bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammatory Biomarkers, Death, and Recurrent Nonfatal Coronary Events After an Acute Coronary Syndrome in the MIRACL Study
Authors: Zamani Payman , Schwartz Gregory G. , Olsson Anders G. , Rifai Nader , Bao Weihang , Libby Peter , Ganz Peter , Kinlay Scott ,   for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators
Published: May 2013

Background

In acute coronary syndromes,
C
‐reactive protein (
CRP
) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome.

Methods and Results

We measured blood concentrations of
CRP
, serum amyloid
A
(
SAA
), interleukin‐6 (
IL
‐6), soluble intercellular adhesion molecule (
ICAM
), soluble vascular cell adhesion molecule (
VCAM
),
E
‐selectin,
P
‐selectin, and tissue plasminogen activator antigen (
tPA
) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using
C
ox proportional hazard models. On univariate analyses, baseline
CRP
(
P
=0.006), SAA (
P
=0.012), and IL‐6 (
P
<0.001) were related to death, but not to recurrent nonfatal acute coronary syndromes.
VCAM
and
tPA
related to the risk of death (
P
<0.001,
P
=0.021, respectively) and to nonfatal acute coronary syndromes (
P
=0.021,
P
=0.049, respectively). Adjusting for significant covariates reduced the strength of the associations; however,
CRP
and
SAA
continued to relate to death.

Conclusions

In acute coronary syndromes, the
CRP
inflammatory axis relates to the risk of death and may reflect myocardial injury.
VCAM
and
tPA
may have greater specificity for processes reflecting inflammation and thrombosis in the epicardial arteries, which determine recurrent coronary events.
Dynamic TIMI Risk Score for STEMI
Authors: Amin Sameer T. , Morrow David A. , Braunwald Eugene , Sloan Sarah , Contant Charles , Murphy Sabina , Antman Elliott M. 
Published: May 2013

Background

Although there are multiple methods of risk stratification for
ST
‐elevation myocardial infarction (
STEMI
), this study presents a prospectively validated method for reclassification of patients based on in‐hospital events. A dynamic risk score provides an initial risk stratification and reassessment at discharge.

Methods and Results

The dynamic
TIMI
risk score for
STEMI
was derived in ExTRACT‐
TIMI
25 and validated in
TRITON
‐
TIMI
38. Baseline variables were from the original
TIMI
risk score for
STEMI
. New variables were major clinical events occurring during the index hospitalization. Each variable was tested individually in a univariate
C
ox proportional hazards regression. Variables with
P
<0.05 were incorporated into a full multivariable
C
ox model to assess the risk of death at 1 year. Each variable was assigned an integer value based on the odds ratio, and the final score was the sum of these values. The dynamic score included the development of in‐hospital
MI
, arrhythmia, major bleed, stroke, congestive heart failure, recurrent ischemia, and renal failure. The
C
‐statistic produced by the dynamic score in the derivation database was 0.76, with a net reclassification improvement (
NRI
) of 0.33 (
P
<0.0001) from the inclusion of dynamic events to the original
TIMI
risk score. In the validation database, the
C
‐statistic was 0.81, with a
NRI
of 0.35 (
P
=0.01).

Conclusions

This score is a prospectively derived, validated means of estimating 1‐year mortality of
STEMI
at hospital discharge and can serve as a clinically useful tool. By incorporating events during the index hospitalization, it can better define risk and help to guide treatment decisions.
Low Body Mass Index but Not Obesity Is Associated With In‐Hospital Adverse Events and Mortality Among Implantable Cardioverter‐Defibrillator Recipients: Insights From the National Cardiovascular Data Registry
Authors: Hsu Jonathan C. , Varosy Paul D. , Bao Haikun , Wang Yongfei , Curtis Jeptha P. , Marcus Gregory M. 
Published: May 2013

Background

Implantable cardioverter‐defibrillators (
ICD
s) are placed in patients at risk for sudden cardiac death, but the procedure may cause adverse events. Patient body habitus may be an important factor responsible for
ICD
implantation complications. We assessed whether underweight or obese compared with normal weight patients, as defined by body mass index (
BMI
), were at increased risk for adverse events from
ICD
implantation.

