bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liver Disease as a Predictor of New‐Onset Atrial Fibrillation
Authors: Huang William A. , Dunipace Eric A. , Sorg Julie M. , Vaseghi Marmar 
Published: September 2018

Background

Impact of liver disease on development of atrial fibrillation (
AF
) is unclear. The purpose of the study was to evaluate prevalence of
AF
in the setting of liver disease and whether increasing severity of liver disease, using Model for End‐Stage Liver Disease (
MELD
), is independently associated with increased risk of
AF
.

Methods and Results

Retrospective data analysis of 1727 patients with liver disease evaluated for liver transplantation between 2006 and 2015 was performed, and patient characteristics were analyzed from billing codes and review of medical records. Multivariable time‐dependent Cox proportional hazards model was performed to determine effect of increasing
MELD
score on risk of developing
AF
. Prevalence of
AF
was 11.2%. Incidence of
AF
at median follow‐up time of 1.04 years was 8.5%. Both prevalence and incidence of
AF
increased with increasing
MELD
scores. Prevalence of
AF
was 3.7%, 6.4%, 16.7%, and 20.2% corresponding with
MELD
quartiles 1 to 10, 11 to 20, 21 to 30, and >30, respectively. Compared with patients with
MELD
quartile 1 to 10, patients with
MELD
quartile of 11 to 20 had hazard ratio of 2.73 (confidence interval, 1.47–5.07), those in the
MELD
quartile of 21 to 30 had a hazard ratio of 5.17 (confidence interval, 2.65–10.09), and those with
MELD
values >30 had hazard ratio of 9.33 (confidence interval, 3.93–22.14) for development of new‐onset
AF
. Other significant variables associated with new‐onset
AF
were age, sleep apnea, valvular heart disease, hemodynamic instability, and reduced left ventricular ejection fraction <50% (hazard ratio, of 1.06, 2.17, 3.21, 2.00, and 2.44, respectively).

Conclusions

Prevalence and incidence of
AF
in patients with liver disease is high. Severity of liver disease, as measured by
MELD
, is an important predictor of new‐onset
AF
. This novel finding suggests an interaction between inflammatory and neurohormonal changes in liver disease and pathogenesis of
AF
.
Engineered Exosomes With Ischemic Myocardium‐Targeting Peptide for Targeted Therapy in Myocardial Infarction
Authors: Wang Xu , Chen Yihuan , Zhao Zhenao , Meng Qingyou , Yu You , Sun Jiacheng , Yang Ziying , Chen Yueqiu , Li Jingjing , Ma Teng , Liu Hanghang , Li Zhen , Yang Junjie , Shen Zhenya 
Published: September 2018

Background
Exosomes are membranous vesicles generated by almost all cells. Recent studies demonstrated that mesenchymal stem cell–derived exosomes possessed many effects, including antiapoptosis, anti‐inflammatory effects, stimulation of angiogenesis, anticardiac remodeling, and recovery of cardiac function on cardiovascular diseases. However, targeting of exosomes to recipient cells precisely in vivo still remains a problem. Ligand fragments or homing peptides discovered by phage display and in vivo biopanning methods fused to the enriched molecules on the external part of exosomes have been exploited to improve the ability of exosomes to target specific tissues or organs carrying cognate receptors. Herein, we briefly elucidated how to improve targeting ability of exosomes to ischemic myocardium.

Methods and Results

We used technology of molecular cloning and lentivirus packaging to engineer exosomal enriched membrane protein (Lamp2b) fused with ischemic myocardium‐targeting peptide CSTSMLKAC (IMTP). In vitro results showed that IMTP‐exosomes could be internalized by hypoxia‐injured H9C2 cells more efficiently than blank‐exosomes. Compared with blank‐exosomes, IMTP‐exosomes were observed to be increasingly accumulated in ischemic heart area (
P
<0.05). Meanwhile, attenuated inflammation and apoptosis, reduced fibrosis, enhanced vasculogenesis, and cardiac function were detected by mesenchymal stem cell–derived IMTP‐exosome treatment in ischemic heart area.

