bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vivo Cardiac Cellular Reprogramming Efficacy Is Enhanced by Angiogenic Preconditioning of the Infarcted Myocardium With Vascular Endothelial Growth Factor
Authors: Mathison Megumi , P. Gersch Robert , Nasser Ahmed , Lilo Sarit , Korman Mallory , Fourman Mitchell , Hackett Neil , Shroyer Kenneth , Yang Jianchang , Ma Yupo , Crystal Ronald G. , Rosengart Todd K.
Published: May 2013

Background

In situ cellular reprogramming offers the possibility of regenerating functional cardiomyocytes directly from scar fibroblasts, obviating the challenges of cell implantation. We hypothesized that pretreating scar with gene transfer of the angiogenic vascular endothelial growth factor (
VEGF
) would enhance the efficacy of this strategy.

Methods and Results

Gata4, Mef2c, and Tbx5 (
GMT
) administration via lentiviral transduction was demonstrated to transdifferentiate rat fibroblasts into (induced) cardiomyocytes in vitro by cardiomyocyte marker studies. Fisher 344 rats underwent coronary ligation and intramyocardial administration of an adenovirus encoding all 3 major isoforms of
VEGF
(Ad
VEGF
‐All6A
+
) or an AdNull control vector (n=12/group). Lentivirus encoding
GMT
or a
GFP
control was administered to each animal 3 weeks later, followed by histologic and echocardiographic analyses.
GMT
administration reduced the extent of fibrosis by half compared with
GFP
controls (12±2% vs 24±3%,
P
<0.01) and reduced the number of myofibroblasts detected in the infarct zone by 4‐fold.
GMT
‐treated animals also demonstrated greater density of cardiomyocyte‐specific marker beta myosin heavy chain 7
+
cells compared with animals receiving
GFP
with or without
VEGF
(
P
<0.01). Ejection fraction was significantly improved after
GMT
vs
GFP
administration (12±3% vs −7±3%,
P
<0.01). Eight (73%)
GFP
animals but no
GMT
animals demonstrated decreased ejection fraction during this interval (
P
<0.01). Also, improvement in ejection fraction was 4‐fold greater in
GMT
/
VEGF
vs
GMT
/null animals (17±2% vs 4±1%,
P
<0.05).

Conclusions

VEGF
administration to infarcted myocardium enhances the efficacy of
GMT
‐mediated cellular reprogramming in improving myocardial function and reducing the extent of myocardial fibrosis compared with the use of
GMT
or
VEGF
alone.
Atrial Fibrillation and Outcomes in Heart Failure With Preserved Versus Reduced Left Ventricular Ejection Fraction
Authors: McManus David D. , Hsu Grace , Sung Sue Hee , Saczynski Jane S. , Smith David H. , Magid David J. , Gurwitz Jerry H. , Goldberg Robert J. , Go Alan S. ,   for the Cardiovascular Research Network PRESERVE Study
Published: May 2013

Background

Atrial fibrillation (
AF
) and heart failure (
HF
) are 2 of the most common cardiovascular conditions nationally and
AF
frequently complicates
HF
. We examined how
AF
has impacts on adverse outcomes in
HF
‐
PEF
versus
HF
‐
REF
within a large, contemporary cohort.

Methods and Results

We identified all adults diagnosed with
HF
‐
PEF
or
HF
‐
REF
based on hospital discharge and ambulatory visit diagnoses and relevant imaging results for 2005–2008 from 4 health plans in the Cardiovascular Research Network. Data on demographic features, diagnoses, procedures, outpatient pharmacy use, and laboratory results were ascertained from health plan databases. Hospitalizations for
HF
, stroke, and any reason were identified from hospital discharge and billing claims databases. Deaths were ascertained from health plan and state death files. Among 23 644 patients with
HF
, 11 429 (48.3%) had documented
AF
(9081 preexisting, 2348 incident). Compared with patients who did not have
AF
, patients with
AF
had higher adjusted rates of ischemic stroke (hazard ratio [
HR
] 2.47 for incident
AF
;
HR
1.57 for preexisting
AF
), hospitalization for
HF
(
HR
2.00 for incident
AF
;
HR
1.22 for preexisting
AF
), all‐cause hospitalization (
HR
1.45 for incident
AF
;
HR
1.15 for preexisting
AF
), and death (incident
AF HR
1.67; preexisting
AF HR
1.13). The associations of
AF
with these outcomes were similar for
HF
‐
PEF
and
HF
‐
REF
, with the exception of ischemic stroke.

Conclusions

AF
is a potent risk factor for adverse outcomes in patients with
HF
‐
PEF
or
HF
‐
REF
. Effective interventions are needed to improve the prognosis of these high‐risk patients.
Novel Tissue‐Specific Mechanism of Regulation of Angiogenesis and Cancer Growth in Response to Hyperglycemia
Authors: Bhattacharyya Sanghamitra , Sul Kristina , Krukovets Irene , Nestor Carla , Li Jianbo , Adognravi Olga Stenina
Published: May 2013

Background

Hyperglycemia is an independent risk factor for the development of vascular diabetic complications, which are characterized by endothelial dysfunction and tissue‐specific aberrant angiogenesis. Tumor growth is also dependent on angiogenesis. Diabetes affects several cancers in a tissue‐specific way. For example, it positively correlates with the incidence of breast cancer but negatively correlates with the incidence of prostate cancer. The tissue‐specific molecular mechanisms activated by hyperglycemia that control angiogenesis are unknown. Here we describe a novel tissue‐ and cell‐specific molecular pathway that is activated by high glucose and regulates angiogenesis.

