bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histone Deacetylase Activity Selectively Regulates Notch‐Mediated Smooth Muscle Differentiation in Human Vascular Cells
Authors: Tang Yuefeng , Boucher Joshua M. , Liaw Lucy 
Published: September 2012

Background
Histone deacetylases (HDACs) modify smooth muscle cell (SMC) proliferation and affect neointimal lesion formation by regulating cell cycle progression. HDACs might also regulate SMC differentiation, although this is not as well characterized.

Methods and Results
Notch signaling activates SMC contractile markers and the differentiated phenotype in human aortic SMCs. Using this model, we found that HDAC inhibition antagonized the ability of Notch to increase levels of smooth muscle α‐actin, calponin1, smooth muscle 22α, and smooth muscle myosin heavy chain. However, inhibition of HDAC activity did not suppress Notch activation of the HRT target genes. In fact, HDAC inhibition increased activation of the canonical C‐promoter binding factor‐1 (CBF‐1)–mediated Notch pathway, which activates HRT transcription. Although CBF‐1–mediated Notch signaling was increased by HDAC inhibition in human SMCs and in a C3H10T1/2 model, SMC differentiation was inhibited in both cases. Further characterization of downstream Notch signaling pathways showed activation of the c‐Jun N‐terminal kinase, p38 mitogen‐activated protein kinase, and PI3K/Akt pathways. The activation of these pathways was sensitive to HDAC inhibition and was positively correlated with the differentiated phenotype.

Conclusions

Our studies define novel signaling pathways downstream of Notch signaling in human SMCs. In addition to the canonical CBF‐1 pathway, Notch stimulates c‐Jun N‐terminal kinase, mitogen‐activated protein kinase, and PI3K cascades. Both canonical and noncanonical pathways downstream of Notch promote a differentiated, contractile phenotype in SMCs. Although CBF‐1–mediated Notch signaling is not suppressed by HDAC inhibition, HDAC activity is required for Notch differentiation signals through mitogen‐activated protein kinase and PI3K pathways in SMCs.

(
J Am Heart Assoc
. 2012;1:e000901 doi

:
10.1161/JAHA.112.000901
)
Trends in Clinical, Demographic, and Biochemical Characteristics of Patients With Acute Myocardial Infarction From 2003 to 2008: A Report From the American Heart Association Get With The Guidelines Coronary Artery Disease Program
Authors: Boyer Nathan M. , Laskey Warren K. , Cox Margueritte , Hernandez Adrian F. , Peterson Eric D. , Bhatt Deepak L. , Cannon Christopher P. , Fonarow Gregg C. 
Published: September 2012

Background
An analysis of the changes in the clinical and demographic characteristics of patients with acute myocardial infarction could identify successes and failures of risk factor identification and treatment of patients at increased risk for cardiovascular events.

Methods and Results

We reviewed data collected from 138 122 patients with acute myocardial infarction admitted from 2003 to 2008 to hospitals participating in the American Heart Association Get With The Guidelines Coronary Artery Disease program. Clinical, demographic, and laboratory characteristics were analyzed for each year stratified on the electrocardiogram at presentation. Patients with non–
ST
‐segment–elevation myocardial infarction were older, more likely to be women, and more likely to have hypertension, diabetes mellitus, and a history of past cardiovascular disease than were patients with ST‐elevation myocardial infarction. In the overall patient sample, significant trends were observed of an increase over time in the proportions of non–ST‐segment–elevation myocardial infarction, patient age of 45 to 65 years, obesity, and female sex. The prevalence of diabetes mellitus decreased over time, whereas the prevalences of hypertension and smoking were substantial and unchanging. The prevalence of “low” high‐density lipoprotein increased over time, whereas that of “high” low‐density lipoprotein decreased. Stratum‐specific univariate analysis revealed quantitative and qualitative differences between strata in time trends for numerous demographic, clinical, and biochemical measures. On multivariable analysis, there was concordance between strata with regard to the increase in prevalence of patients 45 to 65 years of age, obesity, and “low” high‐density lipoprotein and the decrease in prevalence of “high” low‐density lipoprotein. However, changes in trends in age distribution, sex ratio, and prevalence of smokers and the magnitude of change in diabetes mellitus prevalence differed between strata.

