.04). During the afternoon and early night, ie, the postprandial phase, high-frequency power was lower, heart rate was higher; and the ratio of low to high frequency, an index of sympathovagal balance, was increased in direct proportion to the degree of hyperinsulinemia independent of body mass index (partial
r
=0.43,
P
=0.01). In 9 obese subjects who lost 10% to 18% of their body weight, cardiac output decreased and low-frequency power returned toward normal (
P
<0.05).

Conclusions
—In free-living subjects with uncomplicated obesity, chronic hyperinsulinemia is associated with a high-output, low-resistance hemodynamic state, persistent baroreflex downregulation, and episodic (postprandial) sympathetic dominance. Reversal of these changes by weight loss suggests a causal role for insulin.
Abnormal Vascular Reactivity in Growth Hormone Deficiency
Authors: Capaldo Brunella , Guardasole Vincenzo , Pardo Francesco , Matarazzo Margherita , Di Rella Francesca , Numis Fabio , Merola Bartolomeo , Longobardi Salvatore , Saccà Luigi
Published: June 2012

Background
—The reason why patients with growth hormone (GH) deficiency (GHD) are at increased risk for premature cardiovascular death is still unclear. Although a variety of vascular risk factors have been identified in GHD, little is known regarding vascular reactivity and its contribution to premature arteriosclerosis.

Methods and Results
—We assessed vascular function in 7 childhood-onset, GH-deficient nontreated patients (age 22±3 years, body mass index [BMI] 25±1 kg/m
2
) and 10 healthy subjects (age 24±0.4 years, BMI 22±1 kg/m
2
) by using strain gauge plethysmography to measure forearm blood flow in response to vasodilatory agents. The increase in forearm blood flow to intrabrachial infusion of the endothelium-dependent vasodilator acetylcholine was significantly lower in GH-deficient nontreated patients than in control subjects (
P
<0.05). Likewise, forearm release of nitrite and cGMP during acetylcholine stimulation was reduced in GH-deficient nontreated patients (
P
<0.05 and
P
<0.002 versus controls). The response to the endothelium-independent vasodilator sodium nitroprusside was also markedly blunted in GH-deficient patients compared with control subjects (
P
<0.005). To confirm that abnormal vascular reactivity was due to GHD, we also studied 8 patients with childhood-onset GHD (age 31±2 years, BMI 24±1 kg/m
2
) who were receiving stable GH replacement therapy. In these patients, the response to both endothelium-dependent and -independent vasodilators, as well as forearm nitrite and cGMP, release was not different from that observed in normal subjects. Peak hyperemic response to 5-minute forearm ischemia was significantly reduced in GH-deficient nontreated patients (17.2±2.6 mL · dL
−1
· min
−1
,
P
<0.01) but not in GH-treated patients (24.8±3.3 mL · dL
−1
· min
−1
) compared with normal subjects (29.5±3.2 mL · dL
−1
· min
−1
).

Conclusions
—The data support the concept that GH plays an important role in the maintenance of a normal vascular function in humans.
Association of Thrombospondin-1 and Cardiac Allograft Vasculopathy in Human Cardiac Allografts
Authors: Zhao Xiao-Ming , Hu Yenya , Miller Geraldine G. , Mitchell Richard N. , Libby Peter
Published: June 2012

Background
—Despite the expression of angiogenic growth factors in transplanted hearts, neovessel formation appears scant. We therefore hypothesized that cardiac allografts contain endogenous inhibitors of angiogenesis. In particular, we tested the involvement in cardiac allografts of thrombospondin-1 (TSP-1), a matrix glycoprotein that inhibits angiogenesis and facilitates smooth muscle cell (SMC) proliferation.

