bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Microparticles Carry a Functional Endothelial Nitric Oxide Synthase That Is Decreased in Patients With Endothelial Dysfunction
Authors: Horn Patrick , Cortese‐Krott Miriam Margherita , Amabile Nicolas , Hundsdörfer Claas , Kröncke Klaus‐Dietrich , Kelm Malte , Heiss Christian
Published: May 2013

Background

Microparticles (
MP
s) are circulating membrane particles of less than a micrometer in diameter shed from endothelial and blood cells. Recent literature suggests that
MP
s are not just functionally inert cell debris but may possess biological functions and mediate the communication between vascular cells. As a significant proportion of
MP
s originate from platelets and endothelial cells, we hypothesized that
MP
s may harbor functional enzymes including an endothelial
NO
synthase (
eNOS
).

Methods and Results

Using immunoprecipitation and
W
estern blot analysis, we found that human circulating
MP
s carry an
eNOS
. Ca
2+
and
l
‐arginine‐dependent
NOS
activity of crude enzyme extract from
MP
s was determined by measuring the conversion of [
3
H]‐L‐arginine to [
3
H]‐citrulline and
NOS
‐dependent nitrite production.
NOS
‐dependent
NO
production in intact
MP
s was assessed by the
NO
‐specific fluorescent probe
MNIP
‐Cu. In patients with cardiovascular disease, endothelial dysfunction was associated with an increase in the total number of circulating
MP
s as well as a significant decrease in the expression and activity of
eNOS
in
MP
s. No difference in reactive oxygen species was noted in
MP
s isolated from either group.

Conclusions

Our data further support the concept that circulating
MP
s may not only retain phenotypic markers but also preserve the functionality of enzymes of the cells they originate from, including
eNOS
.
Defects of mtDNA Replication Impaired Mitochondrial Biogenesis During
Trypanosoma cruzi
Infection in Human Cardiomyocytes and Chagasic Patients: The Role of Nrf1/2 and Antioxidant Response
Authors: Wan Xianxiu , Gupta Shivali , Zago Maria P. , Davidson Mercy M. , Dousset Pierre , Amoroso Alejandro , Garg Nisha Jain
Published: May 2013

Background

Mitochondrial dysfunction is a key determinant in chagasic cardiomyopathy development in mice; however, its relevance in human
C
hagas disease is not known. We determined if defects in mitochondrial biogenesis and dysregulation of peroxisome proliferator‐activated receptor gamma (
PPAR
γ) coactivator‐1 (
PGC
‐1)–regulated transcriptional pathways constitute a mechanism or mechanisms underlying mitochondrial oxidative‐phosphorylation (
OXPHOS
) deficiency in human
C
hagas disease.

Methods and Results

We utilized human cardiomyocytes and left‐ventricular tissue from chagasic and other cardiomyopathy patients and healthy donors (n>6/group). We noted no change in citrate synthase activity, yet
mRNA
and/or protein levels of subunits of the respiratory complexes were significantly decreased in

T
rypanosoma cruzi

–infected cardiomyocytes (0 to 24 hours) and chagasic hearts. We observed increased
mRNA
and decreased nuclear localization of
PGC
‐1‐coactivated transcription factors, yet the expression of genes for
PPAR
γ‐regulated fatty acid oxidation and nuclear respiratory factor (
NRF
1/2)–regulated
mtDNA
replication and transcription machinery was enhanced in infected cardiomyocytes and chagasic hearts. The
D
‐loop formation was normal or higher, but
mtDNA
replication and
mtDNA
content were decreased by 83% and 40% to 65%, respectively. Subsequently, we noted that reactive oxygen species (
ROS
), oxidative stress, and
mtDNA
oxidation were significantly increased, yet
NRF
1/2‐regulated antioxidant gene expression remained compromised in infected cardiomyocytes and chagasic hearts.

Conclusions

The replication of
mtDNA
was severely compromised, resulting in a significant loss of
mtDNA
and expression of
OXPHOS
genes in
T cruzi–
infected cardiomyocytes and chagasic hearts. Our data suggest increased
ROS
generation and selective functional incapacity of
NRF
2‐mediated antioxidant gene expression played a role in the defects in
mtDNA
replication and unfitness of
mtDNA
for replication and gene expression in
C
hagas disease.
Plasma Fibulin‐1 Is Linked to Restrictive Filling of the Left Ventricle and to Mortality in Patients With Aortic Valve Stenosis
Authors: Dahl Jordi S. , Møller Jacob E. , Videbæk Lars , Poulsen Mikael K. , Rudbæk Torsten R. , Pellikka Patricia A. , Scott Argraves W. , Rasmussen Lars Melholt
Published: May 2013

Background

Plasma fibulin‐1 levels have been associated with
N‐terminal pro–B‐type natriuretic peptide
levels and left atrial size and shown to be predictive of mortality in patients with diabetes. The mechanisms behind these connections are not fully understood but are probably related to its roles as an extracellular matrix protein in cardiovascular tissues.

Methods and Results

One hundred twenty‐five patients with severe aortic stenosis who were scheduled for aortic valve replacement (
AVR
) were evaluated with preoperative echocardiography and their plasma fibulin‐1 levels were determined with
ELISA
. The cohort was followed for a median of 4 years after
AVR
. Increased restrictive left ventricular (
LV
) filling pattern was observed with increased plasma fibulin‐1 levels (2% versus 29% versus 24% in low, middle, and high plasma fibulin‐1 tertile groups,
P
=0.004). Likewise, reduced longitudinal systolic
LV
function (6.6±1.1 versus 6.1±1.3 versus 5.7±1.5 cm/s,
P
=0.05) and increased
LV
filling pressures was systolic velocity of the mitral annulus observed with increasing plasma fibulin‐1 concentrations (ratio of early transmitral flow velocity to early diastolic flow velocity of the mitral annulus 13±4 versus 15±5 versus 16±6 in the fibulin‐1 tertile groups,
P
=0.04).