Methods and Results

We studied 83 312 first‐time
ICD
recipients in the
N
ational
C
ardiovascular
D
ata
R
egistry‐
ICD
Registry implanted between April 2010 and June 2011. Using hierarchical multivariable logistic regression adjusted for patient demographic and clinical characteristics, we examined the association of
BMI
with in‐hospital complications, length of hospital stay, and mortality. Underweight (
BMI
≤18.5 kg/m
2
) patients comprised 1.7% of the cohort (n=1434), whereas obese (
BMI
≥30 kg/m
2
) patients comprised 40.1% (n=33 339). Overall, a higher proportion of underweight patients experienced complications (normal weight, 2.3%; obese, 2.1%; underweight 5.2%;
P
<0.0001) and death (normal weight, 0.3%; obese, 0.3%; underweight 0.8%;
P
=0.026) as a result of
ICD
implantation. After multivariable adjustment, underweight
ICD
recipients had a greater odds of complications (odds ratio [
OR
], 2.15; 95% confidence interval [
CI
], 1.68 to 2.75;
P
<0.0001), hospital stay >3 days (
OR
, 1.62; 95%
CI
, 1.38 to 1.89;
P
<0.0001), and in‐hospital death (
OR
, 2.27; 95%
CI
, 1.21 to 4.27;
P
=0.011) compared with normal weight patients. Obese patients did not exhibit any meaningful differences in the same outcomes.

Conclusions

In a large, real‐world population, underweight first‐time
ICD
recipients experienced significantly more periprocedural complications, prolonged hospital stays, and in‐hospital death compared with normal weight patients.
Bone Morphogenetic Protein‐2 Decreases MicroRNA‐30b and MicroRNA‐30c to Promote Vascular Smooth Muscle Cell Calcification
Authors: Balderman Joshua A. F. , Lee Hae‐Young , Mahoney Christopher E. , Handy Diane E. , White Kevin , Annis Sofia , Lebeche Djamel , Hajjar Roger J. , Loscalzo Joseph , Leopold Jane A. 
Published: May 2013

Background

Vascular calcification resembles bone formation and involves vascular smooth muscle cell (
SMC
) transition to an osteoblast‐like phenotype to express

Runx2

, a master osteoblast transcription factor. One possible mechanism by which

Runx2

protein expression is induced is downregulation of inhibitory micro
RNA
s (mi
R
).

Methods and Results

Human coronary artery
SMCs
(
CASMCs
) treated with bone morphogenetic protein‐2 (
BMP
‐2; 100 ng/mL) demonstrated a 1.7‐fold (
P
<0.02) increase in

Runx2

protein expression at 24 hours. A mi
R
microarray and target prediction database analysis independently identified mi
R
‐30b and mi
R
‐30c (mi
R
‐30b‐c) as mi
R
s that regulate

Runx2

expression. Real‐time–polymerase chain reaction confirmed that
BMP
‐2 decreased mi
R
‐30b and mi
R
‐30c expression. A luciferase reporter assay verified that both mi
R
‐30b and mi
R
‐30c bind to the 3′‐untranslated region of
R
unx2 m
RNA
to regulate its expression.
CASMCs
transfected with antagomirs to downregulate mi
R
‐30b‐c demonstrated significantly increased
R
unx2, intracellular calcium deposition, and mineralization. Conversely, forced expression of mi
R
‐30b‐c by transfection with pre–mi
R
‐30b‐c prevented the increase in

Runx2

expression and mineralization of
SMCs
. Calcified human coronary arteries demonstrated higher levels of
BMP
‐2 and lower levels of mi
R
‐30b than did noncalcified donor coronary arteries.