Methods and Results

We have identified micro
RNA
467 (miR‐467) as a translational suppressor of thrombospondin‐1 (
TSP
‐1), a potent antiangiogenic protein that is implicated in the pathogenesis of several diabetic complications. miR‐467 was upregulated by hyperglycemia in a tissue‐specific manner. It was induced by high glucose in microvascular endothelial cells and in breast cancer cells, where it suppressed the production of
TSP
‐1 by sequestering
mRNA
in the nonpolysomal fraction. Mutation of the miR‐467 binding site in
TSP
‐1 3′
UTR
or miR‐467 inhibitor relieved the translational silencing and restored
TSP
‐1 production. In in vivo angiogenesis models, miR‐467 promoted the growth of blood vessels, and
TSP
‐1 was the main mediator of this effect. Breast cancer tumors showed increased growth in hyperglycemic mice and expressed higher levels of miR‐467. The antagonist of miR‐467 prevented the hyperglycemia‐induced tumor growth.

Conclusions

Our results demonstrate that miR‐467 is implicated in the control of angiogenesis in response to high glucose, which makes it an attractive tissue‐specific potential target for therapeutic regulation of aberrant angiogenesis and cancer growth in diabetes.
Acute ST‐Elevation Myocardial Infarction in Patients Hospitalized for Noncardiac Conditions
Authors: Dai Xuming , Bumgarner Joseph , Spangler Andrew , Meredith Dane , Smith Sidney C. , Stouffer George A.
Published: May 2013

Background

Major advances have been made in the treatment of
ST
‐elevation myocardial infarction (
STEMI
) in outpatients. In contrast, little is known about outcomes in
STEMI
that occur in patients hospitalized for a noncardiac condition.

Methods and Results

This was a retrospective, single‐center study of inpatient
STEMI
s from January 1, 2007, to July 31, 2011. Forty‐eight cases were confirmed to be inpatient
STEMI
s of a total of 139 410 adult discharges. These patients were older and more often female and had higher rates of chronic kidney disease and prior cerebrovascular events compared with 227 patients with outpatient
STEMI
s treated during the same period. Onset of inpatient
STEMI
was heralded most frequently by a change in clinical status (60%) and less commonly by patient complaints (33%) or changes on telemetry. Coronary angiography and percutaneous coronary intervention were performed in 71% and 56% of patients, respectively. The median time to obtain
ECG
(41 [10, 600] versus 5 [2, 10] minutes;
P
<0.001),
ECG
to angiography time (91 [26, 209] versus 35 [25, 46] minutes;
P
<0.001) and
ECG
to first device activation (
FDA
) (129 [65, 25] versus 60 [47, 76] minutes;
P
<0.001) were longer for inpatient versus outpatient
STEMI
. Survival to discharge was lower for inpatient
STEMI
(60% versus 96%;
P
<0.001), and this difference persisted after adjusting for potential confounders.

Conclusions

Patients who develop a
STEMI
while hospitalized for a noncardiac condition are older and more often female, have more comorbidities, have longer
ECG
‐to‐
FDA
times, and are less likely to survive than patients with an outpatient
STEMI
.
Mechanical Unloading Activates FoxO3 to Trigger Bnip3‐Dependent Cardiomyocyte Atrophy
Authors: Cao Dian J. , Jiang Nan , Blagg Andrew , Johnstone Janet L. , Gondalia Raj , Oh Misook , Luo Xiang , Yang Kai‐Chun , Shelton John M. , Rothermel Beverly A. , Gillette Thomas G. , Dorn Gerald W. , Hill Joseph A.
Published: May 2013

Background

Mechanical assist device therapy has emerged recently as an important and rapidly expanding therapy in advanced heart failure, triggering in some patients a beneficial reverse remodeling response. However, mechanisms underlying this benefit are unclear.

Methods and Results

In a model of mechanical unloading of the left ventricle, we observed progressive myocyte atrophy, autophagy, and robust activation of the transcription factor FoxO3, an established regulator of catabolic processes in other cell types. Evidence for FoxO3 activation was similarly detected in unloaded failing human myocardium. To determine the role of FoxO3 activation in cardiac muscle in vivo, we engineered transgenic mice harboring a cardiomyocyte‐specific constitutively active FoxO3 mutant (
caFoxO3

flox

;α
MHC‐Mer‐Cre‐Mer
). Expression of caFoxO3 triggered dramatic and progressive loss of cardiac mass, robust increases in cardiomyocyte autophagy, declines in mitochondrial biomass and function, and early mortality. Whereas increases in cardiomyocyte apoptosis were not apparent, we detected robust increases in Bnip3 (Bcl2/adenovirus E1B 19‐
kD
a interacting protein 3), an established downstream target of FoxO3. To test the role of Bnip3, we crossed the
caFoxO3

flox

;α
MHC‐Mer‐Cre‐Mer
mice with Bnip3‐null animals. Remarkably, the atrophy and autophagy phenotypes were significantly blunted, yet the early mortality triggered by FoxO3 activation persisted. Rather, declines in cardiac performance were attenuated by proteasome inhibitors. Consistent with involvement of FoxO3‐driven activation of the ubiquitin‐proteasome system, we detected time‐dependent activation of the atrogenes program and sarcomere protein breakdown.

Conclusions

In aggregate, these data point to FoxO3, a protein activated by mechanical unloading, as a master regulator that governs both the autophagy‐lysosomal and ubiquitin‐proteasomal pathways to orchestrate cardiac muscle atrophy.
Nuclear Transport Modulation Reduces Hypercholesterolemia, Atherosclerosis, and Fatty Liver
Authors: Liu Yan , Major Amy S. , Zienkiewicz Jozef , Gabriel Curtis L. , Veach Ruth Ann , Moore Daniel J. , Collins Robert D. , Hawiger Jacek
Published: May 2013

Background

Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide.

