bluuebunny/crossref_metadata_2025 huggingface dataset:
Paradoxical Air Microembolism Induces Cerebral Bioelectrical Abnormalities and Occasionally Headache in Patent Foramen Ovale Patients With Migraine
Authors: Sevgi Eser Başak , Erdener Sefik Evren , Demirci Mehmet , Topcuoglu Mehmet Akif , Dalkara Turgay
Published: May 2013

Background

Although controversial, paradoxical embolism via patent foramen ovale (
PFO
) may account for some of the migraine attacks in a subset of migraine with aura (
MA
) patients. Induction of
MA
attacks with air bubble injection during transcranial
D
oppler ultrasound in
MA
patients with
PFO
supports this view. It is likely that cerebral embolism in patients with right‐to‐left shunt induces bioelectrical abnormalities to initiate MA under some conditions.

Methods and Results

We investigated changes in cerebral bioelectrical activity after intravenous microbubble injection in 10
MA
patients with large
PFO
and right‐to‐left cardiac shunt. Eight
PFO
patients without migraine but with large right‐to‐left shunt and 12
MA
patients without
PFO
served as controls. Four
MA
patients with
PFO
were reexamined with sham injections of saline without microbubbles. Bioelectrical activity was evaluated using spectral electroencephalography and, passage of microbubbles through cerebral arteries was monitored with transcranial
D
oppler ultrasound. Microbubble embolism caused significant electroencephalographic power increase in
MA
+
PFO
patients but not in control groups including the sham‐injected
MA
+
PFO
patients. Headache developed in 2
MA
with
PFO
patients after microbubble injection.

Conclusions

These findings demonstrate that air microembolism through large
PFO
s may cause cerebral bioelectrical disturbances and, occasionally, headache in
MA
patients, which may reflect an increased reactivity of their brain to transient subclinical hypoxia–ischemia, and suggest that paradoxical embolism is not a common cause of migraine but may induce headache in the presence of a large
PFO
and facilitating conditions.
Ablation for Atrial Fibrillation in Combination With Left Atrial Appendage Closure: First Results of a Feasibility Study
Authors: Swaans Martin J. , Post Martijn C. , Rensing Benno J.W.M. , Boersma Lucas V.A.
Published: May 2013

Background

Drug‐refractory atrial fibrillation (
AF
) increasingly is being treated with catheter ablation. However, the long‐term success rate, expressed as freedom from
AF
, is <50%. Therefore, vitamin K antagonists, with all their complications, remain necessary. Recently, left atrial appendage (
LAA
) occlusion devices were introduced as an alternative to vitamin K antagonists. Here, we investigated whether
AF
ablation and
LAA
occlusion could be a feasible and safe combination in patients with symptomatic drug‐refractory
AF
and a
CHADS
2
score ≥1 or a contraindication for vitamin K antagonists.

Methods and Results

Ablation was performed by using multielectrode catheters with phased radiofrequency energy.
LAA
was occluded with the Watchman device (Atritech, Inc, Plymouth, MN). Between February 2010 and February 2011, 30 patients were treated (21 male; age, 62.8±8.5 years). Median
CHADS
2
score was 2.5 (25th to 75th percentiles: 2 to 3), median
CHADS
‐
VAS
c score was 3 (25th to 75th percentiles: 3 to 5), 77% had prior stroke, and 27% had a contraindication for vitamin K antagonists. Median
HAS
‐
BLED
score was 2 (range, 1 to 5). Successful device implantation was achieved with a median number of 1.5 devices (median diameter 24 mm [25th to 75th percentiles: 24 to 24 mm]). Total procedure time was 97 minutes (25th to 75th percentiles: 75 to 115 minutes). At 60 days, all patients met the criteria for successful sealing. Follow‐up visit at 12 months showed a 30% rate of documented recurrence of
AF
. A repeated pulmonary vein isolation was performed successfully in 4 patients, without interference of the
LAA
closure device. No thromboembolic events occurred during 1‐year follow‐up.