Conclusions

BMP
‐2 downregulates mi
R
‐30b and mi
R
‐30c to increase

Runx2

expression in
CASMCs
and promote mineralization. Strategies that modulate expression of mi
R
‐30b and mi
R
‐30c may influence vascular calcification.
Altered Nitric Oxide Bioavailability Contributes to Diesel Exhaust Inhalation‐Induced Cardiovascular Dysfunction in Man
Authors: Langrish Jeremy P. , Unosson Jon , Bosson Jenny , Barath Stefan , Muala Ala , Blackwell Scott , Söderberg Stefan , Pourazar Jamshid , Megson Ian L. , Treweeke Andrew , Sandström Thomas , Newby David E. , Blomberg Anders , Mills Nicholas L. 
Published: May 2013

Background

Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric oxide (
NO
) bioavailability in mediating these effects.

Methods and Results

In 2 randomized double‐blind crossover studies, healthy nonsmokers were exposed to diesel exhaust or filtered air.
Study 1
: Bilateral forearm blood flow was measured during intrabrachial infusions of acetylcholine (
AC
h; 5 to 20 μg/min) and sodium nitroprusside (
SNP
; 2 to 8 μg/min) in the presence of the
NO
clamp (
NO
synthase inhibitor

N
G

‐monomethyl‐
l
‐arginine (
l
‐
NMMA
) 8 μg/min coinfused with the
NO
donor
SNP
at 90 to 540 ng/min to restore basal blood flow).
Study 2
: Blood pressure, arterial stiffness, and cardiac output were measured during systemic
NO
synthase inhibition with intravenous
l
‐
NMMA
(3 mg/kg). Following diesel exhaust inhalation, plasma nitrite concentrations were increased (68±48 versus 41±32 nmol/L;
P
=0.006) despite similar
l
‐
NMMA
–induced reductions in basal blood flow (−20.6±14.7% versus −21.1±14.6%;
P
=0.559) compared to air. In the presence of the
NO
clamp,
AC
h and
SNP
caused dose‐dependent vasodilatation that was not affected by diesel exhaust inhalation (
P
>0.05 for both). Following exposure to diesel exhaust,
l
‐
NMMA
caused a greater increase in blood pressure (
P
=0.048) and central arterial stiffness (
P
=0.007), but reductions in cardiac output and increases in systemic vascular resistance (
P
>0.05 for both) were similar to those seen with filtered air.

Conclusions

Diesel exhaust inhalation disturbs normal vascular homeostasis with enhanced
NO
generation unable to compensate for excess consumption. We suggest the adverse cardiovascular effects of air pollution are, in part, mediated through reduced
NO
bioavailability.

Clinical Trial Registration

URL
:
http://www.ClinicalTrials.gov
. Unique identifiers:
NCT
00845767 and
NCT
01060930.
A Risk Score for In‐Hospital Death in Patients Admitted With Ischemic or Hemorrhagic Stroke
Authors: Smith Eric E. , Shobha Nandavar , Dai David , Olson DaiWai M. , Reeves Mathew J. , Saver Jeffrey L. , Hernandez Adrian F. , Peterson Eric D. , Fonarow Gregg C. , Schwamm Lee H. 
Published: May 2013

Background

We aimed to derive and validate a single risk score for predicting death from ischemic stroke (
IS
), intracerebral hemorrhage (
ICH
), and subarachnoid hemorrhage (
SAH
).

Methods and Results

Data from 333 865 stroke patients (
IS
, 82.4%;
ICH
, 11.2%;
SAH
, 2.6%; uncertain type, 3.8%) in the
G
et
W
ith
T
he
G
uidelines—
S
troke database were used. In‐hospital mortality varied greatly according to stroke type (
IS
, 5.5%;
ICH
, 27.2%;
SAH
, 25.1%; unknown type, 6.0%;
P
<0.001). The patients were randomly divided into derivation (60%) and validation (40%) samples. Logistic regression was used to determine the independent predictors of mortality and to assign point scores for a prediction model in the overall population and in the subset with the National Institutes of Health Stroke Scale (
NIHSS
) recorded (37.1%). The c statistic, a measure of how well the models discriminate the risk of death, was 0.78 in the overall validation sample and 0.86 in the model including
NIHSS
. The model with
NIHSS
performed nearly as well in each stroke type as in the overall model including all types (c statistics for
IS
alone, 0.85; for
ICH
alone, 0.83; for
SAH
alone, 0.83; uncertain type alone, 0.86). The calibration of the model was excellent, as demonstrated by plots of observed versus predicted mortality.