Methods and Results

A cell‐penetrating nuclear transport modifier (
NTM
) reduced hyperlipidemia, atherosclerosis, and fatty liver in low‐density lipoprotein receptor‐deficient mice fed a
W
estern diet.
NTM
treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively;
P
<0.005) and liver (41% and 34%, respectively;
P
<0.05) after 8 weeks. Atherosclerosis was reduced by 63% (
P
<0.0005), and liver function improved compared with saline‐treated controls. In addition, fasting blood glucose levels were reduced from 209 to 138 mg/dL (
P
<0.005), and body weight gain was ameliorated (
P
<0.005) in
NTM
‐treated mice, although food intake remained the same as that in control animals. The
NTM
used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress‐responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This
NTM
has now been demonstrated to also modulate nuclear transport of sterol regulatory element‐binding protein (
SREBP
) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis.
NTM
‐modulated translocation of
SREBP
s to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia.

Conclusions

Two‐pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications.
Effect of Remote Ischemic Preconditioning on Phosphorylated Protein Signaling in Children Undergoing Tetralogy of Fallot Repair: A Randomized Controlled Trial
Authors: Pepe Salvatore , Liaw Norman Y. , Hepponstall Michele , Sheeran Freya L. , Yong Matthew S. , d'Udekem Yves , Cheung Michael M. , Konstantinov Igor E.
Published: May 2013

Background

Our previous randomized controlled trial demonstrated cardiorespiratory protection by remote ischemic preconditioning (
RIPC
) in children before cardiac surgery. However, the impact of
RIPC
on myocardial prosurvival intracellular signaling remains unknown in cyanosis.
RIPC
may augment phosphorylated protein signaling in myocardium and circulating leukocytes during tetralogy of
F
allot (ToF) repair.

Methods and Results

Children (n=40) undergoing ToF repair were double‐blind randomized to
RIPC
(n=11 boys, 9 girls) or control (sham
RIPC
: n=9 boys, 11 girls). Blood samples were taken before, immediately after, and 24 hours after cardiopulmonary bypass. Resected right ventricular outflow tract muscle and leukocytes were processed for protein expression and mitochondrial respiration. There was no difference in age (7.1±3.4 versus 7.1±3.4 months), weight (7.7±1.8 versus 7.5±1.9 kg), or bypass or aortic cross‐clamp times between the groups (control versus
RIPC
, mean±
SD
). No differences were seen between the groups for an increase in the ratio of phosphorylated to total protein for protein kinase B, p38 mitogen activated protein kinase, signal transducer and activator of transcription 3, glycogen synthase kinase 3β, heat shock protein 27, Connexin43, or markers associated with promotion of necrosis (serum cardiac troponin I), apoptosis (Bax, Bcl‐2), and autophagy (Parkin, Beclin‐1, LC3B). A high proportion of total proteins were in phosphorylated form in control and
RIPC
myocardium. In leukocytes, mitochondrial respiration and assessed protein levels did not differ between groups.

Conclusions

In patients with cyanotic heart disease, a high proportion of proteins are in phosphorylated form.
RIPC
does not further enhance phosphorylated protein signaling in myocardium or circulating leukocytes in children undergoing ToF repair.

Clinical Trial Registration

URL: (
http://www.anzctr.org.au/trial_view.aspx?id=335613
. Unique identifier: Australian New Zealand Clinical Trials Registry number ACTRN12610000496011.
Cardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator‐Activated Receptorγ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt‐Sensitive Hypertension
Authors: Kusunoki Hiroshi , Taniyama Yoshiaki , Rakugi Hiromi , Morishita Ryuichi
Published: May 2013

Background

“Aldosterone breakthrough” observed in patients receiving long‐term treatment with angiotensin blockade is strongly associated with increased risk of left ventricular hypertrophy, poor exercise capacity, refractory proteinuria, and declining glomerular filtration rate through the profibrotic actions of aldosterone. To overcome aldosterone breakthrough, we examined the additional organ‐protective actions of irbesartan, because irbesartan is an angiotensin II type 1 receptor (AT1R) blocker (ARB) with peroxisome proliferator‐activated receptor
(
PPAR
)γ agonistic effects, which mediate organ‐protective effects independent of AT1R blockade. In this study, we examined the organ‐protective effects of irbesartan in a salt‐sensitive hypertension model using
AT
1aR knockout mice.

Methods and Results

Aldosterone and 1% NaCl treatment resulted in a significant increase in severe cardiac and renal fibrosis. Irbesartan, but not losartan, significantly reduced renal fibrosis, glomerular injury through inhibition of macrophage infiltration, epithelial–mesenchymal transition, and oxidative stress. Similarly, cardiac fibrosis and myocyte hypertrophy were decreased by irbesartan, but not losartan, treatment, associated with a significant reduction in oxidative stress. Importantly, anti–hepatocyte growth factor (HGF) neutralizing antibody and a
PPAR
γ antagonist (
GW
9662) attenuated these organ‐protective effects of irbesartan.
HGF
protein level was increased by irbesartan, especially in the kidney and heart, while
GW
9662 treatment inhibited the increase in
HGF
level.