Conclusions

In patients with symptomatic severe aortic stenosis undergoing AVR, plasma fibulin‐1 is associated with restrictive filling of the
LV
, decreased longitudinal systolic function of the
LV
, and increased
LV
filling pressures.

Clinical Trial Registration

URL:
www.clinicaltrial.gov
with Identifier: NCT00294775
Hydrogen Sulfide Stimulates Ischemic Vascular Remodeling Through Nitric Oxide Synthase and Nitrite Reduction Activity Regulating Hypoxia‐Inducible Factor‐1α and Vascular Endothelial Growth Factor–Dependent Angiogenesis
Authors: Bir Shyamal C. , Kolluru Gopi K. , McCarthy Paul , Shen Xinggui , Pardue Sibile , Pattillo Christopher B. , Kevil Christopher G.
Published: May 2013

Background

Hydrogen sulfide (H
2
S) therapy is recognized as a modulator of vascular function during tissue ischemia with the notion of potential interactions of nitric oxide (
NO
) metabolism. However, little is known about specific biochemical mechanisms or the importance of H
2
S activation of
NO
metabolism during ischemic tissue vascular remodeling. The goal of this study was to determine the effect of H
2
S on
NO
metabolism during chronic tissue ischemia and subsequent effects on ischemic vascular remodeling responses.

Methods and Results

The unilateral, permanent femoral artery ligation model of hind‐limb ischemia was performed in C57BL/6J wild‐type and endothelial NO synthase–knockout mice to evaluate exogenous H
2
S effects on NO bioavailability and ischemic revascularization. We found that H
2
S selectively restored chronic ischemic tissue function and viability by enhancing NO production involving both endothelial NO synthase and nitrite reduction mechanisms. Importantly, H
2
S increased ischemic tissue xanthine oxidase activity, hind‐limb blood flow, and angiogenesis, which were blunted by the xanthine oxidase inhibitor febuxostat. H
2
S treatment increased ischemic tissue and endothelial cell hypoxia‐inducible factor‐1α expression and activity and vascular endothelial growth factor protein expression and function in a NO‐dependent manner that was required for ischemic vascular remodeling.

Conclusions

These data demonstrate that H
2
S differentially regulates
NO
metabolism during chronic tissue ischemia, highlighting novel biochemical pathways to increase
NO
bioavailability for ischemic vascular remodeling.
Prevalence, Distribution, and Risk Factor Correlates of High Thoracic Periaortic Fat in the Framingham Heart Study
Authors: Britton Kathryn A. , Pedley Alison , Massaro Joseph M. , Corsini Erin M. , Murabito Joanne M. , Hoffmann Udo , Fox Caroline S.
Published: May 2013

Background

Thoracic periaortic adipose tissue (
TAT
) is associated with atherosclerosis and cardiovascular disease (
CVD
) risk factors and may play a role in obesity‐mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high
TAT
.

Methods and Results

Participants from the
F
ramingham
H
eart
S
tudy (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high
TAT
and visceral adipose tissue (
VAT
) were defined on the basis of sex‐specific 90th percentiles in a healthy referent sample. The prevalence of high
TAT
was 38.1% in women and 35.7% in men. Among individuals without high
VAT
, 10.1% had high
TAT
. After adjustment for age and
VAT
, both women and men with high
TAT
in the absence of high
VAT
were older and had a higher prevalence of
CVD
(
P
<0.0001) compared with those without high
TAT
. In addition, men in this group were more likely to be smokers (
P
=0.02), whereas women were more likely to have low high‐density lipoprotein cholesterol (
P
=0.005).

Conclusions

Individuals in our community‐based sample with high
TAT
in the absence of high
VAT
were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics.
Delayed Treatment With Hypothermia Protects Against the No‐Reflow Phenomenon Despite Failure to Reduce Infarct Size
Authors: Hale Sharon L. , Herring Michael J. , Kloner Robert A.
Published: May 2013

Background

Many studies have shown that when hypothermia is started after coronary artery reperfusion (
CAR
), it is ineffective at reducing necrosis. However, some suggest that hypothermia may preferentially reduce no‐reflow. Our aim was to test the effects of hypothermia on no‐reflow when initiated close to reperfusion and 30 minutes after reperfusion, times not associated with a protective effect on myocardial infarct size.

Methods and Results

Rabbits received 30 minutes coronary artery occlusion/3 hours
CAR
. In protocol 1, hearts were treated for 1 hour with topical hypothermia (myocardial temperature ≈32°C) initiated at 5 minutes before or 5 minutes after
CAR
, and the results were compared with a normothermic group. In protocol 2, hypothermia was delayed until 30 minutes after
CAR
and control hearts remained normothermic. In protocol 1, risk zones were similar and infarct size was not significantly reduced by hypothermia initiated close to
CAR
. However, the no‐reflow defect was significantly reduced by 43% (5 minutes before CAR) and 38% (5 minutes after CAR) in hypothermic compared with normothermic hearts (
P
=0.004,
ANOVA
,
P
=ns between the 2 treated groups). In protocol 2, risk zones and infarct sizes were similar, but delayed hypothermia significantly reduced no‐reflow in hypothermic hearts by 30% (55±6% of the necrotic region in hypothermia group versus 79±6% with normothermia,
P
=0.008).

Conclusion

These studies suggest that treatment with hypothermia reduces no‐reflow even when initiated too late to reduce infarct size and that the microvasculature is especially receptive to the protective properties of hypothermia and confirm that microvascular damage is in large part a form of true reperfusion injury.
Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers
Authors: Venkatasubramanian Sowmya , Griffiths Megan E. , McLean Steven G. , Miller Mark R. , Luo Rosa , Lang Ninian N. , Newby David E.
Published: May 2013

Background

Urocortin 2 and urocortin 3 are endogenous peptides with an emerging role in cardiovascular pathophysiology. We assessed their pharmacodynamic profile and examined the role of the endothelium in mediating their vasomotor effects in vivo in man.