Conclusions
Our research concludes that exosomes engineered by IMTP can specially target ischemic myocardium, and mesenchymal stem cell–derived IMTP‐exosomes exert enhanced therapeutic effects on acute myocardial infarction.
High Triglycerides Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: A Real‐World Administrative Claims Analysis of Statin‐Treated Patients With High Residual Cardiovascular Risk
Authors: Toth Peter P. , Granowitz Craig , Hull Michael , Liassou Djibril , Anderson Amy , Philip Sephy 
Published: September 2018

Background
The American Heart Association recognizes high triglycerides as a cardiovascular risk factor.

Methods and Results

This retrospective observational administrative claims analysis (Optum Research Database) included statin‐treated patients ≥45 years old with diabetes mellitus and/or atherosclerotic cardiovascular disease, triglycerides 2.26 to 5.64 mmol/L, and a propensity‐matched comparator cohort with triglycerides <1.69 mmol/L and high‐density lipoprotein cholesterol >1.04 mmol/L. In the high‐triglycerides cohort versus comparators (both n=10 990, 49% women), mean age was 61.7 versus 62.2 years and follow‐up was 41.3 versus 42.1 months, respectively. Multivariate analysis of composite major cardiovascular events demonstrated significantly increased risk in the high‐triglycerides (n=13 411 patients) versus comparator (n=32 506 patients) cohorts (hazard ratio [
HR
], 1.35; 95% confidence interval [
CI
], 1.225–1.485;
P
<0.001), with significantly higher risk for nonfatal myocardial infarction (
HR
, 1.35; 95%
CI
, 1.19–1.52;
P
<0.001), nonfatal stroke (
HR
, 1.27; 95%
CI
, 1.14–1.42;
P
<0.001), and need for coronary revascularization (
HR
, 1.51; 95%
CI
, 1.34–1.69;
P
<0.001), but not unstable angina or cardiovascular death. Increased cardiovascular risk in the high‐triglycerides versus comparator cohort was maintained, even with addition of non–high‐density lipoprotein cholesterol to the multivariate model and when analyzing high and low high‐density lipoprotein cholesterol subgroups. Average total healthcare cost per patient per month (cost ratio, 1.15; 95%
CI
, 1.084–1.210;
P
<0.001) and rate of occurrence of inpatient hospital stay (
HR
, 1.17; 95%
CI
, 1.113–1.223;
P
<0.001) were also significantly greater in the high‐triglycerides cohort.

Conclusions
In this real‐world analysis, patients with high cardiovascular risk and high triglycerides had worse composite cardiovascular and health economic outcomes than patients with well‐managed triglycerides and high‐density lipoprotein cholesterol >1.04 mmol/L.
Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial
Authors: Quinn Gene R. , Hellkamp Anne S. , Hankey Graeme J. , Becker Richard C. , Berkowitz Scott D. , Breithardt Günter , Fava Maurizio , Fox Keith A. A. , Halperin Jonathan L. , Mahaffey Kenneth W. , Nessel Christopher C. , Patel Manesh R. , Piccini Jonathan P. , Singer Daniel E. 
Published: September 2018

Background

There is concern that selective serotonin reuptake inhibitors (
SSRI
s) substantially increase bleeding risk in patients taking anticoagulants.