Conclusions

In this study, we showed that irbesartan, which has not only
AT
1aR‐blocking effects, but also
PPAR
γ agonistic effects accompanied by
HGF
expression, inhibited organ damage by aldosterone and salt treatment. Second‐generation
ARB
s such as irbesartan, which has the dual actions of
AT
1R blockade and
PPAR
γ activation, may have clinical value for the treatment of hypertensive patients with aldosterone breakthrough.
MicroRNA‐210 Decreases heme Levels by Targeting Ferrochelatase in Cardiomyocytes
Authors: Qiao Aijun , Khechaduri Arineh , Kannan Mutharasan R. , Wu Rongxue , Nagpal Varun , Ardehali Hossein
Published: May 2013

Background

Micro
RNA
‐210 (miR‐210) increases in hypoxia and regulates mitochondrial respiration through modulation of iron‐sulfur cluster assembly proteins (
ISCU
1/2), a protein that is involved in Fe/S cluster synthesis. However, it is not known how miR‐210 affects cellular iron levels or production of heme, another iron containing molecule that is also needed for cellular and mitochondrial function.

Methods and Results

To screen for micro‐ribonucleic acids (miRNAs) regulated by iron, we performed a mi
RNA
gene array in neonatal rat cardiomyocytes treated with iron chelators. Levels of miR‐210 are significantly increased with iron chelation, however, this response was mediated entirely through the hypoxia‐inducible factor (
HIF
) pathway. Furthermore, miR‐210 reduced cellular heme levels and the activity of mitochondrial and cytosolic heme‐containing proteins by modulating ferrochelatase (
FECH
), the last enzyme in heme biosynthesis. Mutation of the 2 miR‐210 binding sites in the 3′ untranslated region (
UTR
) of
FECH
reversed the miR‐210 response, while mutation of either binding site in isolation did not exert any effects. Changes mediated by miR‐210 in heme and
FECH
were independent of
ISCU
, as overexpression of an
ISCU
construct lacking the 3′
UTR
does not alter miR‐210 regulation of heme and
FECH
. Finally,
FECH
levels increased in hypoxia, and this effect was not reversed by miR‐210 knockdown, suggesting that the effects of miR‐210 on heme are restricted to normoxic conditions, and that the pathway is overriden in hypoxia.

Conclusions

Our results identify a role for miR‐210 in the regulation of heme production by targeting and inhibiting
FECH
under normoxic conditions.
Ross Procedure in Children: 17‐Year Experience at a Single Institution
Authors: Tan Tanny Sharman P. , Yong Matthew S. , d'Udekem Yves , Kowalski Remi , Wheaton Gavin , D'Orsogna Luigi , Galati John C. , Brizard Christian P. , Konstantinov Igor E.
Published: May 2013

Background

The
R
oss procedure in children carries substantial mortality and reoperation rate. Aortic root dilatation is of concern. To prevent dilatation of the neoaortic root, but permit normal growth, we began to apply an absorbable poly‐(
p
‐dioxanone)‐filaments (
PDS
) band at the sino‐tubular (
ST
)‐junction.

Methods and Results

All children (n=100) who underwent
R
oss procedure during 1995–2012 were studied. Mean age at operation was 8.6±6.1 years (median 8.3 years, range 3 days to 18 years); 19 patients were younger than 1 year of age. The root replacement (n=91,
R
oss‐
K
onno procedure in 29 patients), root inclusion (n=6), and subcoronary implantation (n=3) techniques were used. Operative mortality was 6% (6/100, 4 neonates, 2 infants). Age of <1‐year at time of operation was a risk factor for early death (
P
<0.001). Mean follow‐up time was 7.0±4.8 years (median 7.4 years, range 5 days to 16 years). Late mortality was 4.3% (4/94). Freedom from moderate or greater neoaortic valve insufficiency (
AI
) at 5 and 10 years was 89% and 83%, respectively. Freedom from neoaortic valve reoperation at 5 and 10 years was 96% and 86%, respectively. Aortic dilatation to Z‐score >4 was greatest at the
ST
‐junction (23%, 11/48) compared to the aortic annulus (17%, 11/66) and sinuses (14%, 7/50). Since 2001, a
PDS
band was placed around the
ST
‐junction in 19 patients. Survivors with the
PDS
band had less
AI
(0 versus 20%,
P
=0.043) compared to survivors (n=35) without the
PDS
at 4.1±3 years.

Conclusions

The
R
oss procedure in children can be performed with acceptable results. Children younger than 1 year of age have higher mortality, but not an increased autograft reoperation rate. Stabilization of the
ST
‐junction may reduce
AI
.
Magnetic Resonance Imaging Profile of Blood–Brain Barrier Injury in Patients With Acute Intracerebral Hemorrhage
Authors: Aksoy Didem , Bammer Roland , Mlynash Michael , Venkatasubramanian Chitra , Eyngorn Irina , Snider Ryan W. , Gupta Sandeep N. , Narayana Rashmi , Fischbein Nancy , Wijman Christine A. C.
Published: May 2013

Background

Spontaneous intracerebral hemorrhage (
ICH
) is associated with blood–brain barrier (
BBB
) injury, which is a poorly understood factor in
ICH
pathogenesis, potentially contributing to edema formation and perihematomal tissue injury. We aimed to assess and quantify
BBB
permeability following human spontaneous
ICH
using dynamic contrast‐enhanced magnetic resonance imaging (
DCE MRI
). We also investigated whether hematoma size or location affected the amount of
BBB
leakage.

Methods and Results

Twenty‐five prospectively enrolled patients from the Diagnostic Accuracy of
MRI
in Spontaneous intracerebral Hemorrhage (
DASH
) study were examined using
DCE MRI
at 1 week after symptom onset. Contrast agent dynamics in the brain tissue and general tracer kinetic modeling were used to estimate the forward leakage rate (K
trans
) in regions of interest (
ROI
) in and surrounding the hematoma and in contralateral mirror–image locations (control
ROI
). In all patients
BBB
permeability was significantly increased in the brain tissue immediately adjacent to the hematoma, that is, the hematoma rim, compared to the contralateral mirror
ROI
(
P
<0.0001). Large hematomas (>30 mL) had higher K
trans
values than small hematomas (
P
<0.005). K
trans
values of lobar hemorrhages were significantly higher than the K
trans
values of deep hemorrhages (
P
<0.005), independent of hematoma volume. Higher K
trans
values were associated with larger edema volumes.