Methods and Results

Eighteen healthy male volunteers (23±4 years) were recruited into a series of double‐blind, randomized crossover studies using bilateral forearm venous occlusion plethysmography during intra‐arterial urocortin 2 (3.6 to 120 pmol/min), urocortin 3 (1.2 to 36 nmol/min), and substance P (2 to 8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole), and nitric oxide synthase (L‐
NMMA
). Urocortins 2 and 3 evoked arterial vasodilatation (
P
<0.0001) without tachyphylaxis but with a slow onset and offset of action. Inhibition of nitric oxide synthase with L‐
NMMA
reduced vasodilatation to substance P and urocortin 2 (
P
≤0.001 for both) but had little effect on urocortin 3 (
P
>0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (
P
>0.05 for all). In the presence of all 3 inhibitors, urocortin 2– and urocortin 3–induced vasodilatation was attenuated (
P
<0.001 for all) to a greater extent than with L‐
NMMA
alone (
P
≤0.005).

Conclusions

Urocortins 2 and 3 cause potent and prolonged arterial vasodilatation without tachyphylaxis. These vasomotor responses are at least partly mediated by endothelial nitric oxide and cytochrome P450 metabolites of arachidonic acid. The role of urocortins 2 and 3 remains to be explored in the setting of human heart failure, but they have the potential to have major therapeutic benefits.

Clinical Trial Registration

http://www.clinicaltrials.gov/
/. Unique identifier: NCT01096706 and NCT01296607.
Glycemic Associations With Endothelial Function and Biomarkers Among 5 Ethnic Groups: The Multi‐Ethnic Study of Atherosclerosis and the Mediators of Atherosclerosis in South Asians Living in America Studies
Authors: Kanaya Alka M. , Dobrosielski Devon A. , Ganz Peter , Creasman Jennifer , Gupta Ritu , Nelacanti Vidya , Vogel‐Claussen Jens , Herrington David
Published: May 2013

Background

The association of prediabetic states with endothelial dysfunction measured by flow‐mediated dilation (
FMD
) or endothelial biomarker levels remains controversial. We examined data from 5 ethnic groups to determine the association between glucose categories and
FMD
or endothelial biomarkers. We determined whether these associations vary by ethnic group or body mass index.

Methods and Results

We used data from 3516 participants from 5 race/ethnic groups with brachial
FMD
, endothelial biomarkers, and glucose category (normal, impaired fasting glucose [
IFG
], and diabetes) measures. There were significant ethnic differences in
FMD
, biomarker levels, and the prevalence of
IFG
and diabetes. However, all 5 ethnic groups showed similar patterns of higher
FMD
for the
IFG
group compared with the normal glucose and diabetes groups, which was most significant among whites and
A
sian
I
ndians. Associations between glucose categories and endothelial biomarkers were more uniform, with the
IFG
and diabetes groups having higher biomarker levels than the normal glucose group. These associations did not change with further adjustment for fasting insulin levels. Whites with normal
BMI
had higher
FMD
values with higher glucose levels, but those with
BMI
in the overweight or obese categories had the inverse association (
P
for interaction=0.01).

Conclusions

The discordance of
IFG
being associated with higher
FMD
but more abnormal endothelial biomarker levels is a novel finding. This higher
FMD
for the
IFG
group was most notable in whites of normal
BMI
. The higher
FMD
among those with impaired fasting glucose may reflect differences in insulin signaling pathways between the endothelium and skeletal muscle.
Deleterious Effect of the IL‐23/IL‐17A Axis and γδT Cells on Left Ventricular Remodeling After Myocardial Infarction
Authors: Yan Xiaoxiang , Shichita Takashi , Katsumata Yoshinori , Matsuhashi Tomohiro , Ito Hideyuki , Ito Kentaro , Anzai Atsushi , Endo Jin , Tamura Yuichi , Kimura Kensuke , Fujita Jun , Shinmura Ken , Shen Weifeng , Yoshimura Akihiko , Fukuda Keiichi , Sano Motoaki
Published: May 2013

Background

Left ventricular (
LV
) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (
MI
). At the present time, therapeutic options to prevent
LV
remodeling are limited.

Methods and Results

We created a large
MI
by permanent ligation of the coronary artery and identified a potential link between the interleukin (
IL
)–23/
IL
‐17A axis and γδ
T
cells that affects late‐stage
LV
remodeling after
MI
. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild‐type mice, a deficiency in
IL
‐23,
IL
‐17A, or γδ
T
cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating
LV
dilatation and systolic dysfunction on day 28 post‐
MI
. M
1
macrophages and neutrophils were the major cellular source of
IL
‐23, whereas >90% of
IL
‐17A‐producing
T
cells in infarcted heart were
CD
4
−
TCR
γδ
+
(γδ
T
) cells. Toll‐like receptor signaling and
IL
‐1β worked in concert with
IL
‐23 to drive expansion and
IL
‐17A production in cardiac γδ
T
cells, whereas the sphingosine‐1‐phosphate receptor and
CCL
20/
CCR
6 signaling pathways mediated γδ
T
cell recruitment into infarcted heart.
IL
‐17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression.

Conclusions

The
IL
‐23/
IL
‐17A immune axis and γδ
T
cells are potentially promising therapeutic targets after
MI
to prevent progression to end‐stage dilated cardiomyopathy.
Multimorbidity and Blood Pressure Control in 37 651 Hypertensive Patients From Danish General Practice
Authors: Paulsen Maja S. , Andersen Morten , Thomsen Janus L. , Schroll Henrik , Larsen Pia V. , Lykkegaard Jesper , Jacobsen Ib A. , Larsen Mogens L. , Christensen Bo , Sondergaard Jens
Published: May 2013

Background

Patients with hypertension are primarily treated in general practice. However, major studies of patients with hypertension are rarely based on populations from primary care. Knowledge of blood pressure (
BP
) control rates in patients with diabetes and/or cardiovascular diseases (
CVDs
), who have additional comorbidities, is lacking. We aimed to investigate the association of comorbidities with
BP
control using a large cohort of hypertensive patients from primary care practices.