Conclusion

LAA
occlusion with the Watchman device and
AF
ablation can be combined successfully and safely in a single procedure. The Watchman does not interfere with a repeated ablation.
Secreted Wnt Modulators in Symptomatic Aortic Stenosis
Authors: Askevold Erik Tandberg , Gullestad Lars , Aakhus Svend , Ranheim Trine , Tønnessen Theis , Solberg Ole G. , Aukrust Pål , Ueland Thor
Published: May 2013

Background

Valve calcification and inflammation play key roles in the development of aortic stenosis (
AS
). The
W
nt pathways have been linked to inflammation, bone metabolism, angiogenesis, and heart valve formation. We hypothesized that soluble
W
nt modulators may be dysregulated in symptomatic
AS
.

Methods and Results

We measured circulating levels (n=136) and aortic valve tissue expression (n=16) of the secreted
W
nt modulators secreted frizzled related protein‐3, dickkopf‐1 (
DKK‐1
), and
W
nt inhibitory factor‐1 (
WIF‐1
) by enzyme immunoassay, immunostaining, and
RT‐PCR
in patients with symptomatic, severe
AS
and investigated associations with echocardiographic parameters of
AS
and cardiac function. Finally, we assessed the prognostic value of these
W
nt modulators in relation to all‐cause mortality (n=35) during long‐term follow‐up (median 4.6 years; survivors, 4.8 years; nonsurvivors, 1.9 years) in these patients. Our main findings were: (1) serum levels of all
W
nt modulators were markedly elevated in patients with symptomatic
AS
(mean increase 231% to 278%,
P
<0.001), (2) all
W
nt modulators were present in calcified aortic valves but correlated poorly with systemic levels or degree of
AS
, (3) some modulators (ie,
WIF‐1
) were associated with the degree of myocardial function and valvular calcification, (4) all
W
nt modulators, and
DKK‐1
in particular, predicted long‐term mortality in these patients also after adjusting for conventional predictors including
NT
‐pro
BNP
.

Conclusions

Together, these in vivo data support the involvement of
W
nt signaling in the development of
AS
and suggest that circulating
W
nt modulators should be further investigated as risk markers in larger
AS
populations, including patients with asymptomatic disease.
Inhibition of Apoptosis Signal–Regulating Kinase 1 Reduces Myocardial Ischemia–Reperfusion Injury in the Mouse
Authors: Toldo Stefano , Breckenridge David G. , Mezzaroma Eleonora , Van Tassell Benjamin W. , Shryock John , Kannan Harsha , Phan Dillon , Budas Grant , Farkas Daniela , Lesnefsky Edward , Voelkel Norbert , Abbate Antonio
Published: May 2013

Background

Despite the clear advantages of reperfusion in acute myocardial infarction, part of the myocardium is injured during reperfusion by reactive oxygen species. Reactive oxygen species activate apoptosis signal–regulating kinase‐1, a key mediator in cell death. We hypothesized that inhibition of apoptosis signal–regulating kinase‐1 at the time of reperfusion would protect the heart from ischemia–reperfusion injury.

Methods and Results

Male
CD
1 mice underwent transient coronary artery ligation (30 minutes) followed by reperfusion or underwent sham surgery (n=10 to 12 per group). A selective small‐molecule inhibitor of apoptosis signal–regulating kinase‐1 (GS‐459679) was given immediately after reperfusion (10 or 30 mg/kg IP). Infarct size was measured early (at 24 hours, in a subgroup of mice) by triphenyl tetrazolium chloride staining and late (at 7 days) by
M
asson's trichrome staining for fibrosis. Apoptosis was assessed by measurement of caspase‐3 activity and by determination of
DNA
fragmentation in cardiomyocytes bordering the infarct. Transthoracic echocardiography was performed before surgery and then at 24 hours and 7 days later. Treatment with GS‐459679 at reperfusion led to a significant dose‐related reduction in infarct size (31% for 10 mg/kg [
P
<0.001 versus vehicle] and 60% for 30 mg/kg [
P
<0.001 versus vehicle]), inhibition of apoptotic cell death, and preservation of left ventricular dimension and systolic function at both 24 hours and 7 days.

