bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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
.
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.
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.
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.
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.