Methods and Results

Using the
D
anish
G
eneral Practice
D
atabase, we included 37 651 patients with hypertension from 231 general practices in
D
enmark. Recommended
BP
control was defined as
BP
<140/90 mm Hg in general and <130/80 mm Hg in patients with diabetes. The overall control rate was 33.2% (95%
CI
: 32.7 to 33.7). Only 16.5% (95%
CI
: 15.8 to 17.3) of patients with diabetes achieved
BP
control, whereas control rates ranged from 42.9% to 51.4% for patients with ischemic heart diseases or cerebrovascular or peripheral vascular diseases. A diagnosis of cardiac heart failure in addition to diabetes and/or
CVD
was associated with higher
BP
control rates, compared with men and women having only diabetes and/or
CVD
. A diagnosis of asthma in addition to diabetes and
CVD
was associated with higher
BP
control rates in men.

Conclusion

In
D
anish general practice, only 1 of 3 patients diagnosed with hypertension had a
BP
below target.
BP
control rates differ substantially within comorbidities. Other serious comorbidities in addition to diabetes and/or
CVD
were not associated with lower
BP
control rates; on the contrary, in some cases the
BP
control rates were higher when the patient was diagnosed with other serious comorbidities in addition to diabetes and/or
CVD
.
Impact of Proton Pump Inhibitor Therapy on the Efficacy of Clopidogrel in the CAPRIE and CREDO Trials
Authors: Dunn Steven P. , Steinhubl Steven R. , Bauer Deborah , Charnigo Richard J. , Berger Peter B. , Topol Eric J.
Published: May 2013

Background

Proton pump inhibitors (
PPI
s) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear.

Methods and Results

The impact of
PPI
use on the 1‐year primary end point (ischemic stroke, myocardial infarction [
MI
], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28‐day (all‐cause death,
MI
, or urgent target vessel revascularization) and 1‐year (all‐cause death,
MI
, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in
CAPRIE
among
PPI
users (estimated hazard ratio [
EHR
] 2.66, 95%
CI
0.94 to 7.50) while lowering it for non‐
PPI
users (
EHR
0.90, 95%
CI
0.83 to 0.99, interaction
P
=0.047). Moreover,
PPI
use was associated with worse outcomes in patients receiving clopidogrel (
EHR
2.39, 95%
CI
1.74 to 3.28) but not aspirin (
EHR
1.04, 95%
CI
0.70 to 1.57, interaction
P
=0.001). Clopidogrel did not significantly alter risk for the 1‐year primary end point in
CREDO
among
PPI
users (
EHR
0.82, 95%
CI
0.48 to 1.40) while lowering it for non‐
PPI
users (
EHR
0.71, 95%
CI
0.52 to 0.98, interaction
P
=0.682). Also,
PPI
use was associated with worse outcomes in both patients receiving clopidogrel (
EHR
1.67, 95%
CI
1.06 to 2.64) and those receiving placebo (
EHR
1.56, 95%
CI
1.06 to 2.30, interaction
P
=0.811).

Conclusions

In
CREDO
, the efficacy of clopidogrel was not significantly affected by
PPI
use. However, in
CAPRIE
, clopidogrel was beneficial to non‐
PPI
users while apparently harmful to
PPI
users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.
Heterogeneous Upregulation of Apamin‐Sensitive Potassium Currents in Failing Human Ventricles
Authors: Chang Po‐Cheng , Turker Isik , Lopshire John C. , Masroor Saqib , Nguyen Bich‐Lien , Tao Wen , Rubart Michael , Chen Peng‐Sheng , Chen Zhenhui , Ai Tomohiko
Published: May 2013

Background

We previously reported that
I
KAS
are heterogeneously upregulated in failing rabbit ventricles and play an important role in arrhythmogenesis. This study goal is to test the hypothesis that subtype 2 of the small‐conductance Ca
2+
activated K
+
(
SK
2) channel and apamin‐sensitive K
+
currents (
I
KAS
) are upregulated in failing human ventricles.

Methods and Results

We studied 12 native hearts from transplant recipients (heart failure [
HF
] group) and 11 ventricular core biopsies from patients with aortic stenosis and normal systolic function (non‐
HF
group).
I
KAS
and action potential were recorded with patch‐clamp techniques, and
SK
2 protein expression was studied by
W
estern blotting. When measured at 1 μmol/L Ca
2+
concentration,
I
KAS
was 4.22 (median) (25th and 75th percentiles, 2.86 and 6.96) pA/pF for the
HF
group (n=11) and 0.98 (0.54 and 1.72) pA/pF for the non‐
HF
group (n=8,
P
=0.008).
I
KAS
was lower in the midmyocardial cells than in the epicardial and the endocardial cells. The Ca
2+
dependency of
I
KAS
in
HF
myocytes was shifted leftward compared to non‐
HF
myocytes (
K
d
314 versus 605 nmol/L). Apamin (100 nmol/L) increased the action potential durations by 1.77% (−0.9% and 7.3%) in non‐
HF
myocytes and by 11.8% (5.7% and 13.9%) in
HF
myocytes (
P
=0.02).
SK
2 protein expression was 3‐fold higher in
HF
than in non‐
HF
.

Conclusions

There is heterogeneous upregulation of
I
KAS
densities in failing human ventricles. The midmyocardial layer shows lower
I
KAS
densities than epicardial and endocardial layers of cells. Increase in both Ca
2+
sensitivity and
SK
2 protein expression contributes to the
I
KAS
upregulation.
Peroxisome Proliferator‐Activated Receptor‐γ in Capillary Endothelia Promotes Fatty Acid Uptake by Heart During Long‐Term Fasting
Authors: Goto Kosaku , Iso Tatsuya , Hanaoka Hirofumi , Yamaguchi Aiko , Suga Toshihiro , Hattori Akinari , Irie Yasunori , Shinagawa Yuji , Matsui Hiroki , Syamsunarno Mas Rizky A. A. , Matsui Miki , Haque Anwarul , Arai Masashi , Kunimoto Fumio , Yokoyama Tomoyuki , Endo Keigo , Gonzalez Frank J. , Kurabayashi Masahiko
Published: May 2013

Background

Endothelium is a crucial blood–tissue interface controlling energy supply according to organ needs. We investigated whether peroxisome proliferator‐activated receptor‐γ (
PPAR
γ) induces expression of fatty acid–binding protein 4 (
FABP
4) and fatty acid translocase (
FAT
)/
CD
36 in capillary endothelial cells (
EC
s) to promote
FA
transport into the heart.

