bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diminished Antioxidant Activity of High‐Density Lipoprotein–Associated Proteins in Chronic Kidney Disease
Authors: Kennedy David J. , Wilson Tang W. H. , Fan Yiying , Wu Yuping , Mann Shirley , Pepoy Michael , Hazen Stanley L. 
Published: September 2018

Background

Decreased serum arylesterase activity, catalyzed by the high‐density lipoprotein–associated paraoxonase (
PON
)‐1, is associated with increased oxidant stress and atherosclerosis risk. We sought to determine the prognostic value of serum
PON
‐1 activity, as monitored by PON or arylesterase activities, in subjects with chronic kidney disease (
CKD
), particularly in relation to established cardiac biomarkers.

Methods and Results

Serum arylesterase and PON activities were measured in sequential subjects with
CKD
(n=630; estimated glomerular filtration rate [
eGFR
] <60 mL/min per 1.73 m
2
) and an age‐ and sex‐matched control group of non‐
CKD
subjects (n=315) presenting for cardiac evaluations and prospectively followed for incident (3‐year) major adverse cardiac events (composite of death, nonfatal myocardial infarction, and stroke). Serum arylesterase activity in
CKD
subjects was lower compared with that in non‐
CKD
control subjects [median (interquartile range) 94 (77 to 112) versus 103 (85 to 121) μmol(L·min) per mL,
P
<0.001]; similarly, PON activity in
CKD
subjects was lower compared with that in non‐
CKD
control subjects [median (interquartile range) 474 (275 to 936) versus 586 (301 to 1118) nmol(L·min) per mL,
P
<0.001]. Lower serum arylesterase (hazard ratio 1.8, 95% CI 1.26 to 2.57,
P
<0.01) was a predictor of poorer outcomes. After adjusting for traditional risk factors and medication use, lower serum arylesterase (hazard ratio 1.55, 95% CI 1.08 to 2.23,
P
<0.05) still conferred an increased risk of major adverse cardiac events at 3 years.

Conclusions

In patients with
CKD
, decreased serum arylesterase activity, a measure of diminished antioxidant properties of
PON
‐1, predicts higher risk of incident long‐term adverse cardiovascular events (heart attack, stroke, or death) in multivariable models adjusting for established clinical and biochemical risk factors.
Metabolic Syndrome in Adults With Congenital Heart Disease
Authors: Deen Jason F. , Krieger Eric V. , Slee April E. , Arslan Alex , Arterburn David , Stout Karen K. , Portman Michael A. 
Published: September 2018

Background

Metabolic syndrome increases risk for atherosclerotic coronary artery disease, and its prevalence increases with increasing age and body mass index. Adults with congenital heart disease (
ACHD
) are now living longer and accruing coronary artery disease risk factors. However, the prevalence of metabolic syndrome in
ACHD
patients is unknown.

Methods and Results

We conducted a retrospective cohort study of
ACHD
patients at our center to quantify the prevalence of metabolic syndrome in an
ACHD
population. Using case‐control matching, we constructed a comparable control group from a population‐based sample of 150 104 adults. International Diabetes Federation criteria were used to define metabolic syndrome. We used logistic regression to compare the risk of metabolic syndrome across the resulting cohorts, which were composed of 448
ACHD
patients and 448 controls matched by age and sex. Mean age of both groups was 32.4±11.3 years, and 51.3% were female. Obesity was present in 16.1% of the
ACHD
patients and 16.7% of the controls. Metabolic syndrome was more common in
ACHD
patients than in controls (15.0% versus 7.4%; odds ratio 1.82, 95%
CI
1.25–2.65).

Conclusions

Our data suggest that metabolic syndrome is more common among adults with congenital heart disease than in the general population. Thus, patients with congenital heart disease should be screened for metabolic syndrome and risk factors mitigated where possible to prevent atherosclerotic coronary artery disease. Preventive cardiology should be included during routine
ACHD
care.
Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor‐2 With Oxidative Stress Inhibition
Authors: Liu Yang , Liu Yu , Liu Xun , Chen Jie , Zhang Kun , Huang Feifei , Wang Jing‐Feng , Tang Wanchun , Huang Hui 
Published: September 2018

Background

Type 4 cardiorenal syndrome (
CRS
) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac injury in patients with type 4
CRS
, determine whether the antioxidant apocynin attenuated cardiac injury in rats with type 4
CRS
, and explore potential mechanisms.