Conclusions

A single prediction score for all stroke types can be used to predict risk of in‐hospital death following stroke admission. Incorporation of
NIHSS
information substantially improves this predictive accuracy.
Genetic‐Genomic Replication to Identify Candidate Mouse Atherosclerosis Modifier Genes
Authors: Hsu Jeffrey , Smith Jonathan D. 
Published: May 2013

Objective
Genetics plays a large role in atherosclerosis susceptibility in humans and mice. We attempted to confirm previously determined mouse atherosclerosis‐associated loci and use bioinformatics and transcriptomics to create a catalog of candidate atherosclerosis modifier genes at these loci.

Methods and Results

A strain intercross was performed between
AKR
and
DBA
/2 mice on the apoE
−/−
background generating 166 F
2
progeny. Using the phenotype log10 of the aortic root lesion area, we identified 3 suggestive atherosclerosis quantitative trait loci (Ath
QTL
s). When combined with our prior strain intercross, we confirmed 3 significant Ath
QTL
s on chromosomes 2, 15, and 17, with combined logarithm of odds scores of 5.9, 5.3, and 5.6, respectively, which each met the genome‐wide 5% false discovery rate threshold. We identified all of the protein coding differences between these 2 mouse strains within the Ath
QTL
intervals. Microarray gene expression profiling was performed on macrophages and endothelial cells from this intercross to identify expression
QTL
s (
eQTLs
), the loci that are associated with variation in the expression levels of specific transcripts. Cross tissue
eQTL
s and macrophage
eQTL
s that replicated from a prior strain intercross were identified. These bioinformatic and
eQTL
analyses produced a comprehensive list of candidate genes that may be responsible for the Ath
QTL
s.

Conclusions

Replication studies for clinical traits as well as gene expression traits are worthwhile in identifying true versus false genetic associations. We have replicated 3 loci on mouse chromosomes 2, 15, and 17 that are associated with atherosclerosis. We have also identified protein coding differences and multiple replicated
eQTL
s, which may be useful in the identification of atherosclerosis modifier genes.
Genetic Deletion of NP1 Prevents Hypoxic‐Ischemic Neuronal Death Via Reducing AMPA Receptor Synaptic Localization in Hippocampal Neurons
Authors: Rahim Md Al , Hossain Mir Ahamed 
Published: May 2013

Background

Trafficking of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors (
AMPARs
) to excitatory synapses is critical to their synaptic functions. Previously, we have shown induction of neuronal pentraxin 1 (
NP
1) and its colocalization with
AMPAR
subunit GluR1 in hypoxic‐ischemic (
HI
) brain injury. However, the role of
NP
1 in mediating GluR1 surface expression, trafficking, and clustering at synapses in
HI
neuronal death is unclear.