Conclusions
There were notable differences in risk factors and patient characteristics among patients with ST‐elevation myocardial infarction and those with non–ST‐segment–elevation myocardial infarction. The increasing prevalence of dysmetabolic markers in a growing proportion of patients with acute myocardial infarction suggests further opportunities for risk factor modification.
High Level of Plasma Estradiol as a New Predictor of Ischemic Arterial Disease in Older Postmenopausal Women: The Three‐City Cohort Study
Authors: Scarabin‐Carré Valérie , Canonico Marianne , Brailly‐Tabard Sylvie , Trabado Séverine , Ducimetière Pierre , Giroud Maurice , Ryan Joanne , Helmer Catherine , Plu‐Bureau Geneviève , Guiochon‐Mantel Anne , Scarabin Pierre‐Yves 
Published: September 2012

Background
Despite evidence that estrogens may be involved in atherothrombosis, the role of endogenous sex steroid hormones in ischemic arterial disease among postmenopausal women remains uncertain.

Methods and Results

In the Three‐City prospective cohort study of subjects (n=9294) >65 years of age, we investigated the association of total 17β‐estradiol, bioavailable 17β‐estradiol, and total testosterone with the 4‐year incidence of ischemic arterial disease among postmenopausal women who did not use any hormone therapy. We designed a case–cohort study including a random sample of 537 subjects and 106 incident cases of first cardiovascular events. Weighted Cox proportional‐hazards models with age as the time scale were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for ischemic arterial disease by a 1–standard deviation increase in sex steroid hormones. In univariate analysis, HR of ischemic arterial disease was positively and significantly associated with both total and bioavailable estradiol levels. These associations remained significant after adjustment for traditional cardiovascular risk factors, including body mass index, diabetes, hypercholesterolemia, hypertension, and smoking status (HR: 1.42, 95% CI: 1.12–1.79,
P
<0.01; and HR: 1.42, 95% CI: 1.12–1.78,
P
<0.01, respectively). Separate analysis for coronary heart disease yielded similar results (adjusted HR: 1.49, 95% CI: 1.10–2.02,
P
=0.01; and adjusted HR: 1.50, 95% CI: 1.11–2.04,
P
<0.01, respectively), and a borderline significant trend was observed for ischemic stroke (HR: 1.34, 95% CI: 0.95–1.89,
P
=0.08; and HR: 1.32, 95% CI: 0.94–1.84,
P
=0.11, respectively). By contrast, no significant association was found between total testosterone and ischemic arterial disease in both univariate and adjusted analyses.

Conclusions

High plasma level of endogenous estradiol emerges as a new predictor of ischemic arterial disease in older postmenopausal women.

(
J Am Heart Assoc
. 2012;1:e001388 doi

:
10.1161/JAHA.112.001388
.)
Changes in Carotid Intima‐Media Thickness During the Cardiac Cycle: The Multi‐Ethnic Study of Atherosclerosis
Authors: Polak Joseph F. , Johnson Craig , Harrington Anita , Wong Quenna , O'Leary Daniel H. , Burke Gregory , Yanez N. David 
Published: September 2012

Background

Common carotid artery intima‐media thickness (
IMT
), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.

Methods and Results

Far‐wall
IMT
measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi‐Ethnic Study of Atherosclerosis (
MESA
). Multivariable regression models were generated with end‐diastolic
IMT
, peak‐systolic
IMT
, and change in
IMT
during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid
IMT
during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean
IMT
of 0.68 mm. End‐diastolic
IMT
and peak‐systolic
IMT
were similarly associated with risk factors. In a fully adjusted model, change in carotid
IMT
during the cardiac cycle was associated with ethnicity and pulse pressure (
P
=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in
IMT
than did non‐Hispanic whites. With peak‐systolic
IMT
reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of
IMT
and at high risk for cardiovascular disease than would be expected when
IMT
is measured at end diastole.

Conclusions

Measurable differences in
IMT
are seen during the cardiac cycle. This affects the interpretation of
IMT
measurements used for cardiovascular risk assessment, given published normative data with
IMT
measured at peak systole.