Methods and Results

We studied 737 patients taking
SSRI
s in the
ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation)
trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking
SSRI
s. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in
ROCKET AF
. Over a mean 1.6 years of follow‐up, the rate of major/
nonmajor clinically relevant
bleeding was 18.57 events/100 patient‐years for
SSRI
users versus 16.84 events/100 patient‐years for matched comparators, adjusted hazard ratio (
aHR
) of 1.16 (95%
confidence interval [CI],
0.95–1.43). The
aHR
s were similar in patients taking rivaroxaban (
aHR
1.11 [95%
CI,
0.82–1.51]) and those taking warfarin (
aHR
1.21 [95%
CI,
0.91–1.60]). For the rarer outcome of major bleeding, the
aHR
for
SSRI
users versus those not taking
SSRI
s was 1.13 (95%
CI,
0.62–2.06) for rivaroxaban; for warfarin, the
aHR
was higher, at 1.58 (95%
CI
, 0.96–2.60) but not statistically significantly elevated.

Conclusions

We found no significant increase in bleeding risk when
SSRI
s were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with
SSRI
s added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that
SSRI
s can be safely added to anticoagulants in patients with
atrial fibrillation
.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
00403767.
Hospitalization Trends and Health Resource Use for Adult Congenital Heart Disease–Related Heart Failure
Authors: Burchill Luke J. , Gao Lina , Kovacs Adrienne H. , Opotowsky Alexander R. , Maxwell Bryan G. , Minnier Jessica , Khan Abigail M. , Broberg Craig S. 
Published: September 2018

Background

This study assessed trends in heart failure (
HF)
hospitalizations and health resource use in patients with adult congenital heart disease (
ACHD
).

Methods and Results

The Nationwide Inpatient Sample was used to compare
ACHD
with non‐
ACHD HF
hospitalization and health resource trends. Health resource use was assessed using total hospital charges, hospital length of stay, and procedural burden. A total of 87 175±2676
ACHD
‐related
HF
hospitalizations occurred between 1998 and 2011. During this time,
ACHD HF
hospitalizations increased 91% (4620±438–8809±740,
P
<0.0001) versus a 21% increase in non‐
ACHD HF
hospitalizations (
P
=0.003).
ACHD HF
hospitalization was associated with longer length of stay (
ACHD HF
versus non‐
ACHD HF,
7.2±0.09 versus 6.8±0.02 days;
P
<0.0001), greater procedural burden, and higher charges ($81 332±$1650 versus $52 050±$379;
P
<0.0001).
ACHD HF
hospitalization charges increased 258% during the study period ($26 533±$1816 in 1998 versus $94 887±$8310 in 2011;
P
=0.0002), more than double that for non‐
ACHD HF
(
P
=0.04). Patients with
ACHD HF
hospitalized in high‐volume
ACHD
centers versus others were more likely to undergo invasive hemodynamic testing (30.2±0.6% versus 20.7±0.5%;
P
<0.0001) and to receive cardiac resynchronization/defibrillator devices (4.7±0.3% versus 1.8±0.2%;
P
<0.0001) and mechanical circulatory support (3.9±0.2% versus 2.4±0.2%;
P
<0.0001).

Conclusions

ACHD
‐related
HF
hospitalizations have increased dramatically in recent years and are associated with disproportionately higher costs, procedural burden, and health resource use.
Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype
Authors: Wang Mingyi , Zhang Li , Zhu Wanqu , Zhang Jing , Kim Soo Hyuk , Wang Yushi , Ni Leng , Telljohann Richard , Monticone Robert E. , McGraw Kimberly , Liu Lijuan , de Cabo Rafael , Lakatta Edward G. 
Published: September 2018

Background

Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction (
CR
) in rats improves arterial function and extends both health span and life span. How
CR
affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated.

Methods and Results

Aortae were harvested from young (6‐month‐old) and old (24‐month‐old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40%
CR
beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that
CR
markedly reduced age‐associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that
CR
effectively prevented an age‐associated increase in the density of platelet‐derived growth factor, matrix metalloproteinase type
II
activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho‐mothers against decapentaplegic homolog‐2/3 (p‐
SMAD
‐2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from
AL
and
CR
rat aortae,
CR
alleviated the age‐associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet‐derived growth factor.