Methods and Results
—Levels of TSP-1 mRNA in endomyocardial biopsy samples of human cardiac allografts substantially exceeded those in normal hearts. The ratio of TSP to GAPDH mRNA determined with quantitative RT-PCR was 6.54±1.6 in cardiac allografts versus 0.26±0.02 (
P
=0.001) in normal hearts. Analysis in sequential biopsies revealed a strong association between persistent elevation of TSP-1 in allografts and the development of cardiac allograft vasculopathy (CAV). The CAV score was 2.4±0.8 in patients with persistent TSP-1 elevation compared with 0.2±0.2 in patients without elevation (
P
=0.001). Immunohistochemistry demonstrated intense expression of TSP-1 in cardiac allografts, predominantly in cardiac myocytes and neointimal SMCs. In vitro experiments demonstrated that T cells expressed TSP-1, acidic fibroblast growth factor, and vascular endothelial cell growth factor on allogeneic stimulation. Cytokines known to be elevated in cardiac allografts (interleukin-1β, interferon-γ, and tumor necrosis factor-α) induced TSP-1 in SMCs but inhibited TSP-1 in endothelial cells.

Conclusions
—Persistent elevation of TSP-1 in cardiac allografts correlates with the development of CAV. Allogeneic stimulation induces angiogenic growth factors and TSP-1 in T cells. Cytokines differentially regulate TSP-1 expression in SMCs versus endothelial cells. Increased levels of TSP-1 in human cardiac allografts may alter vascular responses to angiogenic growth factors by inhibiting angiogenesis and promoting SMC proliferation characteristic of CAV.
Combination of a Brief Irrigation With Tissue Factor Pathway Inhibitor (TFPI) and Adenovirus-Mediated Local TFPI Gene Transfer Additively Reduces Neointima Formation in Balloon-Injured Rabbit Carotid Arteries
Authors: Atsuchi Nobuhiko , Nishida Takahiro , Marutsuka Kousuke , Asada Yujiro , Kamikubo Yuichi , Takeshita Akira , Ueno Hikaru
Published: June 2012

Background
—Tissue factor pathway inhibitor (TFPI) is a physiological antagonist of TF. We tested whether a brief irrigation with TFPI protein (rTFPI) or TFPI gene transfer into injured arteries would suppress TF activity and reduce fibroproliferative changes and investigated whether a combination of these methods would show an additive effect.

Methods and Results
—We prepared adenoviruses expressing either TFPI (AdTFPI) or bacterial β-galactosidase (AdLacZ). Rabbit carotid arteries were balloon-injured and either infected with AdTFPI (or AdLacZ) or irrigated briefly with rTFPI (or saline). After injury, TF activity in arteries increased and was sustained; however, it was suppressed during the initial 24 hours by rTFPI irrigation (but not by gene transfer) and for a substantial period of time by TFPI gene transfer (but not by rTFPI irrigation). Four weeks later, the ratio of the intimal to medial areas was 34.3±8.7% (mean±SD, n=14) in saline-treated arteries and 33.3±4.2% in AdLacZ-infected arteries (
P
=NS versus saline). However, it was reduced to 25.5±8.5% in rTFPI-irrigated arteries (
P
<0.01 versus saline) and to 20.7±5.3% in AdTFPI-infected arteries (
P
<0.01 versus AdLacZ). With a combination of irrigation and gene transfer, the ratio was further reduced to 12.6±4.7% (
P
<0.01 versus rTFPI,
P
<0.05 versus AdTFPI). Systemic coagulation status was not affected in these animals.

Conclusions
—A combination of rTFPI irrigation and TFPI gene transfer overcomes the shortcomings shown by each method when used alone and achieves a full coverage of TF activity suppression, thereby enhancing their therapeutic effects without systemic side effects. This combination may be an effective strategy for the prevention of thrombosis and proliferative changes after angioplasty in humans.
Tissue Doppler Imaging Differentiates Transmural From Nontransmural Acute Myocardial Infarction After Reperfusion Therapy
Authors: Derumeaux Geneviève , Loufoua Joseph , Pontier Gérard , Cribier Alain , Ovize Michel
Published: June 2012

Background
—The evaluation of transmural extent of necrosis after acute myocardial infarction remains a major problem in clinical practice. We sought to determine whether color M-mode tissue Doppler imaging (TDI) could differentiate transmural from nontransmural myocardial infarction.