Methods and Results

A cross‐sectional study was conducted among patients with type 4
CRS
(n=17) and controls (n=16). Compared with controls, patients with type 4
CRS
showed elevated oxidative stress, which was significantly correlated with cardiac hypertrophy and decreased ejection fraction. In vivo study, male Sprague‐Dawley rats underwent 5/6 subtotal nephrectomy and sham surgery, followed with apocynin or vehicle treatment for 8 weeks. Eight weeks after surgery, the 5/6 subtotal nephrectomy rats mimicked type 4
CRS
, showing increased serum creatinine, cardiac hypertrophy and fibrosis, and decreased ejection fraction compared with sham‐operated animals. Cardiac malondialdehyde,
NADPH
oxidase activity, fibroblast growth factor‐2, and extracellular signal‐regulated kinase 1/2 (ERK1/2) phosphorylation increased significantly in the 5/6 subtotal nephrectomy rats. These changes were significantly attenuated by apocynin. In vitro study showed that apocynin reduced angiotensin
II
–induced
NADPH
oxidase–dependent oxidative stress, upregulation of fibroblast growth factor‐2 and fibrosis biomarkers, and
ERK
1/2 phosphorylation in cardiac fibroblasts. Importantly, the
ERK
1/2 inhibitor U0126 reduced the upregulation of fibroblast growth factor‐2 and fibrosis biomarkers in angiotensin
II
–treated fibroblasts.

Conclusions

Oxidative stress is a candidate mediator for type 4
CRS
. Apocynin attenuated cardiac injury in type 4
CRS
rats via inhibiting
NADPH
oxidase–dependent oxidative stress‐activated
ERK
1/2 pathway and subsequent fibroblast growth factor‐2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4
CRS
.
Serum Amyloid A Facilitates Early Lesion Development in
Ldlr

−/−

Mice
Authors: Krishack Paulette A. , Bhanvadia Clarissa V. , Lukens John , Sontag Timothy J. , De Beer Maria C. , Getz Godfrey S. , Reardon Catherine A. 
Published: September 2018

Background

Atherosclerosis is a chronic inflammatory disorder, and several studies have demonstrated a positive association between plasma serum amyloid A (
SAA
) levels and cardiovascular disease risk. The aim of the study was to examine whether
SAA
has a role in atherogenesis, the underlying basis of most cardiovascular disease.

Methods and Results

Mice globally deficient in acute‐phase isoforms
Saa1
and
Saa2
(
Saa

−/−

) were crossed to
Ldlr

−/−

mice (
Saa

−/−

Ldlr

−/−

).
Saa

−/−

Ldlr

−/−

mice demonstrated a 31% reduction in lesional area in the ascending aorta but not in the aortic root or innominate artery after consuming a high‐fat, high‐cholesterol Western‐type diet for 6 weeks. The lesions were predominantly macrophage foam cells. The phenotype was lost in more mature lesions in mice fed a Western‐type diet for 12 weeks, suggesting that
SAA
is involved in early lesion development. The decreased atherosclerosis in the
Saa

−/−

Ldlr

−/−

mice occurred despite increased levels of blood monocytes and was independent of plasma lipid levels.
SAA
is produced predominantly by hepatocytes and macrophages. To determine which source of
SAA
may have a dominant role in lesion development, bone marrow transplantation was performed.
Ldlr

−/−

mice that received bone marrow from
Saa

−/−

Ldlr

−/−

mice had slightly reduced ascending aorta atherosclerosis compared with
Saa

−/−

Ldlr

−/−

mice receiving bone marrow from
Ldlr

−/−

mice, indicating that the expression of
SAA
by macrophages may have an important influence on atherogenesis.

Conclusions

The results indicate that
SAA
produced by macrophages promotes early lesion formation in the ascending aorta.
Short‐Term, High‐Dose Fish Oil Supplementation Increases the Production of Omega‐3 Fatty Acid–Derived Mediators in Patients With Peripheral Artery Disease (the OMEGA‐PAD I Trial)
Authors: Grenon S. Marlene , Owens Christopher D. , Nosova Emily V. , Hughes‐Fulford Millie , Alley Hugh F. , Chong Karen , Perez Sandra , Yen Priscilla K. , Boscardin John , Hellmann Jason , Spite Matthew , Conte Michael S. 
Published: September 2018

Background

Patients with peripheral artery disease (
PAD
) experience significant morbidity and mortality. The
OMEGA
‐
PAD
I Trial, a randomized, double‐blinded, placebo‐controlled trial, addressed the hypothesis that short‐duration, high‐dose n‐3 polyunsaturated fatty acids (n‐3
PUFA
) oral supplementation improves endothelial function and inflammation in
PAD
.