Methods and Results

Primary hippocampal neurons, isolated from wild‐type (
WT
) and
NP
1‐knockout (C57BL/6 background) mice at
DIV
12 to 14 were exposed to 2 to 8 hours of oxygen glucose deprivation (
OGD
)—in vitro conditions that mimic human stroke.
OGD
exposure resulted in time‐dependent induction of
NP
1 (∼4‐fold), enhanced redistribution of
AMAP
GluR1 receptors at excitatory synapses, and increased neuronal death. We observed a significant increase in surface and synaptic GluR1 clusters that colocalized with
PSD
‐95 on dendrites with a simultaneous decrease in internalized GluR1. Surface cross‐linking with
BS
3
showed enhanced membrane insertions of GluR1, and increased phosphorylation at Ser‐845 further supported enhanced surface availability of GluR1 after
OGD
.
NP
1 protein colocalized with GluR1 and
PSD
‐95, and
OGD
significantly increased their synaptic coclustering. Most strikingly, the genetic deletion of
NP
1 resulted in decreases in surface GluR1 cluster density, synaptic localization, phospho‐GluR1 (Ser‐845) levels, and neuronal death after
OGD
compared with
WT
neurons.
AMPA
(50 μmol/L) induced
NP
1 and significant cell death in
WT
but not in
NP
1−/− neurons.

Conclusions

Our results indicate that
NP
1 plays a key role in synaptic clustering of GluR1, suggesting that targeting
NP
1 might be a practical approach to preventing ischemic brain damage.
P2Y
12
Receptor Blockade Augments Glycoprotein IIb‐IIIa Antagonist Inhibition of Platelet Activation, Aggregation, and Procoagulant Activity
Authors: Berny‐Lang Michelle A. , Jakubowski Joseph A. , Sugidachi Atsuhiro , Barnard Marc R. , Michelson Alan D. , Frelinger Andrew L. 
Published: May 2013

Background

New antiplatelet agents that provide greater, more consistent inhibition of the platelet
ADP
receptor P2Y
12
may be used in combination with glycoprotein (
GP
)
II
b‐
III
a antagonists, but their combined effect on platelet function and procoagulant activity is not well studied. Therefore, the objective of this study was to evaluate the independent and complementary effects of P2Y
12
and
GPII
b‐
III
a inhibition on platelet function and procoagulant activity.

Methods and Results
Healthy donor blood was treated with the active metabolite of prasugrel (R‐138727 5 μmol/L), GPIIb‐IIIa antagonists (abciximab 3 μg/mL or eptifibatide 0.9 μg/mL), and combinations thereof, exposed to physiologically relevant agonists (collagen and ADP) and then evaluated for markers of platelet activation and procoagulant activity. Significant interactions between R‐138727 and GPIIb‐IIIa antagonists were observed. R‐138727 and the GPIIb‐IIIa antagonists had additive inhibitory effects on collagen‐stimulated platelet aggregation and on the collagen plus ADP–stimulated level of activated platelet surface GPIIb‐IIIa. R‐138727 and abciximab each inhibited collagen plus ADP–stimulated platelet phosphatidylserine expression and prothrombin cleavage, and the combination produced greater inhibition than achieved with abciximab alone. In contrast, eptifibatide did not inhibit, but instead enhanced, collagen plus ADP–stimulated prothrombin cleavage. Addition of R‐138727 reduced prothrombin cleavage in eptifibatide‐treated samples, suggesting a novel mechanism for potential benefit from combined prasugrel and eptifibatide treatment.

Conclusions
The complementary effects of abciximab and R‐138727 on platelet activation, aggregation, and procoagulant activity suggest their combined use may, to a greater degree than with either agent alone, reduce thrombus formation in vivo.
Psoriasis and Major Adverse Cardiovascular Events: A Systematic Review and Meta‐Analysis of Observational Studies
Authors: Armstrong Ehrin J. , Harskamp Caitlin T. , Armstrong April W. 
Published: May 2013

Background
Psoriasis is a chronic inflammatory disease that may be associated with increased risk of cardiovascular events, including cardiovascular mortality, myocardial infarction, and stroke.