Methods and Results
—Twenty-one anesthetized open-chest dogs underwent 90 or 120 minutes of left anterior descending coronary artery occlusion followed by 180 minutes of reperfusion. The transmural extension of infarct was measured by triphenyltetrazolium chloride (TTC) staining. Segment shortening in the endocardium and epicardium of the anterior and posterior walls was assessed by sonomicrometry. Regional myocardial blood flow was measured by radioactive microspheres. TDI was obtained from an epicardial short-axis view. We calculated systolic and diastolic velocities within the endocardium and epicardium of myocardial walls and the subsequent myocardial velocity gradient (MVG). TTC staining could identify 2 groups according to the transmural extent of necrosis: 15 dogs had a nontransmural (NT) necrosis (42±3% of wall thickness), and 6 dogs developed a transmural (T) infarct (81±4% of wall thickness). In both groups, ischemia resulted in a significant and similar reduction in endocardial and epicardial velocities, with a resulting low systolic MVG in the anterior wall (0.10±0.07 in NT and 0.10±0.08 s
−1
in T). At 60 minutes of reperfusion, systolic MVG failed to change significantly in the transmural group (−0.20±0.09 s
−1
). In contrast, it increased significantly after reflow in the NT group compared with ischemic values (−0.99±0.20 versus 0.10±0.07 s
−1
,
P
<0.05).

Conclusions
—TDI can differentiate transmural from nontransmural myocardial infarction early after reperfusion.
Intravascular Ultrasound
Authors: Nissen Steven E. , Yock Paul
Published: June 2012

Abstract
—Intravascular ultrasound (IVUS) is a valuable adjunct to angiography, providing new insights in the diagnosis of and therapy for coronary disease. Angiography depicts only a 2D silhouette of the lumen, whereas IVUS allows tomographic assessment of lumen area, plaque size, distribution, and composition. The safety of IVUS is well documented, and the assessment of luminal dimensions represents an important application of this modality. Comparative studies show the greatest disparities between angiography and ultrasound after mechanical interventions. In young subjects, normal intimal thickness is typically ≈0.15 mm. With IVUS, lipid-laden lesions appear hypoechoic, fibromuscular lesions generate low-intensity echoes, and fibrous or calcified tissues are echogenic. Calcium obscures the underlying wall (acoustic shadowing). The extent and severity of disease by angiography and ultrasound are frequently discrepant. Arterial remodeling refers to changes in vascular dimensions during the development of atherosclerosis. At diseased sites, the external elastic membrane may actually shrink in size, contributing to luminal stenosis. The interpretation of IVUS relies on simple visual inspection of acoustic reflections to determine plaque composition. However, different tissue components may look quite similar, and artifacts may adversely affect ultrasound images. IVUS commonly detects occult disease in angiographically “normal” sites. In ambiguous lesions, ultrasound permits lesion quantification, particularly for left main coronary disease. IVUS has emerged as the optimal method for the detection of transplant vasculopathy. An important potential application of ultrasound is the identification of atheromas at risk of rupture. The mechanisms of action of interventional devices have been elucidated using IVUS, and ultrasound is used by some operators to select the most suitable interventional device. IVUS-derived residual plaque burden is the most useful predictor of clinical outcome. In restenosis after balloon angioplasty, negative remodeling is a major mechanism of late lumen loss. IVUS is not routinely used for stent optimization, and there is no consensus regarding optimal procedural end points. Ultrasound has proven useful in evaluating brachytherapy. New and emerging applications for IVUS are continuing to evolve, particularly in atherosclerosis regression-progression trials.
Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia
Authors: Kawamoto Atsuhiko , Gwon Heon-Cheol , Iwaguro Hideki , Yamaguchi Jun-Ichi , Uchida Shigeki , Masuda Haruchika , Silver Marcy , Ma Hong , Kearney Marianne , Isner Jeffrey M. , Asahara Takayuki
Published: June 2012

Background
—We investigated the therapeutic potential of ex vivo expanded endothelial progenitor cells (EPCs) for myocardial neovascularization.