Methods and Results

Eighty patients with stable claudication received 4.4 g of fish oil or placebo for 1 month. The primary end point was endothelial function as measured by brachial artery flow‐mediated vasodilation. Secondary end points included biomarkers of inflammation, n‐3 polyunsaturated fatty acids metabolome changes, lipid profile, and walking impairment questionnaires. Although there was a significant increase in FMD in the fish oil group following treatment (0.7±1.8% increase from baseline,
P
=0.04), this response was not different then the placebo group (0.6±2.5% increase from baseline,
P
=0.18; between‐group
P
=0.86) leading to a negative finding for the primary endpoint. There was, however, a significant reduction in triglycerides (fish oil: −34±46 mg/
dL
,
P
<0.001; placebo −10±43 mg/
dL
,
P
=0.20; between‐group differential
P
‐value: 0.02), and an increase in the omega‐3 index of 4±1% (
P
<0.001) in the fish oil group (placebo 0.1±0.9%,
P
=0.49; between‐group
P
<0.0001). We observed a significant increase in the production of pathway markers of specialized pro‐resolving mediators generated from n‐3 polyunsaturated fatty acids in the fish oil group.

Conclusions

High‐dose, short‐duration fish oil supplementation did not lead to a different response in the primary end point of endothelial function between the treatment and placebo group, but improved serum triglycerides and increased the production of downstream n‐3 polyunsaturated fatty acids–derived products and mediators in patients with
PAD
.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
01310270.
Manganese‐Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri‐Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia–Reperfusion Model
Authors: Dash Rajesh , Kim Paul J. , Matsuura Yuka , Ikeno Fumiaki , Metzler Scott , Huang Ngan F. , Lyons Jennifer K. , Nguyen Patricia K. , Ge Xiaohu , Wong Po Foo Cheryl , McConnell Michael V. , Wu Joseph C. , Yeung Alan C. , Harnish Phillip , Yang Phillip C. 
Published: September 2018

Background

The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri‐infarct region (
PIR
) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese‐enhanced magnetic resonance imaging [
MEMRI]
), myocardial scar (delayed gadolinium enhancement
MRI
), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.

Methods and Results

Twelve adult swine underwent ischemia–reperfusion injury. Digital subtraction of
MEMRI
‐negative myocardium (intrainfarct region) from delayed gadolinium enhancement
MRI
–positive myocardium (
PIR
and intrainfarct region) clearly delineated the
PIR
in which the
MEMRI
‐positive signal reflected
PIR
viability. Human amniotic mesenchymal stem cells (
hAMSC
s) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine
PIR
. Immediately following
hAMSC
delivery,
MEMRI
demonstrated an increased
PIR
viability signal compared with control. Direct
PIR
viability remained higher in
hAMSC
‐treated hearts for >6 weeks. Increased
PIR
viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and
hAMSC
engraftment, as confirmed by immunocytochemistry. Increased
MEMRI
and positron emission tomography reporter gene signal in the intrainfarct region and the
PIR
correlated with sustained functional augmentation (global and regional) within the
hAMSC
group (mean change, left ventricular ejection fraction:
hAMSC
85±60%, control 8±10%;
P
<0.05) and reduced chamber dilatation (left ventricular end‐diastole volume increase:
hAMSC
24±8%, control 110±30%;
P
<0.05).

Conclusions

The positron emission tomography reporter gene signal of
hAMSC
engraftment correlates with the improved
MEMRI
signal in the
PIR
. The increased
MEMRI
signal represents
PIR
viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real‐time method of tracking
PIR
viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.
Effects of Cardiac Resynchronization Therapy on Cardiac Remodeling and Contractile Function: Results From Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE)
Authors: St. John Sutton Martin , Cerkvenik Jeffrey , Borlaug Barry A. , Daubert Claude , Gold Michael R. , Ghio Stefano , Chirinos Julio A. , Linde Cecilia , Ky Bonnie 
Published: September 2018

Background
Cardiac resynchronization therapy results in improved ejection fraction in patients with heart failure. We sought to determine whether these effects were mediated by changes in contractility, afterload, or volumes.