Methods and Results

Expression of
FABP
4 and
CD
36 was induced by the
PPAR
γ agonist pioglitazone in human cardiac microvessel
EC
s (
HCMEC
s), but not in human umbilical vein
EC
s. Real‐time
PCR
and immunohistochemistry of the heart tissue of control (
Pparg
fl/null
) mice showed an increase in expression of
FABP
4 and
CD
36 in capillary
EC
s by either pioglitazone treatment or 48 hours of fasting, and these effects were not found in mice deficient in endothelial
PPAR
γ (
Pparg
∆

EC

/null
). Luciferase reporter constructs of the
Fabp4
and

CD
36

promoters were markedly activated by pioglitazone in
HCMEC
s through canonical
PPAR
‐responsive elements. Activation of
PPAR
γ facilitated
FA
uptake by
HCMEC
s, which was partially inhibited by knockdown of either
FABP
4 or
CD
36. Uptake of an
FA
analogue,
125
I‐
BMIPP
, was significantly reduced in heart, red skeletal muscle, and adipose tissue in
Pparg
∆

EC

/null
mice as compared with
Pparg
fl/null
mice after olive oil loading, whereas those values were comparable between
Pparg
fl/null
and
Pparg
∆

EC

/null
null mice on standard chow and a high‐fat diet. Furthermore,
Pparg
∆

EC

/null
mice displayed slower triglyceride clearance after olive oil loading.

Conclusions

These findings identified a novel role for capillary endothelial
PPAR
γ as a regulator of
FA
handing in
FA
‐metabolizing organs including the heart in the postprandial state after long‐term fasting.
Sex‐Specific Differences in the Predictive Value of Cholesterol Homeostasis Markers and 10‐Year Cardiovascular Disease Event Rate in Framingham Offspring Study Participants
Authors: Matthan Nirupa R. , Zhu Lei , Pencina Michael , D'Agostino Ralph B. , Schaefer Ernst J. , Lichtenstein Alice H.
Published: May 2013

Background

Available data are inconsistent regarding factors influencing plasma cholesterol homeostasis marker concentrations and their value in predicting subsequent cardiovascular disease (
CVD
) events.

Methods and Results

To address this issue, the relationship between markers of cholesterol absorption (campesterol, sitosterol, cholestanol) and synthesis (squalene, desmosterol, lathosterol) and 10‐year
CVD
incidence was assessed in
F
ramingham
O
ffspring
S
tudy participants (cycle 6) who were without
CVD
at baseline and not taking lipid‐lowering medications (N=2616). The primary end point was “hard” coronary heart disease (
HCHD
; coronary death and myocardial infarction), and the secondary end point was full
CVD
(
HCHD
plus stroke, coronary insufficiency, angina pectoris, peripheral artery disease, and congestive heart failure). In cross‐sectional analysis, significant differences by sex, age, body mass index, blood pressure, and smoking status were observed. In both women and men, lower cholesterol absorption was associated with higher triglyceride and lower high‐density lipoprotein (
HDL
) cholesterol concentrations, whereas lower cholesterol synthesis was associated with higher low‐density lipoprotein (
LDL
) cholesterol concentrations (
P
for trend <0.05). In women only, lower cholesterol synthesis and absorption were associated with higher non–
HDL
cholesterol concentrations. Using
C
ox proportional hazards model adjusting for standard
CVD
risk factors, squalene concentrations were associated with lower
HCHD
in women (hazard ratio=0.70 [0.5 to 0.9]). In contrast, squalene (hazard ratio=1.40 [1.1 to 1.8]) concentrations were associated with higher
HCHD
in men (
P
<0.0001 for interaction). The cholesterol absorption markers were not predictive of
HCHD
or full
CVD
in either women or men.

Conclusions

These data suggest significant sex differences in the 10‐year prognostic value of cholesterol synthesis markers and
HCHD
, specifically coronary death and incidence of myocardial infarction.

Clinical Trial Registration

URL:
http://ClinicalTrials.gov
. Unique identifier: NCT00074464.
Status of Cardiovascular Health Among Adult Americans in the 50 States and the District of Columbia, 2009
Authors: Fang Jing , Yang Quanhe , Hong Yuling , Loustalot Fleetwood
Published: May 2013

Background

With ideal cardiovascular health metrics, the
A
merican
H
eart
A
ssociation established a goal of improving cardiovascular health for all
A
mericans by 20% by 2020. Determining how the metrics vary by state is important to the individual states as well as to researchers and policy makers nationwide.

Methods and Results

Using 2009 data from
B
ehavioral
R
isk
F
actor
S
urveillance
S
ystem, a state‐based telephone survey with 356 441 eligible participants, we examined the 7 metrics defined by the
A
merican
H
eart
A
ssociation: hypertension, high cholesterol, smoking, body mass index, diabetes, physical activity, and consumption of fruits and vegetables. The 3 primary outcomes of this study were (1) the percentage of the population achieving ideal health status on all 7 factors, (2) the percentage of the population with only 0 to 2 of the 7 metrics (poor cardiovascular health); and (3) the mean overall score (number of ideal metrics). Overall, 3.3% of population was in ideal cardiovascular health, and 9.9% was in poor cardiovascular health. The mean overall score was 4.42. The percentage with ideal cardiovascular health varied from 1.2% (
O
klahoma) to 6.9% (
D
istrict of
C
olumbia ). The adjusted prevalence ratio of ideal cardiovascular health ranged from 0.38, 95% confidence interval 0.29 to 0.52 (
O
klahoma), to 1.91, 95% confidence interval 1.51 to 2.42 (
D
istrict of
C
olumbia), with
I
llinois as the referent.