Conclusions

BBB
leakage in the brain tissue immediately bordering the hematoma can be measured and quantified by
DCE MRI
in human
ICH
.
BBB
leakage at 1 week is greater in larger hematomas as well as in hematomas in lobar locations and is associated with larger edema volumes.
Coronary Artery Revascularization Evaluation—A Multicenter Registry With Seven Years of Follow‐Up
Authors: Kurlansky Paul , Herbert Morley , Prince Syma , Mack Michael J.
Published: May 2013

Background

Data from randomized clinical trials comparing coronary artery bypass grafting (
CABG
) and percutaneous coronary intervention (
PCI
) may not accurately reflect current clinical practice, in which there is off‐label usage of drug‐eluting stents (
DES
). We undertook a prospective registry of coronary revascularization by
CABG
on‐ and off‐pump and
PCI
with bare‐metal stents (
BMS
s),
DES
s, or percutaneous transluminal coronary angioplasty (
PTCA
) to determine clinical outcomes.

Methods and Results

All patients undergoing isolated coronary revascularization in 8 community‐based hospitals were enrolled. Final follow‐up was obtained after 5 years by patient and/or physician contact and the Social Security Death Index.
ST
‐elevation myocardial infarction and salvage patients were excluded. Five or more years of follow‐up was obtained on 81.5% (3156) of the eligible patients—968
CABG
patients (82.0%) and 2188
PCI
patients (81.3%). Overall follow‐up was 63.5±27.9 months (median
,
79.7 months). The incidence of initial major adverse cardiac events (
MACE
s) at follow‐up for
CABG
versus
PCI
was 29.2% versus 41.8% (
P
<0.001). Analysis of stent subgroups showed more events with
BMS
s (equivalent to
PTCA
alone) compared with
DES
s. All stents had more events than on‐ or off‐pump
CABG
groups. Using propensity score–matched groups, the odds ratio for
CABG
to
PCI
was 0.69 (95% confidence interval [
CI
], 0.56 to 0.85;
P
<0.001) for mortality and 0.58 (95%
CI
, 0.45 to 0.75;
P
<0.001) for any
MACE
.

Conclusions

In the current era of
DES
and off‐pump surgery, in a community hospital setting, comparable patients undergoing coronary revascularization appear to benefit from improved long‐term survival and reduced
MACE
with
CABG
versus
PCI
.
Risk‐Treatment Paradox in the Selection of Transradial Access for Percutaneous Coronary Intervention
Authors: Wimmer Neil J. , Resnic Frederic S. , Mauri Laura , Matheny Michael E. , Piemonte Thomas C. , Pomerantsev Eugene , Ho Kalon K. L. , Robbins Susan L. , Waldman Howard M. , Yeh Robert W.
Published: May 2013

Background

Access site complications contribute to morbidity and mortality during percutaneous coronary intervention (
PCI
). Transradial arterial access significantly lowers the risk of access site complications compared to transfemoral arteriotomy. We sought to develop a prediction model for access site complications in patients undergoing
PCI
with femoral arteriotomy, and assess whether transradial access was selectively used in patients at high risk for complications.

Methods and Results

We analyzed 17 509 patients who underwent
PCI
without circulatory support from 2008 to 2011 at 5 institutions. Transradial arterial access was used in 17.8% of patients. In those who underwent transfemoral access, 177 (1.2%) patients had access site complications. Using preprocedural clinical and demographic data, a prediction model for femoral arteriotomy complications was generated. The variables retained in the model included: elevated age (
P
<0.001), female gender (
P
<0.001), elevated troponin (
P
<0.001), decreased renal function or dialysis (
P
=0.002), emergent
PCI
(
P
=0.01), prior
PCI
(
P
=0.005), diabetes (
P
=0.008), and peripheral artery disease (
P
=0.003). The model showed moderate discrimination (optimism‐adjusted c‐statistic=0.72) and was internally validated via bootstrap resampling. Patients with higher predicted risk of complications via transfemoral access were less likely to receive transradial access (
P
<0.001). Similar results were seen in patients presenting with and without
ST
‐segment myocardial infarction and when adjusting for individual physician operator.

Conclusions

We generated and validated a model for transfemoral access site complications during
PCI
. Paradoxically, patients most likely to develop access site complications from transfemoral access, and therefore benefit from transradial access, were the least likely to receive transradial access.
Smooth Muscle–Selective Inhibition of Nuclear Factor‐κB Attenuates Smooth Muscle Phenotypic Switching and Neointima Formation Following Vascular Injury
Authors: Yoshida Tadashi , Yamashita Maho , Horimai Chihiro , Hayashi Matsuhiko
Published: May 2013

Background

Vascular proliferative diseases such as atherosclerosis are inflammatory disorders involving multiple cell types including macrophages, lymphocytes, endothelial cells, and smooth muscle cells (
SMC
s). Although activation of the nuclear factor‐κB (
NF
‐κB) pathway in vessels has been shown to be critical for the progression of vascular diseases, the cell‐autonomous role of
NF
‐κB within
SMC
s has not been fully understood.