Methods and Results

We searched the
MEDLINE
,
EMBASE
, and
C
ochrane
C
entral
R
egister databases for relevant studies in English between January 1, 1980, and January 1, 2012. Extraction was by 3 independent reviewers. Summary incidence, risk ratios (
RR
s), and confidence intervals (
CI
s) were calculated using fixed‐effects and random‐effects modeling. Meta‐regression was also performed to identify sources of between‐study variation. Nine studies were included, representing a total of 201 239 patients with mild and 17 415 patients with severe psoriasis. The level of covariate adjustment varied among studies, leading to the possibility of residual confounding. Using the available adjusted effect sizes, mild psoriasis remained associated with a significantly increased risk of myocardial infarction (
RR
, 1.29; 95%
CI
, 1.02 to 1.63) and stroke (
RR
, 1.12; 95%
CI
, 1.08 to 1.16). Severe psoriasis was associated with a significantly increased risk of cardiovascular mortality (
RR
, 1.39; 95%
CI
, 1.11 to 1.74), myocardial infarction (
RR
, 1.70; 95%
CI
, 1.32 to 2.18), and stroke (
RR
, 1.56 95%
CI
, 1.32 to 1.84). Based on these risk ratios and the background population event rates, psoriasis is associated with an estimated excess of 11 500 (95%
CI
, 1169 to 24 407) major adverse cardiovascular events each year.

Conclusions
Mild and severe psoriasis are associated with an increased risk of myocardial infarction and stroke. Severe psoriasis is also associated with an increased risk of cardiovascular mortality. Future studies should include more complete covariate adjustment and characterization of psoriasis severity.
Genetic Deletion of Uncoupling Protein 3 Exaggerates Apoptotic Cell Death in the Ischemic Heart Leading to Heart Failure
Authors: Perrino Cinzia , Schiattarella Gabriele G. , Sannino Anna , Pironti Gianluigi , Petretta Maria Piera , Cannavo Alessandro , Gargiulo Giuseppe , Ilardi Federica , Magliulo Fabio , Franzone Anna , Carotenuto Giuseppe , Serino Federica , Altobelli Giovanna G. , Cimini Vincenzo , Cuocolo Alberto , Lombardi Assunta , Goglia Fernando , Indolfi Ciro , Trimarco Bruno , Esposito Giovanni 
Published: May 2013

Background
Uncoupling protein 3 (ucp3) is a member of the mitochondrial anion carrier superfamily of proteins uncoupling mitochondrial respiration. In this study, we investigated the effects of ucp3 genetic deletion on mitochondrial function and cell survival under low oxygen conditions in vitro and in vivo.

Methods and Results

To test the effects of
ucp3
deletion in vitro, murine embryonic fibroblasts and adult cardiomyocytes were isolated from wild‐type (
WT
, n=67) and ucp3 knockout mice (ucp3
−/−
, n=70). To test the effects of ucp3 genetic deletion in vivo, myocardial infarction (
MI
) was induced by permanent coronary artery ligation in
WT
and ucp3
−/−
mice. Compared with
WT
, ucp3
−/−
murine embryonic fibroblasts and cardiomyocytes exhibited mitochondrial dysfunction and increased mitochondrial reactive oxygen species generation and apoptotic cell death under hypoxic conditions in vitro (terminal deoxynucleotidyl transferase‐dUTP nick end labeling–positive nuclei:
WT
hypoxia, 70.3±1.2%; ucp3
−/−
hypoxia, 85.3±0.9%;
P
<0.05). After
MI
, despite similar areas at risk in the 2 groups, ucp3
−/−
hearts demonstrated a significantly larger infarct size compared with
WT
(infarct area/area at risk:
WT
, 48.2±3.7%; ucp3
−/−
, 65.0±2.9%;
P
<0.05). Eight weeks after
MI
, cardiac function was significantly decreased in ucp3
−/−
mice compared with
WT
(fractional shortening:
WT MI
, 42.7±3.1%; ucp3
−/−
MI
, 24.4±2.9;
P
<0.05), and this was associated with heightened apoptotic cell death (terminal deoxynucleotidyl transferase‐dUTP nick end labeling–positive nuclei:
WT MI
, 0.7±0.04%; ucp3
−/−
MI
, 1.1±0.09%,
P
<0.05).

Conclusions
Our data indicate that ucp3 levels regulate reactive oxygen species levels and cell survival during hypoxia, modulating infarct size in the ischemic heart.