Clinical Trial Registration

URL:
www.ClinicalTrials.gov
. Unique identifier: NCT00063440.
Vulnerable Myocardial Interstitium in Patients With Isolated Left Ventricular Hypertrophy and Sudden Cardiac Death: A Postmortem Histological Evaluation
Authors: Tamarappoo Balaji K. , John Benjamin T. , Reinier Kyndaron , Teodorescu Carmen , Uy‐Evanado Audrey , Gunson Karen , Jui Jonathan , Chugh Sumeet S. 
Published: September 2012

Background
Concentric left ventricular hypertrophy (LVH) is independently associated with increased risk of sudden cardiac death (SCD). Some animal models of LVH display specific alterations of the myocardial interstitium that could increase myocardial vulnerability to ventricular arrhythmias, but these merit evaluation in humans with LVH and SCD.

Methods and Results

Twelve consecutive patients with isolated LVH and SCD (LVH+SCD) in the absence of hypertrophic cardiomyopathy, coronary disease, or other cardiac structural abnormality were ascertained in the Oregon Sudden Unexpected Death Study. Detailed postmortem comparisons were conducted with 18 controls who had isolated LVH and unnatural deaths (Control Group A) and 6 controls who had structurally normal hearts and unnatural deaths (Control Group B). Postmortem left ventricular myocardial sections were obtained for measurement of collagen volume fraction, characterization of gap junctions, and quantification of collagen subtypes. Heart weight normalized to body weight was higher in LVH+SCD cases (6.9±1.2 g/kg) than in Control Group A (5.3±1.4 g/kg) and Control Group B (4.2±0.3 g/kg);
P
=0.001. Collagen volume fraction was also higher in LVH+SCD cases (3.1±0.4) than in Control Group A (2.3±0.4) and Control Group B (1.6±0.3);
P
=0.0002. The relative amount of collagen III was significantly higher in LVH+SCD cases (33.0±4.4%) than in Control Group A (20.9±4.3%) and Control Group B (13.4±3.5%);
P
=0.0001. There was an overall increase in the number of connexin 43–labeled gap junctions with increasing myocyte size. No subject was found to have high‐risk hypertrophic cardiomyopathy mutations.

Conclusions

In addition to the expected increase in myocardial mass and overall collagen content, SCD with isolated LVH was associated with relative abundance of type III collagen, a novel finding that warrants further mechanistic evaluation.

(
J Am Heart Assoc
. 2012;1:e001511 doi

:
10.1161/JAHA.112.001511
.)
Risk of Idiopathic Dilated Cardiomyopathy in 29 000 Patients With Celiac Disease
Authors: Emilsson Louise , Andersson Bert , Elfström Peter , Green Peter H.R. , Ludvigsson Jonas F. 
Published: September 2012

Background
Dilated cardiomyopathy (DCM) is a rare disease of largely unknown origin. Previous studies have suggested an increased prevalence of celiac disease (CD) in patients with DCM. These studies, however, were based on a maximum of 5 patients with both CD and DCM. In the present large Swedish population‐based cohort study, we examined the risk of idiopathic DCM in patients with CD determined by small‐intestinal histopathology.

Methods and Results

From 2006 to 2008, we collected duodenal/jejunal biopsy data on CD (equal to villous atrophy, Marsh stage 3, n=29 071 unique individuals) from (all) 28 pathology departments in Sweden. These individuals were compared with 144 429 reference individuals matched for age, sex, calendar year, and county. Data on DCM were obtained through the National Patient Register and confirmed by patient charts and echocardiography data. During follow‐up, 17 patients with CD and 52 reference individuals developed idiopathic DCM. Thus, patients with CD were at an increased risk of idiopathic DCM (hazard ratio, 1.73; 95% confidence interval, 1.00 to 3.00), although the risk estimate failed to attain statistical significance (
P
=0.052).

Conclusion

This nationwide study found a moderately but not statistically significantly increased risk of idiopathic DCM in patients with biopsy‐verified CD.

(
J Am Heart Assoc
. 2012;1:e001594 doi

:
10.1161/JAHA.112.001594
.)
Reduction of Ischemia/Reperfusion Injury With Bendavia, a Mitochondria‐Targeting Cytoprotective Peptide
Authors: Kloner Robert A. , Hale Sharon L. , Dai Wangde , Gorman Robert C. , Shuto Takashi , Koomalsingh Kevin J. , Gorman Joseph H. , Sloan Ruben C. , Frasier Chad R. , Watson Corinne A. , Bostian Phillip A. , Kypson Alan P. , Brown David A. 
Published: September 2012

Background
Manifestations of reperfusion injury include myocyte death leading to infarction, contractile dysfunction, and vascular injury characterized by the “no‐reflow” phenomenon. Mitochondria‐produced reactive oxygen species are believed to be centrally involved in each of these aspects of reperfusion injury, although currently no therapies reduce reperfusion injury by targeting mitochondria specifically.