Conclusions

Inhibition of apoptosis signal–regulating kinase‐1 at the time of reperfusion limits infarct size and preserves left ventricular function in a model of acute myocardial infarction in the mouse.
Myeloid Mineralocorticoid Receptor During Experimental Ischemic Stroke: Effects of Model and Sex
Authors: Frieler Ryan A. , Ray Jessica J. , Meng He , Ramnarayanan Sai P. , Usher Michael G. , Su Enming J. , Berger Stefan , Pinsky David J. , Lawrence Daniel A. , Wang Michael M. , Mortensen Richard M.
Published: May 2013

Background

Mineralocorticoid receptor (
MR
) antagonists have protective effects in the brain during experimental ischemic stroke, and we have previously demonstrated a key role for myeloid
MR
during stroke pathogenesis. In this study, we explore both model‐ and sex‐specific actions of myeloid
MR
during ischemic stroke.

Methods and Results

The
MR
antagonist eplerenone significantly reduced the infarct size in male (control, 99.5 mm
3
; eplerenone, 74.2 mm
3
; n=8 to 12 per group) but not female (control, 84.0 mm
3
; eplerenone, 83.7 mm
3
; n=6 to 7 per group) mice after transient (90‐minute) middle cerebral artery occlusion. In contrast to
MR
antagonism, genetic ablation of myeloid
MR
in female mice significantly reduced infarct size (myeloid MR knockout, 9.4 mm
3
[5.4 to 36.6]; control, 66.0 mm
3
[50.0 to 81.4]; n=6 per group) after transient middle cerebral artery occlusion. This was accompanied by reductions in inflammatory gene expression and improvement in neurological function. In contrast to ischemia‐reperfusion, myeloid MR–knockout mice were not protected from permanent middle cerebral artery occlusion. The infarct size and inflammatory response after permanent occlusion showed no evidence of protection by myeloid MR knockout in photothrombotic and intraluminal filament models of permanent occlusion.

Conclusions

These studies demonstrate that
MR
antagonism is protective in male but not female mice during transient middle cerebral artery occlusion, whereas genetic ablation of myeloid
MR
is protective in both male and female mice. They also highlight important mechanistic differences in the role of myeloid cells in different models of stroke and confirm that specific myeloid phenotypes play key roles in stroke protection.
Resting Heart Rate and the Risk of Microvascular Complications in Patients With Type 2 Diabetes Mellitus
Authors: Hillis Graham S. , Hata Jun , Woodward Mark , Perkovic Vlado , Arima Hisatomi , Chow Clara K. , Zoungas Sophia , Patel Anushka , Poulter Neil R. , Mancia Giuseppe , Williams Bryan , Chalmers John
Published: May 2013

Background

A higher resting heart rate is associated with an increased probability of cardiovascular complications and premature death in patients with type 2 diabetes mellitus. The impact of heart rate on the risk of developing microvascular complications, such as diabetic retinopathy and nephropathy, is, however, unknown. The present study tests the hypothesis that a higher resting heart rate is associated with an increased incidence and a greater progression of microvascular complications in patients with type 2 diabetes mellitus.

Methods and Results

The relation between baseline resting heart rate and the development of a major microvascular event was examined in 11 140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. Major microvascular events were defined as a composite of new or worsening nephropathy or new or worsening retinopathy. Patients with a higher baseline heart rate were at increased risk of a new major microvascular complication during follow‐up (adjusted hazard ratio: 1.13 per 10 beats per minute; 95% confidence interval: 1.07–1.20;
P
<0.001). The excess hazard was evident for both nephropathy (adjusted hazard ratio: 1.16 per 10 beats per minute; 95% confidence interval: 1.08–1.25) and retinopathy (adjusted hazard ratio: 1.11 per 10 beats per minute; 95% confidence interval: 1.02–1.21).

Conclusion

Patients with type 2 diabetes mellitus who have a higher resting heart rate experience a greater incidence of new‐onset or progressive nephropathy and retinopathy.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00145925.
http://www.advance-trial.com/static/html/prehome/prehome.asp
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.
Protein Kinase G Iα Inhibits Pressure Overload–Induced Cardiac Remodeling and Is Required for the Cardioprotective Effect of Sildenafil In Vivo
Authors: Blanton Robert M. , Takimoto Eiki , Lane Angela M. , Aronovitz Mark , Piotrowski Robert , Karas Richard H. , Kass David A. , Mendelsohn Michael E.
Published: May 2013

Background

Cyclic
GMP
(
cGMP
) signaling attenuates cardiac remodeling, but it is unclear which
cGMP
effectors mediate these effects and thus might serve as novel therapeutic targets. Therefore, we tested whether the
cGMP
downstream effector,
cGMP
‐dependent protein kinase
G
Iα (
PKG
Iα), attenuates pressure overload–induced remodeling in vivo.