Methods and Results

In 610 patients with New York Heart Association class I/
II
heart failure from the
Re
synchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (
REVERSE
) study, we performed detailed quantitative echocardiography assessment prior to and following cardiac resynchronization therapy. We derived measures of contractility (the slope [end‐systolic elastance] and the volume intercept of the end‐systolic pressure–volume relationship, stroke work, and preload recruitable stroke work), measures of arterial load and ventricular–arterial coupling, and measures of chamber size (volume intercept, end‐systolic and end‐diastolic volumes). At 6 and 12 months, cardiac resynchronization therapy was associated with a reduction in the volume intercept and end‐systolic and end‐diastolic volumes (
P
<0.01). There were no consistent effects on end‐systolic elastance, stroke work, preload recruitable stroke work, or ventricular–arterial coupling. In the active cardiac resynchronization therapy population, baseline measures of arterial load were associated with the clinical composite score (odds ratio 1.30, 95%
CI
1.04 to 1.63,
P
=0.02). The volume intercept was associated with mortality (hazard ratio 1.90, 95%
CI
1.01 to 3.59,
P
=0.047) and more modestly with the combined end point of mortality or heart failure hospitalization (hazard ratio 1.48, 95%
CI
0.8 to 2.25,
P
=0.06). In contrast, end‐systolic elastance, stroke work, preload recruitable stroke work, and ventricular–arterial coupling were not associated with any outcomes.

Conclusion

In patients with
NYHA
Class I/
II
heart failure, cardiac resynchronization therapy exerts favorable changes in left ventricular end‐systolic and end‐diastolic volumes and the volume intercept. The volume intercept may be useful to gain insight into prognosis in heart failure.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
00271154.
Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo
Authors: Kobayashi Hatasu , Matsuda Yoshiko , Hitomi Toshiaki , Okuda Hiroko , Shioi Hirotomo , Matsuda Tetsuya , Imai Hirohiko , Sone Masakatsu , Taura Daisuke , Harada Kouji H. , Habu Toshiyuki , Takagi Yasushi , Miyamoto Susumu , Koizumi Akio 
Published: September 2018

Background

P.R4810K of

RNF
213

(mysterin: rs112735431), which is an
AAA
+
ATP
ase, is the susceptibility polymorphism for moyamoya disease (
MMD
) in East Asians. However, the role of
RNF
213 R4810K in the etiology of
MMD
is unknown.

Methods and Results

To clarify the role of
RNF
213 in known angiogenic pathways,
RNF
213 expression was analyzed in endothelial cells (
EC
s) treated with several angiogenic and antiangiogenic factors, including interferons (
IFN
s).
RNF
213 was upregulated by
IFN
‐β through signal transducer and activator of transcription x in the promoter and mediated antiangiogenic activity of
IFN
‐β.
RNF
213 wild‐type (
WT
) overexpression could not lower angiogenesis without
IFN
‐β, but
RNF
213 R4810K overexpression could. To correlate biochemical function as
ATP
ase and the role of
RNF
213 oligomer formation with antiangiogenic activity, we investigated the effects of mutations in the
AAA
+
module. A mutation of the Walker B motif (
WEQ
), which stabilizes oligomerization, inhibited angiogenesis, but
AAA
+
module deletion, which cannot initiate oligomerization, did not. Intriguingly, R4810K, similar to
WEQ
, decreased
ATP
ase activity, suggesting its antiangiogenic activity through stabilizing oligomers. To confirm the antiangiogenic effect of
RNF
213 upregulation in vivo, vascular
EC
‐ or smooth muscle cell‐specific Rnf213 R4757K (R4810K ortholog) or
WT
transgenic (Tg) mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in EC‐specific Rnf213 R4757K Tg mice, whereas it was not suppressed in other mice.