Methods and Results

We generated
SMC
‐selective truncated IκB expressing (
SM
22α‐Cre/IκBΔN) mice, in which
NF
‐κB was inhibited selectively in
SMC
s, and analyzed their phenotype following carotid injury. Results showed that neointima formation was markedly reduced in
SM
22α‐Cre/IκBΔN mice after injury. Although vascular injury induced downregulation of expression of
SMC
differentiation markers and
myocardin
, a potent activator of
SMC
differentiation markers, repression of these markers and
myocardin
was attenuated in
SM
22α‐Cre/IκBΔN mice. Consistent with these findings,
NF
‐κB activation by interleukin‐1β (
IL
‐1β) decreased expression of
SMC
differentiation markers as well as
myocardin
in cultured
SMC
s. Inhibition of
NF
‐κB signaling by
BAY
11‐7082 attenuated repressive effects of
IL
‐1β. Of interest, Krüppel‐like factor 4 (Klf4), a transcription factor critical for regulating
SMC
differentiation and proliferation, was also involved in
IL
‐1β‐mediated
myocardin
repression. Promoter analyses and chromatin immunoprecipitation assays revealed that
NF
‐κB repressed
myocardin
by binding to the
myocardin
promoter region in concert with Klf4.

Conclusions

These results provide novel evidence that activation of the
NF
‐κB pathway cell‐autonomously mediates
SMC
phenotypic switching and contributes to neointima formation following vascular injury.
Ambient Fine Particulate Matter Alters Cerebral Hemodynamics in the Elderly
Authors: Wellenius Gregory A. , Boyle Luke D. , Wilker Elissa H. , Sorond Farzaneh A. , Coull Brent A. , Koutrakis Petros , Mittleman Murray A. , Lipsitz Lewis A.
Published: May 2013

Background and Purpose—

Short-term elevations in fine particulate matter air pollution (PM
2.5
) are associated with increased risk of acute cerebrovascular events. Evidence from the peripheral circulation suggests that vascular dysfunction may be a central mechanism. However, the effects of PM
2.5
on cerebrovascular function and hemodynamics are unknown.

Methods—

We used transcranial Doppler ultrasound to measure beat-to-beat blood flow velocity in the middle cerebral artery at rest and in response to changes in end-tidal CO
2
(cerebral vasoreactivity) and arterial blood pressure (cerebral autoregulation) in 482 participants from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. We used linear mixed effects models with random subject intercepts to evaluate the association between cerebrovascular hemodynamic parameters and mean PM
2.5
levels 1 to 28 days earlier adjusting for age, race, medical history, meteorologic covariates, day of week, temporal trends, and season.

Results—

An interquartile range increase (3.0 µg/m
3
) in mean PM
2.5
levels during the previous 28 days was associated with an 8.6% (95% confidence interval, 3.7%–13.8%;
P
<0.001) higher cerebral vascular resistance and a 7.5% (95% confidence interval, 4.2%–10.6%;
P
<0.001) lower blood flow velocity at rest. Measures of cerebral vasoreactivity and autoregulation were not associated with PM
2.5
levels.

Conclusions—

In this cohort of community-dwelling seniors, exposure to PM
2.5
was associated with higher resting cerebrovascular resistance and lower cerebral blood flow velocity. If replicated, these findings suggest that alterations in cerebrovascular hemodynamics may underlie the increased risk of particle-related acute cerebrovascular events.
Systolic Blood Pressure After Intravenous Antihypertensive Treatment and Clinical Outcomes in Hyperacute Intracerebral Hemorrhage
Authors: Sakamoto Yuki , Koga Masatoshi , Yamagami Hiroshi , Okuda Satoshi , Okada Yasushi , Kimura Kazumi , Shiokawa Yoshiaki , Nakagawara Jyoji , Furui Eisuke , Hasegawa Yasuhiro , Kario Kazuomi , Arihiro Shoji , Sato Shoichiro , Kobayashi Junpei , Tanaka Eijirou , Nagatsuka Kazuyuki , Minematsu Kazuo , Toyoda Kazunori
Published: May 2013

Background and Purpose—

Blood pressure (BP) lowering is often conducted as part of general acute management in patients with acute intracerebral hemorrhage. However, the relationship between BP after antihypertensive therapy and clinical outcomes is not fully known.

Methods—

Hyperacute (<3 hours from onset) intracerebral hemorrhage patients with initial systolic BP (SBP) >180 mm Hg were included. All patients received intravenous antihypertensive treatment, based on predefined protocol to lower and maintain SBP between 120 and 160 mm Hg. BPs were measured every 15 minutes during the initial 2 hours and every 60 minutes in the next 22 hours (a total of 30 measurements). The mean achieved SBP was defined as the mean of 30 SBPs, and associations between the mean achieved SBP and neurological deterioration (≥2 points’ decrease in Glasgow Coma Score or ≥4 points’ increase in National Institutes of Health Stroke Scale score), hematoma expansion (>33% increase), and unfavorable outcome (modified Rankin Scale score 4–6 at 3 months) were assessed with multivariate logistic regression analyses.

Results—

Of the 211 patients (81 women, median age 65 [interquartile range, 58–74] years, and median initial National Institutes of Health Stroke Scale score 13 [8–17]) enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, mean achieved SBP was independently associated with neurological deterioration (odds ratio, 4.45; 95% confidence interval, 2.03–9.74 per 10 mm Hg increment), hematoma expansion (1.86; 1.09–3.16), and unfavorable outcome (2.03; 1.24–3.33) after adjusting for known predictive factors.

Conclusions—

High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.
Profiles of the National Institutes of Health Stroke Scale Items as a Predictor of Patient Outcome
Authors: Sucharew Heidi , Khoury Jane , Moomaw Charles J. , Alwell Kathleen , Kissela Brett M. , Belagaje Samir , Adeoye Opeolu , Khatri Pooja , Woo Daniel , Flaherty Matthew L. , Ferioli Simona , Heitsch Laura , Broderick Joseph P. , Kleindorfer Dawn
Published: May 2013

Background and Purpose—

Initial National Institutes of Health Stroke Scale (NIHSS) score is highly predictive of outcome after ischemic stroke. We examined whether grouping strokes by presence of individual NIHSS symptoms could provide prognostic information additional or alternative to the NIHSS total score.