Methods and Results
—Peripheral blood mononuclear cells obtained from healthy human adults were cultured in EPC medium and harvested 7 days later. Myocardial ischemia was induced by ligating the left anterior descending coronary artery in male Hsd:RH-rnu (athymic nude) rats. A total of 10
6
EPCs labeled with 1,1′-dioctadecyl-1 to 3,3,3′,3′-tetramethylindocarbocyanine perchlorate were injected intravenously 3 hours after the induction of myocardial ischemia. Seven days later, fluorescence-conjugated Bandeiraea simplicifolia lectin I was administered intravenously, and the rats were immediately killed. Fluorescence microscopy revealed that transplanted EPCs accumulated in the ischemic area and incorporated into foci of myocardial neovascularization. To determine the impact on left ventricular function, 5 rats (EPC group) were injected intravenously with 10
6
EPCs 3 hours after ischemia; 5 other rats (control group) received culture media. Echocardiography, performed just before and 28 days after ischemia, disclosed ventricular dimensions that were significantly smaller and fractional shortening that was significantly greater in the EPC group than in the control group by day 28. Regional wall motion was better preserved in the EPC group. After euthanization on day 28, necropsy examination disclosed that capillary density was significantly greater in the EPC group than in the control group. Moreover, the extent of left ventricular scarring was significantly less in rats receiving EPCs than in controls. Immunohistochemistry revealed capillaries that were positive for human-specific endothelial cells.

Conclusions
—Ex vivo expanded EPCs incorporate into foci of myocardial neovascularization and have a favorable impact on the preservation of left ventricular function.
Cellular Mechanisms of Depressed Atrial Contractility in Patients With Chronic Atrial Fibrillation
Authors: Schotten Ulrich , Ausma Jannie , Stellbrink Christoph , Sabatschus Ingo , Vogel Miriam , Frechen Dirk , Schoendube Friedrich , Hanrath Peter , Allessie Maurits A.
Published: June 2012

Background
—After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood.

Methods and Results
—Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (≥3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. β-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca
2+
, isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca
2+
was maintained, and the postrest potentiation was preserved. β-Adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients.

Conclusions
—After prolonged AF, atrial contractility was reduced by 75%. The impairment of β-adrenergic modulation of contractile force cannot be explained by downregulation of β-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca
2+
channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca
2+
shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.
Characterization of Reentrant Circuit in Macroreentrant Right Atrial Tachycardia After Surgical Repair of Congenital Heart Disease
Authors: Nakagawa Hiroshi , Shah Nayyar , Matsudaira Kagari , Overholt Edward , Chandrasekaran Krishnaswamy , Beckman Karen J. , Spector Peter , Calame James D. , Rao Arun , Hasdemir Can , Otomo Kenichiro , Wang Zulu , Lazzara Ralph , Jackman Warren M.
Published: June 2012

Background
—The purpose of this study was to characterize the circuit of macroreentrant right atrial tachycardia (MacroAT) in patients after surgical repair of congenital heart disease (SR-CHD).

Methods and Results
—Sixteen patients with atrial tachycardia (AT) after SR-CHD were studied (atrial septal defect in 6, tetralogy of Fallot in 4, and Fontan procedure in 6). Electroanatomic right atrial maps were obtained during 15 MacroATs in 13 patients, focal AT in 1 patient, and atrial pacing in 2 patients without stable AT. A large area of low bipolar voltage (≤0.5 mV) involved most of the free wall in all patients and contained 2 to 7 dense scars or lines of double potentials, forming 29 narrow channels (width ≤2.7 cm) between scars in all but 1 patient, who had a single scar and only focal AT. All 15 MacroATs were propagated through narrow channels. Ablation within the channel eliminated all 15 MacroATs with 1 to 3 (median 1) radiofrequency applications. Ablation was performed in 9 other channels identified during MacroAT (5 patients) and in 5 channels identified during atrial pacing (2 patients). Conduction block was obtained across 28 of 29 channels. After ablation, reproducible sustained right AT was not induced in any patient. During follow-up (median 13.5 months), new MacroATs, atrial fibrillation, or palpitations occurred in 3 of 16 patients.