Conclusions

In the
U
nited
S
tates, the cardiovascular health status of the population varies substantially by state. The estimates here could help state programs charged with preventing heart disease and stroke to set their goals for reducing risk and improving cardiovascular health in their jurisdictions.
Activation of cGMP/Protein Kinase G Pathway in Postconditioned Myocardium Depends on Reduced Oxidative Stress and Preserved Endothelial Nitric Oxide Synthase Coupling
Authors: Inserte Javier , Hernando Victor , Vilardosa Úrsula , Abad Elena , Poncelas‐Nozal Marcos , Garcia‐Dorado David
Published: May 2013

Background

The
cGMP
/
protein kinase G (PKG)
pathway is involved in the cardioprotective effects of postconditioning (
PoCo
). Although
PKG
signaling in
PoCo
has been proposed to depend on the activation of the phosphatidylinositol 3‐kinase (PI3K)/Akt cascade, recent data bring into question a causal role of reperfusion injury signaling kinase (
RISK
) in
PoCo
protection. We hypothesized that
PoCo
increases
PKG
activity by reducing oxidative stress–induced endothelial nitric oxide synthase (
NOS
) uncoupling at the onset of reperfusion.

Methods and Results

Isolated rat hearts were submitted to 40 minutes of ischemia and reperfusion with and without a
PoCo
protocol.
PoCo
reduced infarct size by 48% and
cGMP
depletion. Blockade of
cGMP
synthesis (

1
H
‐[1,2,4]oxadiazolo[4,3‐
a
]quinoxalin‐1‐one

) and inhibition of
PKG
(
KT
5823) or
NOS
(
l
‐
NAME
) abolished protection, but inhibition of PI3K/Akt cascade (LY294002) did not (n=5 to 7 per group). Phosphorylation of the
RISK
pathway was higher in
PoCo
hearts. However, this difference is due to increased cell death in control hearts because in hearts reperfused with the contractile inhibitor blebbistatin, a drug effective in preventing cell death at the onset of reperfusion,
RISK
phosphorylation increased during reperfusion without differences between control and
PoCo
groups. In these hearts,
PoCo
reduced the production of superoxide (O
2
−
) and protein nitrotyrosylation and increased nitrate/nitrite levels in parallel with a significant decrease in the oxidation of tetrahydrobiopterin (BH
4
) and in the monomeric form of endothelial
NOS
.

Conclusions

These results demonstrate that
PoCo
activates the
cGMP
/
PKG
pathway via a mechanism independent of the PI3K/Akt cascade and dependent on the reduction of O
2
−
production at the onset of reperfusion, resulting in attenuated oxidation of BH
4
and reduced
NOS
uncoupling.
Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans
Authors: Japp Alan G. , Chelliah Raj , Tattersall Laura , Lang Ninian N. , Meng Xu , Weisel Kathleen , Katz Arie , Burt David , Fox Keith A. A. , Feuerstein Giora Z. , Connolly Thomas M. , Newby David E.
Published: May 2013

Background

Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of
P
‐selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis.
P
‐selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel
P
‐selectin antagonist
PSI
‐697 on platelet–monocyte aggregate formation in humans.

Methods and Results

In a double‐blind, randomized, placebo‐controlled crossover study, healthy smokers were randomized to receive either oral
PSI
‐697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both
PSI
‐697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor‐activating peptide (
TRAP
; 0.1 to 1.0 μm/L). The
ex vivo
addition of
TRAP
caused a concentration‐dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% (
P
<0.001). At 4 and 24 hours, plasma concentrations of
PSI
‐697 increased to 1906 and 83 ng/mL, respectively (
P
<0.001).
PSI
‐697 had no demonstrable effect on either stimulated or unstimulated platelet–monocyte aggregates at 4 or 24 hours (
P
>0.05).
P
‐selectin‐blocking antibody (
CLB
‐Thromb6), but not
PSI
‐697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro (
P
<0.001).

Conclusions

The novel small‐molecule
P
‐selectin antagonist
PSI
‐697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established.

Clinical Trial Registration

URL
:
http://EudraCT.ema.europa.eu
Unique identifier: 2007‐005695‐14.
Novel Mechanism for Disrupted Circadian Blood Pressure Rhythm in a Rat Model of Metabolic Syndrome—The Critical Role of Angiotensin II
Authors: Sueta Daisuke , Kataoka Keiichiro , Koibuchi Nobutaka , Toyama Kensuke , Uekawa Ken , Katayama Tetsuji , MingJie Ma , Nakagawa Takashi , Waki Hidefumi , Maeda Masanobu , Yasuda Osamu , Matsui Kunihiko , Ogawa Hisao , Kim‐Mitsuyama Shokei
Published: May 2013

Background

This study was performed to determine the characteristics and mechanism of hypertension in
SHR
/
ND
mcr‐cp(+/+) rats (
SHR
cp), a new model of metabolic syndrome, with a focus on the autonomic nervous system, aldosterone, and angiotensin II.

Methods and Results

We measured arterial blood pressure (
BP
) in
SHR
cp by radiotelemetry combined with spectral analysis using a fast Fourier transformation algorithm and examined the effect of azilsartan, an
AT
1 receptor blocker. Compared with control
W
istar‐
K
yoto rats (
WKY
) and
SHR
,
SHR
cp exhibited a nondipper‐type hypertension and displayed increased urinary norepinephrine excretion and increased urinary and plasma aldosterone levels. Compared with
WKY
and
SHR
,
SHR
cp were characterized by an increase in the low‐frequency power (
LF
) of systolic
BP
and a decrease in spontaneous baroreflex gain (
sBRG
), indicating autonomic dysfunction. Thus,
SHR
cp are regarded as a useful model of human hypertension with metabolic syndrome. Oral administration of azilsartan once daily persistently lowered
BP
during the light period (inactive phase) and the dark period (active phase) in
SHR
cp more than in
WKY
and
SHR
. Thus, angiotensin II seems to be involved in the mechanism of disrupted diurnal
BP
rhythm in
SHR
cp. Azilsartan significantly reduced urinary norepinephrine and aldosterone excretion and significantly increased urinary sodium excretion in
SHR
cp. Furthermore, azilsartan significantly reduced
LF
of systolic
BP
and significantly increased
sBRG
in SHRcp.