Methods—

Ischemic strokes from the Greater Cincinnati Northern Kentucky Stroke Study in 2005 were used to develop the model. Latent class analysis was implemented to form groups of patients with similar retrospective NIHSS (rNIHSS) item responses. Profile group was then used as an independent predictor of discharge modified Rankin and mortality, using logistic regression and Cox proportional hazards model.

Results—

A total of 2112 stroke patients were identified in 2005. Six distinct profiles were characterized. Consistent with the profile patterns, the median rNIHSS total score decreased from profile A “most severe” (median [interquartile range], 20 [15–25]) to profile F “mild” (1[1–2]). Two profiles falling between these extremes, C and D, both had median rNIHSS total score of 5, but different survival rates. Compared with A, C was associated with 59% risk reduction for death, whereas D with 70%. C patients were more likely to have decreased level of consciousness and abnormal language, whereas D patients were more likely to have abnormal right arm and right leg motor function.

Conclusions—

Six rNIHSS profiles were identifiable using latent class analysis. In particular, 2 symptom profiles with identical median rNIHSSS were observed with widely disparate outcomes, which may prove useful both clinically and for research studies as an enhancement to the overall NIHSS score.
Cholesterol Levels and Risk of Hemorrhagic Stroke
Authors: Wang Xiang , Dong Yan , Qi Xiangqian , Huang Chengguang , Hou Lijun
Published: May 2013

Background and Purpose—

Cholesterol levels are inconsistently associated with the risk of hemorrhagic stroke. The purpose of this study is to assess their relationships using a meta-analytic approach.

Methods—

We searched PubMed and Embase for pertinent articles published in English. Only prospective studies that reported effect estimates with 95% confidential intervals (CIs) of hemorrhagic stroke for ≥3 categories of cholesterol levels, for high and low comparison, or for per 1 mmol/L increment of cholesterol concentrations were included. We used the random-effects model to pool the study-specific results.

Results—

Twenty-three prospective studies were included, totaling 1 430 141 participants with 7960 (5.6%) hemorrhagic strokes. In high versus low analysis, the summary relative risk of hemorrhagic stroke was 0.69 (95% CI, 0.59–0.81) for total cholesterol, 0.98 (95% CI, 0.80–1.19) for high-density lipoprotein cholesterol, and 0.62 (95% CI, 0.41–0.92) for low-density lipoprotein cholesterol. In dose–response analysis, the summary relative risk of hemorrhagic stroke for 1 mmol/L increment of total cholesterol was 0.85 (95% CI, 0.80–0.91), for high-density lipoprotein cholesterol was 1.11 (95% CI, 0.99–1.25), and for low-density lipoprotein cholesterol was 0.90 (95% CI, 0.77–1.05). The pooled relative risk for intracerebral hemorrhage was 1.17 (95% CI, 1.02–1.35) for high-density lipoprotein cholesterol.

Conclusions—

Total cholesterol level is inversely associated with risk of hemorrhagic stroke. Higher level of low-density lipoprotein cholesterol seems to be associated with lower risk of hemorrhagic stroke. High-density lipoprotein cholesterol level seems to be positively associated with risk of intracerebral hemorrhage.
Policy Makers and Researchers Schooling Each Other: Lessons in Educational Policy from New York
Authors: Cunningham Deborah H. , Wyckoff Jim
Published: May 2013

Policy makers and researchers are intrigued with but also frequently frustrated by each other. Although these differences are understandable and predictable, it is clear that research on a variety of educational issues has been both influential and valuable in the development of policy and practice. There is much to suggest that researchers and policy makers should be collaborating to improve student outcomes. There are important instances of sustained collaborations between educational researchers and educational policy makers. We summarize some of these efforts but describe in more detail the Education Finance Research Consortium, a long-standing collaboration between university-based researchers and the New York State Education Department. Given the current intense focus on the role of evidence in the development of education policy, some of the lessons from this collaboration may be useful to those seeking to expand the use of evidence in policies intended to improve student learning.
The Problem with Briefs, in Brief
Authors: Conaway Carrie L.
Published: May 2013

Policy briefs written by academics—the kind typically published in Education Finance and Policy—should be a crucial source of information for policy makers. Yet too frequently these briefs fail to garner the consideration they deserve. Their authors are too focused on the potential objections of their fellow academics, who are concerned with rigor and internal validity, instead of the objections of policy makers, who are concerned with generalizability, understandability, and utility. And researchers too often believe that simply publishing a brief is sufficient to communicate its results. By focusing briefs on topics on the policy agenda, helping policy makers see their constituents in the results, writing clearly, studying implementation and not just outcomes, weighing evidence and drawing conclusions, and reaching out to policy makers beyond publication, researchers have the greatest potential to see their work influence public policy.
Multi-Track Year-Round Schooling as Cost Saving Reform: Not Just a Matter of Time
Authors: Graves Jennifer , McMullen Steven , Rouse Kathryn
Published: May 2013