Conclusions
—MacroAT after SR-CHD requires a large area of low voltage containing ≥2 scars forming narrow channels. Ablation within the channels eliminates MacroAT.
Right Bundle Branch Block, Right Precordial ST-Segment Elevation, and Sudden Death in Young People
Authors: Corrado Domenico , Basso Cristina , Buja Gianfranco , Nava Andrea , Rossi Lino , Thiene Gaetano
Published: June 2012

Background
—Patients with the ECG pattern of right bundle branch block and right precordial ST-segment elevation may experience sudden death in the setting of either arrhythmogenic right ventricular cardiomyopathy (ARVC) or a functional electrical disorder such as Brugada syndrome.

Methods and Results
—Among a series of 273 young (≤35 years) victims of cardiovascular sudden death who were prospectively studied from 1979 to 1998 in the Veneto Region of Italy, 12-lead ECG was available in 96 cases. Thirteen (14%; 12 males and 1 female aged 24±8 years) had right precordial ST-segment elevation, either isolated (9 cases) or associated with right bundle branch block (4 cases). At autopsy, all patients had ARVC (92%) except one, who had no evidence of structural heart disease. Compared with the 19 young sudden death victims with ARVC and no ST-segment abnormalities from the same series, those with AVRC and right precordial ST-segment elevation included fewer competitive athletes (17% versus 58%;
P
=0.03), more often died suddenly at rest or during sleep (83% versus 26%;
P
=0.003), and showed serial ECG changes over time (83% versus 0;
P
=0.015), polymorphic ventricular tachycardia (33% versus 0;
P
=0.016), and predominant fatty replacement of the right ventricular anterior wall (58% versus 21%;
P
=0.05),

Conclusions
—Right precordial ST-segment elevation was found in 14% of young sudden death victims with available ECG. It mostly reflected underlying ARVC with predominant right ventricular anterior wall involvement and characterized a subgroup of patients who share with Brugada patients the propensity to die from non–exercise-related cardiac arrest and to exhibit dynamic ECG changes and polymorphic ventricular tachycardia.
Tumor Necrosis Factor-α (TNF-α) Plays a Protective Role in Acute Viral Myocarditis in Mice
Authors: Wada Hisayasu , Saito Kuniaki , Kanda Tsugiyasu , Kobayashi Isao , Fujii Hidehiko , Fujigaki Suwako , Maekawa Naoya , Takatsu Hisato , Fujiwara Hisayoshi , Sekikawa Kenji , Seishima Mitsuru
Published: June 2012

Background
—It has been reported that tumor necrosis factor-α (TNF-α) is expressed in the heart with viral myocarditis and that its expression aggravates the condition. The pathophysiological effects of TNF-α on viral myocarditis, however, have not been fully elucidated.

Methods and Results
—To investigate the role of TNF-α in the progression of viral myocarditis, we used TNF-α gene–deficient mice (TNF-α
−/−
) and induced acute myocarditis by infection with encephalomyocarditis virus (EMCV). The survival rate of TNF-α
−/−
mice after EMCV infection was significantly lower than that of TNF-α
+/+
mice (0% versus 67% on day 14). Injection of recombinant human TNF-α (0.2 to 4.0 μg/mouse IV) improved the survival of TNF-α
−/−
mice in a dose-dependent manner, indicating that TNF-α is essential for protection against viral myocarditis. The levels of viral titer and viral genomic RNA of EMCV in the myocardium were significantly higher in TNF-α
−/−
than in TNF-α
+/+
mice. Histopathological examination showed that the inflammatory changes of the myocardium were less marked in TNF-α
−/−
than in TNF-α
+/+
mice. Immunohistochemical analysis revealed that the levels of immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the myocardium were decreased in TNF-α
−/−
mice compared with TNF-α
+/+
mice.

Conclusions
—These observations suggested that TNF-α is necessary for adhesion molecule expression and to recruit leukocytes to inflammatory sites, and thus, the lack of this cytokine resulted in failure of elimination of infectious agents. We concluded that TNF-α plays a protective role in the acute stage of viral myocarditis.