Methods and Results

We investigated the cardioprotective effects of a mitochondria‐targeted peptide, Bendavia (Stealth Peptides), across a spectrum of experimental cardiac ischemia/reperfusion models. Postischemic administration of Bendavia reduced infarct size in an in vivo sheep model by 15% (
P
=0.02) and in an ex vivo guinea pig model by 38% to 42% (
P
<0.05). In an in vivo rabbit model, the extent of coronary no‐reflow was assessed with Thioflavin S staining and was significantly smaller in the Bendavia group for any given ischemic risk area than in the control group (
P
=0.0085). Myocardial uptake of Bendavia was ≈25% per minute, and uptake remained consistent throughout reperfusion. Postischemic recovery of cardiac hemodynamics was not influenced by Bendavia in any of the models studied. Isolated myocytes exposed to hypoxia/reoxygenation showed improved survival when treated with Bendavia. This protection appeared to be mediated by lowered reactive oxygen species–mediated cell death during reoxygenation, associated with sustainment of mitochondrial membrane potential in Bendavia‐treated myocytes.

Conclusions

Postischemic administration of Bendavia protected against reperfusion injury in several distinct models of injury. These data suggest that Bendavia is a mitochondria‐targeted therapy that reduces reperfusion injury by maintaining mitochondrial energetics and suppressing cellular reactive oxygen species levels.

(
J Am Heart Assoc
. 2012;1:e001644 doi

:
10.1161/JAHA.112.001644
.)
Measurement of Reverse Cholesterol Transport Pathways in Humans: In Vivo Rates of Free Cholesterol Efflux, Esterification, and Excretion
Authors: Turner Scott , Voogt Jason , Davidson Michael , Glass Alex , Killion Salena , Decaris Julie , Mohammed Hussein , Minehira Kaori , Boban Drina , Murphy Elizabeth , Luchoomun Jayraz , Awada Mohamad , Neese Richard , Hellerstein Marc 
Published: September 2012

Background

Reverse cholesterol transport from peripheral tissues is considered the principal atheroprotective mechanism of high‐density lipoprotein, but quantifying reverse cholesterol transport in humans in vivo remains a challenge. We describe here a method for measuring flux of cholesterol though 3 primary components of the reverse cholesterol transport pathway in vivo in humans: tissue free cholesterol (
FC
) efflux, esterification of
FC
in plasma, and fecal sterol excretion of plasma‐derived
FC
.

Methods and Results

A constant infusion of [2,3‐
13
C
2
]‐cholesterol was administered to healthy volunteers. Three‐compartment
SAAM

II
(Simulation, Analysis, and Modeling software; SAAM Institute, University of Washington, WA) fits were applied to plasma
FC
, red blood cell
FC
, and plasma cholesterol ester
13
C–enrichment profiles. Fecal sterol excretion of plasma‐derived
FC
was quantified from fractional recovery of intravenous [2,3‐
13
C
2
]‐cholesterol in feces over 7 days. We examined the key assumptions of the method and evaluated the optimal clinical protocol and approach to data analysis and modeling. A total of 17 subjects from 2 study sites (n=12 from first site, age 21 to 75 years, 2 women; n=5 from second site, age 18 to 70 years, 2 women) were studied. Tissue
FC
efflux was 3.79±0.88 mg/kg per hour (mean ± standard deviation), or ≈8 g/d. Red blood cell–derived flux into plasma
FC
was 3.38±1.10 mg/kg per hour. Esterification of plasma
FC
was ≈28% of tissue
FC
efflux (1.10±0.38 mg/kg per hour). Recoveries were 7% and 12% of administered [2,3‐
13
C
2
]‐cholesterol in fecal bile acids and neutral sterols, respectively.