Methods and Results

The effect of transaortic constriction (
TAC
)–induced left ventricular (
LV
) pressure overload was examined in mice with selective mutations in the
PKG
Iα leucine zipper interaction domain. Compared with wild‐type littermate controls, in response to
TAC
, these
L
eucine
Z
ipper
M
utant (
LZM
) mice developed significant
LV
systolic and diastolic dysfunction by 48 hours (n=6
WT
sham, 6
WT TAC
, 5
LZM
sham, 9
LZM TAC
). In response to 7‐day
TAC
, the
LZM
mice developed increased pathologic hypertrophy compared with controls (n=5
WT
sham, 4
LZM
sham, 8
WT TAC
, 11
LZM TAC
). In
WT
mice, but not in
LZM
mice, phosphodiesterase 5 (
PDE
5) inhibition with sildenafil (
Sil
) significantly inhibited
TAC
‐induced cardiac hypertrophy and
LV
systolic dysfunction in
WT
mice, but this was abolished in the
LZM
mice (n=3
WT
sham, 4
LZM
sham, 3
WT TAC
vehicle, 6
LZM TAC
vehicle, 4
WT TAC Sil
, 6
LZM TAC Sil
). And in response to prolonged, 21‐day
TAC
(n=8
WT
sham, 7
LZM
sham, 21
WT TAC
, 15
LZM TAC
), the
LZM
mice developed markedly accelerated mortality and congestive heart failure.
TAC
induced activation of
JNK
, which inhibits cardiac remodeling in vivo, in
WT
, but not in
LZM
, hearts, identifying a novel signaling pathway activated by
PKG
Iα in the heart in response to
LV
pressure overload.

Conclusions

These findings reveal direct roles for
PKG
Iα in attenuating pressure overload–induced remodeling in vivo and as a required effector for the cardioprotective effects of sildenafil.
Associations of Plasma Phospholipid and Dietary Alpha Linolenic Acid With Incident Atrial Fibrillation in Older Adults: The Cardiovascular Health Study
Authors: Fretts Amanda M. , Mozaffarian Dariush , Siscovick David S. , Heckbert Susan R. , McKnight Barbara , King Irena B. , Rimm Eric B. , Psaty Bruce M. , Sacks Frank M. , Song Xiaoling , Spiegelman Donna , Lemaitre Rozenn N.
Published: May 2013

Background

Few studies have examined the relationship of α‐linolenic acid (
ALA
18:3n‐3), an intermediate‐chain essential n‐3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (
AF
).

Methods and Results

The study population included participants from the
C
ardiovascular
H
ealth
S
tudy, a community‐based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary
ALA
with incident
AF
using
C
ox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid
ALA
and incident
AF
. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for
AF
were 1.11 (95%
CI
, 0.90 to 1.37), 1.09 (95%
CI
, 0.88 to 1.35), and 0.92 (95%
CI
, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (
P
trend=0.48). When dietary
ALA
was considered the exposure of interest, results were similar.

Conclusions

Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary
ALA
and incident
AF
.
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.
Heart‐Specific Overexpression of Choline Acetyltransferase Gene Protects Murine Heart Against Ischemia Through Hypoxia‐Inducible Factor‐1α–Related Defense Mechanisms
Authors: Kakinuma Yoshihiko , Tsuda Masayuki , Okazaki Kayo , Akiyama Tsuyoshi , Arikawa Mikihiko , Noguchi Tatsuya , Sato Takayuki
Published: May 2013

Background

Murine and human ventricular cardiomyocytes rich in acetylcholine (
Ach
) receptors are poorly innervated by the vagus, compared with whole ventricular innervation by the adrenergic nerve. However, vagal nerve stimulation produces a favorable outcome even in the murine heart, despite relatively low ventricular cholinergic nerve density. Such a mismatch and missing link suggest the existence of a nonneuronal cholinergic system in ventricular myocardium.