In the face of school crowding and fears about inequality-inducing summer learning loss, many schools have started to adopt multi-track year-round school calendars, which keep the same number of school days, but spread them more evenly across the calendar year. This change allows schools to support a larger student population by rotating which students are on break at any point in time. While year-round schooling can save money, the impact on academic achievement is uncertain and only recently have large-scale studies become available for policy makers. This brief examines research on the effects of multi-track year-round schooling, focusing on two rigorously executed case studies. This research gives little support for claims that year-round schooling will boost student achievement. Except as a remedy for highly over-crowded schools, year-round schooling seems to have little impact on achievement, and has even been shown to decrease achievement, especially among the most high-risk student populations.
Learning from Experience? Evidence on the Impact and Distribution of Teacher Experience and the Implications for Teacher Policy
Authors: Rice Jennifer King
Published: May 2013

Teacher experience has long been a central pillar of teacher workforce policies in U.S. school systems. The underlying assumption behind many of these policies is that experience promotes effectiveness, but is this really the case? What does existing evidence tell us about how, why, and for whom teacher experience matters? This policy brief distills the research on teacher experience into four general findings: (1) the effect of experience is most evident during the first few years of teaching; (2) the early-career experience effect varies by level of education and subject area; (3) inexperienced teachers are most likely to teach in high-poverty schools; and (4) the impact of experience differs for teachers in high- versus low-poverty schools. The brief concludes by discussing the implications of these findings for several key policy measures including teacher compensation, support and professional development, and the unequal distribution of teachers across schools.
Financial Aid's Role in Meeting State College Completion Goals
Authors: Hillman Nicholas W. , Orians Erica Lee
Published: May 2013

This brief utilizes the most recent and rigorous financial aid research to inform state higher education leaders about innovative and effective financial aid practices. By simplifying aid eligibility requirements, improving the aid application process, and engaging in early awareness efforts, states could improve the effectiveness of existing aid programs. Additionally, by targeting aid in ways that encourage college completion, more students (particularly those who are most constrained by finances) will improve their chances of earning postsecondary degrees. In recent years, several states have adopted goals of greatly increasing educational attainment levels, so we argue that innovative financial aid policy reform is one of the necessary steps toward meeting these goals. This brief can inform ongoing policy negotiations between state commissioners of higher education, state education task forces, and education and workforce legislative committees.
The Role of Politics and Governance in Educational Accountability Systems
Authors: Brewer Dominic J. , Killeen Kieran M. , Welsh Richard O.
Published: May 2013

This brief utilizes case study methodology to illustrate the role of governance in educational accountability systems. Most research on the effectiveness of such systems has focused on technical components, such as standards-setting, assessments, rewards and sanctions, and data collection and reporting. This brief seeks to demonstrate that this focus may miss the importance of the institutional set-up. We argue that effective accountability systems are largely dependent on associated government structures, rules, and procedures, and the individuals responsible for implementing them. We use an illustrative case from the state of Oklahoma, where a lack of independent oversight, few checks and balances, and little in-state technical capacity combine to call into question the effectiveness of this state's accountability system. We urge researchers and policy makers to focus more attention on the “messy” governance and politics of educational accountability, and conclude the brief with specific policy proposals to strengthen state education accountability systems.
Leisure and Entertainment (malāhī) in Contemporary Islamic Legal Thought: Music and the Audio-Visual Media
Authors: Al-Atawneh Muhammad
Published: May 2013

The status of leisure and entertainment (hereafter: malāhī) is an age-old issue that emerged during the very early stages of Islam and is still being debated today. Generations of Muslim scholars and jurists have attempted to identify and delineate the permissible and the forbidden in this regard to accommodate the socio-cultural contexts of their respective societies. This article examines contemporary Islamic discourse on entertainment, particularly music and audio-visual media, e.g., television, Internet, cinema and theater. How do contemporary Muslim scholars define and relate to malāhī? What is the nature and characteristics of legitimate entertainment and leisuretime activities from the Islamic religio-legal perspective? I suggest that modern-day Muslim scholars, like their predecessors, never came to an agreement on the nature and scope of malāhī. These scholars merely acknowledge that different ethico-legal boundaries are applied to malāhī in contemporary Muslim societies.
Human Capabilities and Economic Development:The Extreme Outlier Societies
Authors: Marsh Robert M.
Published: May 2013

Abstract

One of the problems Amartya Sen raised in his capabilities approach was: why do people in some societies realize a much lower level of various kinds of human capabilities than would be expected on the basis of their GDP per capita, while other societies do better than expected? This paper focuses on six capabilities and functionings: life expectancy, schooling, living in a society with less income inequality and less gender inequality, political freedom and life satisfaction. Empirically I start with data on 156 societies and use regression analysis and case diagnostics to identify societies that are extreme outliers. These are identified as Singapore, Saudi Arabia and South Africa, each of which does significantly worse than expected (given their relatively high level of economic development) on two or more of the six capabilities. I then use qualitative analysis to specify, through “process-tracing”, the causal mechanisms that explain why these particular societies are so “unbalanced” in the relationship between their economic development and their human capabilities.
Physiological stress hormone levels and mating behaviour are negatively correlated in male rhesus macaques (Macaca mulatta)
Authors: McFarland Richard , MacLarnon Ann , Heistermann Michael , Semple Stuart
Published: May 2013

In order to understand the factors that cause and mediate stress in social animals, many studies have examined differences in male physiological stress levels between mating and non-mating seasons, and related these differences to levels of male-male competition. Very few have explicitly tested whether variation in stress levels is related to mating behaviour itself. We provide preliminary evidence of a negative relationship between faecal levels of glucocorticoid metabolites and mounting frequency in free-ranging male rhesus macaques (Macaca mulatta). This finding may help explain the previous observation that male rhesus macaques show no difference in their levels of faecal glucocortocoids between the breeding and non-breeding season, despite the former being associated with elevated levels of aggression. Our study highlights the importance of directly quantifying mating behaviour when investigating the potential impact of reproductive competition and seasonality on stress physiology.