Conclusions

This study suggests the importance of inflammatory signals as environmental factors and R4810K carriers for susceptibility to cerebral hypoxia. A specific inhibitor of
ATP
binding to the first
AAA
+
could be a promising therapeutic candidate for
MMD
.
Association of Acute and Chronic Hyperglycemia With Acute Ischemic Stroke Outcomes Post‐Thrombolysis: Findings From Get With The Guidelines‐Stroke
Authors: Masrur Shihab , Cox Margueritte , Bhatt Deepak L. , Smith Eric E. , Ellrodt Gray , Fonarow Gregg C. , Schwamm Lee 
Published: September 2018

Background

Hyperglycemia has been associated with adverse outcomes in patients with acute ischemic stroke (
AIS
) and may influence outcomes after tissue plasminogen activator (
tPA
). We sought to analyze the association of acute and chronic hyperglycemia on clinical outcomes in
tPA‐
treated patients.

Methods and Results

We identified 58 265
AIS
patients from 1408 sites who received
tPA
from 2009 to 2013 in Get With The Guidelines‐Stroke. Acute hyperglycemia at admission was defined as a plasma glucose level >140 mg/dL. Chronic hyperglycemia was defined by plasma glycosylated hemoglobin (HbA1c) >6.5%. Post‐
tPA
outcomes were analyzed using logistic regression. Blood glucose >140 mg/dL and HbA1c >6.5 were associated with worse clinical outcomes (symptomatic intracranial hemorrhage [
sICH
], life‐threatening hemorrhage, and in‐hospital mortality and length of stay) in diabetic and nondiabetic patients. Among patients with documented history of diabetes, increasing admission glucose up to 200 mg/dL was associated with increased adjusted odds ratio (
aOR
) of in‐hospital mortality (
aOR,
1.07) and
sICH
(
aOR,
1.05) per 10 mg/dL increase in blood glucose. Increasing HbA1C to 8% was associated with increased odds of in‐hospital mortality (
aOR,
1.19) and
sICH
(
aOR,
1.16) per 1% increase in HbA1c. Similar findings were observed in patients without a documented history of diabetes. There was no further increase in poor outcomes above the blood glucose level of 200 mg/dL or HbA1c >8.

Conclusion

Acute and chronic hyperglycemia are both associated with increased mortality and worse clinical outcomes in
AIS
patients treated with
tPA
. Controlled trials are needed to determine whether acute correction of hyperglycemia can improve outcomes after thrombolysis.
Metformin and Myocardial Injury in Patients With Diabetes and ST‐Segment Elevation Myocardial Infarction: A Propensity Score Matched Analysis
Authors: Basnet Suresh , Kozikowski Andrzej , Makaryus Amgad N. , Pekmezaris Renee , Zeltser Roman , Akerman Meredith , Lesser Martin , Wolf‐Klein Gisele 
Published: September 2018

Background

Although animal studies have documented metformin's cardioprotective effects, the impact in humans remains elusive. The study objective was to explore the association between metformin and myocardial infarct size in patients with diabetes presenting with
ST
‐segment elevation myocardial infarction.

Methods and Results

Data extraction used the National Cardiovascular Data Cath
PCI
Registry in all patients with diabetes aged >18 years presenting with
ST
‐segment elevation myocardial infarction at 2 academic medical centers from January 2010 to December 2013. The exposure of interest was ongoing metformin use before the event. Propensity score matching was used for the metformin and nonmetformin groups on key prognostic variables. All matched pairs had acceptable D scores of <10%, confirming an efficient matching procedure. The primary outcome was myocardial infarct size, reflected by peak serum creatine kinase–myocardial band, troponin T, and hospital discharge left ventricular ejection fraction. Of all 1726
ST
‐segment elevation myocardial infarction cases reviewed, 493 patients had diabetes (28.5%), with 208 metformin users (42.1%) and 285 nonusers. Matched pairs analysis yielded 137 cases per group. The difference between metformin and nonmetformin groups was −18.1 ng/mL (95%
CI
−55.0 to 18.8;
P
=0.56) for total peak serum creatine kinase–myocardial band and −1.1 ng/mL (95%
CI
−2.8 to 0.5;
P
=0.41) for troponin T. Median discharge left ventricular ejection fraction in both groups was 45, and the difference between metformin and nonmetformin users was 0.7% (95%
CI
−2.2 to 3.6;
P
=0.99).

Conclusions

No statistically significant association of cardioprotection was found between metformin and myocardial infarct size in patients with diabetes and acute
ST
‐segment elevation myocardial infarction.