Methods and Results

To examine the role of the nonneuronal cardiac cholinergic system, we generated choline acetyltransferase (
ChAT
)–expressing cells and heart‐specific
ChAT
transgenic (
ChAT
‐tg) mice. Compared with cardiomyocytes of wild‐type (
WT
) mice, those of the
ChAT
‐tg mice had high levels of
ACh
and hypoxia‐inducible factor (
HIF
)‐1α protein and augmented glucose uptake. These phenotypes were also reproduced by
ChAT
‐overexpressing cells, which utilized oxygen less. Before myocardial infarction (
MI
), the
WT
and
ChAT
‐tg mice showed similar hemodynamics; after
MI
, however, the
ChAT
‐tg mice had better survival than did the
WT
mice. In the
ChAT
‐tg hearts, accelerated angiogenesis at the ischemic area, and accentuated glucose utilization prevented post‐
MI
remodeling. The
ChAT
‐tg heart was more resistant to ischemia–reperfusion injury than was the
WT
heart.

Conclusions

These results suggest that the activated cardiac
ACh
‐
HIF
‐1α cascade improves survival after
MI
. We conclude that de novo synthesis of
ACh
in cardiomyocytes is a pivotal mechanism for self‐defense against ischemia.
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.
Circulating Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Cardiac Amyloidosis
Authors: Tanaka Komei , Essick Eric E. , Doros Gheorghe , Tanriverdi Kahraman , Connors Lawreen H. , Seldin David C. , Sam Flora
Published: May 2013

Background

Cardiac amyloidosis due to amyloid fibril deposition in the heart results in cardiomyopathy (
CMP
) with heart failure (
HF
) and/or conduction disturbances. Immunoglobulin light chain–related
CMP
(
AL
‐
CMP
) features rapidly progressive
HF
with an extremely poor prognosis compared with a
CMP
due to the deposition of mutant (
ATTR
) amyloidosis or wild‐type (senile systemic amyloidosis,
SSA
) transthyretin (
TTR
) proteins. Amyloid fibril deposition disrupts the myocardial extracellular matrix (
ECM
) homeostasis, which is partly regulated by matrix metalloproteinases (
MMP
s) and their tissue inhibitors (
TIMP
s). We therefore tested the hypothesis that circulating levels of
MMP
s and
TIMP
s in patients with
AL
‐
CMP
and
TTR
‐related
CMP
(
TTR
‐
CMP
) are dissimilar and indicative of cardiac amyloid disease type.

Methods and Results

Fifty
AL
‐
CMP
patients were compared with 50
TTR
‐
CMP
patients (composed of 38
SSA
and 12
ATTR
patients). Clinical and laboratory evaluations including echocardiography were performed at the initial visit to our center and analyzed. Serum
MMP
‐2,
MMP
‐9,
TIMP
‐1, and
TIMP
‐2 levels were determined by
ELISA
. Compared with
TTR
‐
CMP
patients,
AL
‐
CMP
patients had higher levels of brain natriuretic peptide (
BNP
), troponin I (TnI),
MMP
‐2,
TIMP
‐1, and
MMP
‐2/
TIMP
‐2 ratio, despite less left ventricular (
LV
) hypertrophy and better preserved
LV
ejection fraction. Mortality was worse in
AL
‐
CMP
patients than in
TTR
‐
CMP
patients (log‐rank
P
<0.01).
MMP
‐2/
TIMP
‐2 plus
BNP
and TnI showed the highest discriminative ability for distinguishing
AL
‐
CMP
from
TTR
‐
CMP
. Female sex (
HR
, 2.343;
P
=0.049) and
BNP
(
HR
, 1.041;
P
<0.01) were predictors for mortality for all patients with cardiac amyloidoses. Only
BNP
was a predictor of death in
AL
‐
CMP
patients (
HR
, 1.090;
P
<0.01). There were no prognostic factors for all‐cause death in
TTR
‐
CMP
patients.