Conclusions

These results strongly suggest that impairment of autonomic function and increased aldosterone in
SHR
cp mediate the effect of angiotensin II on circadian blood pressure rhythms.
FAMP, a Novel ApoA‐I Mimetic Peptide, Suppresses Aortic Plaque Formation Through Promotion of Biological HDL Function in ApoE‐Deficient Mice
Authors: Uehara Yoshinari , Ando Setsuko , Yahiro Eiji , Oniki Kosuke , Ayaori Makoto , Abe Satomi , Kawachi Emi , Zhang Bo , Shioi Seijiro , Tanigawa Hiroyuki , Imaizumi Satoshi , Miura Shin‐ichiro , Saku Keijiro
Published: May 2013

Background

Apolipoprotein (apo) A‐I is a major high‐density lipoprotein (
HDL
) protein that causes cholesterol efflux from peripheral cells through the
ATP
‐binding cassette transporter A1 (
ABCA
1), thus generating
HDL
and reversing the macrophage foam cell phenotype. Pre‐β
1
HDL
is the smallest subfraction of
HDL
, which is believed to represent newly formed
HDL
, and it is the most active acceptor of free cholesterol. Furthermore it has a possible protective function against cardiovascular disease (
CVD
). We developed a novel apoA‐I mimetic peptide without phospholipids (Fukuoka University ApoA‐I Mimetic Peptide,
FAMP
).

Methods and Results

FAMP
type 5 (
FAMP
5) had a high capacity for cholesterol efflux from A172 cells and mouse and human macrophages in vitro, and the efflux was mainly dependent on
ABCA
1 transporter. Incubation of
FAMP
5 with human
HDL
or whole plasma generated small
HDL
particles, and charged apoA‐I‐rich particles migrated as pre‐β
HDL
on agarose gel electrophoresis. Sixteen weeks of treatment with
FAMP
5 significantly suppressed aortic plaque formation (scrambled
FAMP
, 31.3±8.9% versus high‐dose
FAMP
5, 16.2±5.0%;
P
<0.01) and plasma C‐reactive protein and monocyte chemoattractant protein‐1 in apoE‐deficient mice fed a high‐fat diet. In addition, it significantly enhanced
HDL
‐mediated cholesterol efflux capacity from the mice.

Conclusions

A newly developed apoA‐I mimetic peptide,
FAMP
, has an antiatherosclerotic effect through the enhancement of the biological function of
HDL
.
FAMP
may have significant atheroprotective potential and prove to be a new therapeutic tool for
CVD
.
Improved Survival After Heart Failure: A Community‐Based Perspective
Authors: Joffe Samuel W. , Webster Kristy , McManus David D. , Kiernan Michael S. , Lessard Darleen , Yarzebski Jorge , Darling Chad , Gore Joel M. , Goldberg Robert J.
Published: May 2013

Background

Heart failure is a highly prevalent, morbid, and costly disease with a poor long‐term prognosis. Evidence‐based therapies utilized over the past 2 decades hold the promise of improved outcomes, yet few contemporary studies have examined survival trends in patients with acute heart failure. The primary objective of this population‐based study was to describe trends in short‐ and long‐term survival in patients hospitalized with acute decompensated heart failure (
ADHF
). A secondary objective was to examine patient characteristics associated with decreased long‐term survival.

Methods and Results

We reviewed the medical records of 9748 patients hospitalized with
ADHF
at all 11 medical centers in central Massachusetts during 1995, 2000, 2002, and 2004. Patients hospitalized with
ADHF
were more likely to be elderly and to have been diagnosed with multiple comorbidities in 2004 compared with 1995. Over this period, survival was significantly improved in‐hospital, and at 1, 2, and 5 years postdischarge. Five‐year survival rates increased from 20% in 1995 to 29% in 2004. Although survival improved substantially over time, older patients and patients with chronic kidney disease, chronic obstructive pulmonary disease, anemia, low body mass index, and low blood pressures had consistently lower postdischarge survival rates than patients without these comorbidities.

Conclusion

Between 1995 and 2004, patients hospitalized with
ADHF
have become older and increasingly comorbid. Although there has been a significant improvement in survival among these patients, their long‐term prognosis remains poor, as fewer than 1 in 3 patients hospitalized with
ADHF
in 2004 survived more than 5 years.
Prevalence of the American Heart Association's “Ideal Cardiovascular Health” Metrics in a Rural, Cross‐sectional, Community‐Based Study: The Heart of New Ulm Project
Authors: Kim Jacqueline I. , Sillah Arthur , Boucher Jackie L. , Sidebottom Abbey C. , Knickelbine Thomas
Published: May 2013

Background

The
A
merican
H
eart
A
ssociation (
AHA
) recently created the construct of “ideal cardiovascular health” based on 7 cardiovascular health metrics to measure progress toward their 2020
I
mpact
G
oal. The present study applied this construct to assess the baseline cardiovascular health of a rural population targeted with a community‐based cardiovascular disease prevention program.

Methods and Results

The sample consists of 4754
N
ew
U
lm, Minn, adult residents who participated in either the 2009 or 2011 community heart health screenings offered by the
H
earts
B
eat
B
ack:
T
he
H
eart of
N
ew
U
lm (
HONU
) Project (mean age 52.1 years, 58.3% women). Data collected at the screenings were analyzed to replicate the
AHA
's ideal cardiovascular health measure and the 7 metrics that comprise the construct. Screening participants met, on average (±SD), 3.4 (±1.4) ideal cardiovascular health metrics. Only 1.0% of participants met the
AHA
's definition of ideal health in all metrics and 7.1% met ≤1 ideal health metric. Higher proportions of women met the ideal category in all metrics except physical activity. Women over the age of 60 were less likely to meet the ideal category for cholesterol and hypertension than were men in the same age range.