Conclusions
Three components of systemic reverse cholesterol transport can be quantified, allowing dissection of this important function of high‐density lipoprotein in vivo. Effects of lipoproteins, genetic mutations, lifestyle changes, and drugs on these components can be assessed in humans.
Interleukin‐1 Mediates Neuroinflammatory Changes Associated With Diet‐Induced Atherosclerosis
Authors: Denes Adam , Drake Caroline , Stordy Jing , Chamberlain Janet , McColl Barry W. , Gram Hermann , Crossman David , Francis Sheila , Allan Stuart M. , Rothwell Nancy J. 
Published: September 2012

Background
Systemic inflammation contributes to brain pathology in cerebrovascular disease through mechanisms that are poorly understood.

Methods and Results
Here we show that atherosclerosis, a major systemic inflammatory disease, is associated with severe cerebrovascular inflammation in mice and that this effect is mediated by the proinflammatory cytokine interleukin‐1 (IL‐1). Apolipoprotein E–deficient mice fed Paigen or Western diets develop vascular inflammation, microglial activation, and leukocyte recruitment in the brain, which are absent in apolipoprotein E–deficient mice crossed with IL‐1 type 1 receptor–deficient mice. Systemic neutralization of IL‐1β with an anti–IL‐1β antibody reversed aortic plaque formation (by 34% after a Paigen and 45% after a Western diet) and reduced inflammatory cytokine expression in peripheral organs. Central, lipid accumulation–associated leukocyte infiltration into the choroid plexus was reversed by IL‐1β antibody administration. Animals fed a Western diet showed 57% lower vascular inflammation in the brain than that of mice fed a Paigen diet, and this was reduced further by 24% after IL‐1β antibody administration.

Conclusions

These results indicate that IL‐1 is a key driver of systemically mediated cerebrovascular inflammation and that interventions against IL‐1β could be therapeutically useful in atherosclerosis, dementia, or stroke.

(
J Am Heart Assoc
. 2012;1:e002006 doi

:
10.1161/JAHA.112.002006
.)
Microvascular Resistance Predicts Myocardial Salvage and Infarct Characteristics in ST‐Elevation Myocardial Infarction
Authors: Payne Alexander R. , Berry Colin , Doolin Orla , McEntegart Margaret , Petrie Mark C. , Lindsay M. Mitchell , Hood Stuart , Carrick David , Tzemos Niko , Weale Peter , McComb Christie , Foster John , Ford Ian , Oldroyd Keith G. 
Published: September 2012

Background
The pathophysiology of myocardial injury and repair in patients with ST‐elevation myocardial infarction is incompletely understood. We investigated the relationships among culprit artery microvascular resistance, myocardial salvage, and ventricular function.

Methods and Results

The index of microvascular resistance (IMR) was measured by means of a pressure‐ and temperature‐sensitive coronary guidewire in 108 patients with ST‐elevation myocardial infarction (83% male) at the end of primary percutaneous coronary intervention. Paired cardiac MRI (cardiac magnetic resonance) scans were performed early (2 days; n=108) and late (3 months; n=96) after myocardial infarction. T
2
‐weighted‐ and late gadolinium–enhanced cardiac magnetic resonance delineated the ischemic area at risk and infarct size, respectively. Myocardial salvage was calculated by subtracting infarct size from area at risk. Univariable and multivariable models were constructed to determine the impact of IMR on cardiac magnetic resonance–derived surrogate outcomes. The median (interquartile range) IMR was 28 (17–42) mm Hg/s. The median (interquartile range) area at risk was 32% (24%–41%) of left ventricular mass, and the myocardial salvage index was 21% (11%–43%). IMR was a significant multivariable predictor of early myocardial salvage, with a multiplicative effect of 0.87 (95% confidence interval 0.82 to 0.92) per 20% increase in IMR;
P
<0.001. In patients with anterior myocardial infarction, IMR was a multivariable predictor of early and late myocardial salvage, with multiplicative effects of 0.82 (95% confidence interval 0.75 to 0.90;
P
<0.001) and 0.92 (95% confidence interval 0.88 to 0.96;
P
<0.001), respectively. IMR also predicted the presence and extent of microvascular obstruction and myocardial hemorrhage.

Conclusion

Microvascular resistance measured during primary percutaneous coronary intervention significantly predicts myocardial salvage, infarct characteristics, and left ventricular ejection fraction in patients with ST‐elevation myocardial infarction.

(
J Am Heart Assoc
. 2012;1:e002246 doi

:
10.1161/JAHA.112.002246
)