Conclusions

Circulating concentrations of
MMP
s and
TIMP
s may be useful in differentiating patients with
AL
‐
CMP
from those with
TTR
‐
CMP
, resulting in earlier diagnostic vigilance, and may add prognostic information. In addition to an elevated
BNP
level, female sex increased the risk of death in patients with cardiac amyloidoses.
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.
Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome
Authors: Pinney Jennifer H. , Whelan Carol J. , Petrie Aviva , Dungu Jason , Banypersad Sanjay M. , Sattianayagam Prayman , Wechalekar Ashutosh , Gibbs Simon D. J. , Venner Christopher P. , Wassef Nancy , McCarthy Carolyn A. , Gilbertson Janet A. , Rowczenio Dorota , Hawkins Philip N. , Gillmore Julian D. , Lachmann Helen J.
Published: May 2013

Background

Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (
ATTR
wt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of
ATTR
wt compared with cardiac‐isolated
AL
amyloidosis and calculate the probability of disease diagnosis of
ATTR
wt from baseline factors.

Methods and Results

All patients with biopsy‐proven
ATTR
wt (102 cases) and isolated cardiac
AL
(36 cases) seen from 2002 to 2011 at the
UK
National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the
ATTR
wt group and 1.7 years in the
AL
group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in
ATTR
wt patients on univariate analysis. All patients with isolated cardiac
AL
and 24.1% of patients with
ATTR
wt had evidence of a plasma cell dyscrasia. Older age and lower
N
‐terminal pro‐
B
‐type natriuretic peptide (
NT
pro‐
BNP
) were factors significantly associated with
ATTR
wt. Patients aged 70 years and younger with an
NT
pro‐
BNP
<183 pmol/L were more likely to have
ATTR
wt, as were patients older than 70 years with an
NT
pro‐
BNP
<1420 pmol/L.

Conclusions

Factors at baseline associated with a worse outcome in
ATTR
wt are positive troponin T, a pacemaker, and
NYHA
class
IV
symptoms. The age of the patient at diagnosis and
NT
pro‐
BNP
level can aid in distinguishing
ATTR
wt from
AL
amyloidosis.
Dietary and Plasma Magnesium and Risk of Coronary Heart Disease Among Women
Authors: Chiuve Stephanie E. , Sun Qi , Curhan Gary C. , Taylor Eric N. , Spiegelman Donna , Willett Walter C. , Manson JoAnn E. , Rexrode Kathryn M. , Albert Christine M.
Published: May 2013

Background

Magnesium is associated with lower risk of sudden cardiac death, possibly through antiarrhythmic mechanisms. Magnesium influences endothelial function, inflammation, blood pressure, and diabetes, but a direct relation with coronary heart disease (
CHD
) risk has not been established.

Methods and Results

We prospectively examined the association between dietary and plasma magnesium and risk of
CHD
among women in the Nurses' Health Study. The association for magnesium intake was examined among 86 323 women free of disease in 1980. Information on magnesium intake and lifestyle factors was ascertained every 2 to 4 years through questionnaires. Through 2008, 3614 cases of
CHD
(2511 nonfatal/1103 fatal) were documented. For plasma magnesium, we conducted a nested case–control analysis, with 458 cases of incident
CHD
(400 nonfatal/58 fatal) matched to controls (1:1) on age, smoking, fasting status, and date of blood sampling. Higher magnesium intake was not associated with lower risk of total
CHD
(
P
‐linear trend=0.12) or nonfatal
CHD
(
P
‐linear trend=0.88) in multivariable models. However, magnesium intake was inversely associated with risk of fatal
CHD
. The
RR
comparing quintile 5 to quintile 1 of magnesium intake was 0.61 (95%
CI
, 0.45 to 0.84;
P
‐linear trend=0.003). The association between magnesium intake and risk of fatal
CHD
appeared to be mediated partially by hypertension. Plasma magnesium levels above 2.0 mg/
dL
were associated with lower risk of
CHD
, although not independent of other cardiovascular biomarkers (
RR
, 0.67; 95%
CI
, 0.44 to 1.04).

Conclusions

Dietary and plasma magnesium were not associated with total
CHD
incidence in this population of women. Dietary magnesium intake was inversely associated with fatal
CHD
, which may be mediated in part by hypertension.