Conclusion

Prevalence of ideal cardiovascular health is extremely low in this rural population. To make progress toward the 2020
I
mpact
G
oal, targeted community‐based interventions must be implemented based on the most prevalent cardiovascular risk factors.
Enhanced Lipid Peroxidation and Platelet Activation as Potential Contributors to Increased Cardiovascular Risk in the Low‐HDL Phenotype
Authors: Vazzana Natale , Ganci Antonina , Cefalù Angelo Baldassare , Lattanzio Stefano , Noto Davide , Santoro Nicole , Saggini Raoul , Puccetti Luca , Averna Maurizio , Davì Giovanni
Published: May 2013

Background

Low high‐density lipoprotein (
HDL
) levels are major predictors of cardiovascular (
CV
) events, even in patients on statin treatment with low‐density lipoprotein (
LDL
) at target. In animal models
HDL
s protect
LDL
from oxidation and blunt platelet activation. Our study aimed to examine whether
HDL
levels are related to in vivo oxidative stress and platelet activation, as determinants of atherothrombosis.

Methods and Results

Urinary 8‐iso‐PGF
2α
and 11‐dehydro‐TXB
2
, in vivo markers of oxidative stress and platelet activation, respectively, were measured in 65 coronary heart disease (CHD) normocholesterolemic patients with HDL ≤35 mg/
dL
, and in 47 CHD patients with HDL >35 mg/
dL
. The 2 eicosanoids were also measured before and after an intensive exercise program in sedentary people (n=18) and before and after fenofibrate treatment in otherwise healthy subjects with low HDL (n=10). Patients with HDL ≤35 mg/
dL
showed significantly higher urinary 8‐iso‐PGF
2α
(median [25th to 75th percentiles]: 289 [189 to 380] versus 216 [171 to 321] pg/mg creatinine,
P
=0.019) and 11‐dehydro‐TXB
2
(563 [421 to 767] versus 372 [249 to 465] pg/mg creatinine,
P
=0.0001) than patients with higher HDL. A direct correlation was found between urinary 8‐iso‐PGF
2α
and 11‐dehydro‐TXB
2
in the entire group of patients (ρ=0.77,
P
<0.0001). HDL levels were inversely related to both 8‐iso‐PGF
2α
(ρ=−0.32,
P
=0.001) and 11‐dehydro‐TXB
2
(ρ=−0.52,
P
<0.0001). On multiple regression, only 8‐iso‐PGF
2α
(β=0.68,
P
<0.0001) and HDL level (β=−0.29,
P
<0.0001) were associated with urinary 11‐dehydro‐TXB
2
excretion, independent of sex, age, smoking, hypertension, diabetes, previous myocardial infarction, total cholesterol, LDL, and triglycerides. Both intensive exercise and fenofibrate treatment significantly reduced the 2 eicosanoids in healthy subjects, in parallel with an HDL increase.

Conclusions

A low
HDL
phenotype, both in
CHD
patients and in healthy subjects, is associated with increased lipid peroxidation and platelet activation. These data provide novel insight into the mechanisms linking low
HDL
with increased
CV
risk.
Therapeutic Cardiac‐Targeted Delivery of
miR‐1
Reverses Pressure Overload–Induced Cardiac Hypertrophy and Attenuates Pathological Remodeling
Authors: Karakikes Ioannis , Chaanine Antoine H. , Kang Soojeong , Mukete Bertrand N. , Jeong Dongtak , Zhang Shihong , Hajjar Roger J. , Lebeche Djamel
Published: May 2013

Background

Micro
RNA
s (mi
RNA
s) play a key role in the development of heart failure, and recent studies have shown that the muscle‐specific
miR‐1
is a key regulator of cardiac hypertrophy. We tested the hypothesis that chronic restoration of
miR‐1
gene expression in vivo will regress hypertrophy and protect against adverse cardiac remodeling induced by pressure overload.

Methods and Results

Cardiac hypertrophy was induced by left ventricular pressure overload in male
S
prague‐
D
awley rats subjected to ascending aortic stenosis. When the hypertrophy was established at 2 weeks after surgery, the animals were randomized to receive either an adeno‐associated virus expressing
miR‐1
(
AAV
9.
miR‐1
) or green fluorescent protein (
GFP
) as control (
AAV
9.

GFP

) via a single‐bolus tail‐vein injection. Administration of
miR‐1
regressed cardiac hypertrophy (left ventricular posterior wall thickness,; 2.32±0.08 versus 2.75±0.07 mm,
P
<0.001) and (left ventricular septum wall thickness, 2.23±0.06 versus 2.54±0.10 mm,
P
<0.05) and halted the disease progression compared with control‐treated animals, as assessed by echocardiography (fractional shortening, 37.60±5.01% versus 70.68±2.93%,
P
<0.05) and hemodynamic analyses (end‐systolic pressure volume relationship/effective arterial elastance, 1.87±0.46 versus 0.96±0.38,
P
<0.05) after 7 weeks of treatment. Additionally,
miR‐1
replacement therapy lead to a marked reduction of myocardial fibrosis, an improvement in calcium handling, inhibition of apoptosis, and inactivation of the mitogen‐activated protein kinase signaling pathways, suggesting a favorable effect on preventing the maladaptive ventricular remodeling. We also identified and validated a novel bona fide target of
miR‐1
, Fibullin‐2 (
Fbln2
), a secreted protein implicated in extracellular matrix remodeling.

Conclusions

Taken together, our findings suggest that restoration of
miR‐1
gene expression is a potential novel therapeutic strategy to reverse pressure‐induced cardiac hypertrophy and prevent maladaptive cardiac remodeling.