Conclusions

CR
reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet‐derived growth factor signaling. Thus,
CR
reduces the platelet‐derived growth factor–associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.
Outcomes Associated With a Strategy of Adjuvant Metolazone or High‐Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis
Authors: Brisco‐Bacik Meredith A. , ter Maaten Jozine M. , Houser Steven R. , Vedage Natasha A. , Rao Veena , Ahmad Tariq , Wilson F. Perry , Testani Jeffrey M. 
Published: September 2018

Background
In acute decompensated heart failure, guidelines recommend increasing loop diuretic dose or adding a thiazide diuretic when diuresis is inadequate. We set out to determine the adverse events associated with a diuretic strategy relying on metolazone or high‐dose loop diuretics.

Methods and Results

Patients admitted to 3 hospitals using a common electronic medical record with a heart failure discharge diagnosis who received intravenous loop diuretics were studied in a propensity‐adjusted analysis of all‐cause mortality. Secondary outcomes included hyponatremia (sodium <135
mE
q/L), hypokalemia (potassium <3.5
mE
q/L) and worsening renal function (a ≥20% decrease in estimated glomerular filtration rate). Of 13 898 admissions, 1048 (7.5%) used adjuvant metolazone. Metolazone was strongly associated with hyponatremia, hypokalemia, and worsening renal function (
P
<0.0001 for all) with minimal effect attenuation following covariate and propensity adjustment. Metolazone remained associated with increased mortality after multivariate and propensity adjustment (hazard ratio=1.20, 95% confidence interval 1.04–1.39,
P
=0.01). High‐dose loop diuretics were associated with hypokalemia and hyponatremia (
P
<0.002) but only worsening renal function retained significance (
P
<0.001) after propensity adjustment. High‐dose loop diuretics were not associated with reduced survival after multivariate and propensity adjustment (hazard ratio=0.97 per 100 mg of IV furosemide, 95% confidence interval 0.90–1.06,
P
=0.52).

Conclusions
During acute decompensated heart failure, metolazone was independently associated with hypokalemia, hyponatremia, worsening renal function and increased mortality after controlling for the propensity to receive metolazone and baseline characteristics. However, under the same experimental conditions, high‐dose loop diuretics were not associated with hypokalemia, hyponatremia, or reduced survival. The current findings suggest that until randomized control trial data prove otherwise, uptitration of loop diuretics may be a preferred strategy over routine early addition of thiazide type diuretics when diuresis is inadequate.
Small Molecule Derived From Carboxyethylpyrrole Protein Adducts Promotes Angiogenesis in a Mouse Model of Peripheral Arterial Disease
Authors: Hou Luqia , Yang Guang , Tang Shibing , Alcazar Cynthia , Joshi Prajakta , Strassberg Zachary , Kim Michael , Kawamura Masashi , Woo Y. Joseph , Shrager Joseph , Ding Sheng , Huang Ngan F. 
Published: September 2018

Background

CEP (ω‐[2‐carboxyethyl]pyrrole) protein adducts are the end products of lipid oxidation associated with inflammation and have been implicated in the induction of angiogenesis in pathological conditions such as tissue ischemia. We synthesized small molecules derived from
CEP
protein adducts and evaluated the angiogenic effect of the
CEP
analog
CEP
03 in the setting of peripheral arterial disease.

Methods and Results

The angiogenic effect of
CEP
03 was assessed by in vitro analysis of primary human microvascular endothelial cell proliferation and tubelike formation in Matrigel (Corning). In the presence of
CEP
03, proliferation of endothelial cells in vitro increased by 27±18% under hypoxic (1% O
2
) conditions, reaching similar levels to that of
VEGF
A (vascular endothelial growth factor A) stimulation (22±10%), relative to the vehicle control treatment. A similar effect of
CEP
03 was demonstrated in the increased number of tubelike branches in Matrigel, reaching >70% induction in hypoxia, compared with the vehicle control. The therapeutic potential of
CEP
03 was further evaluated in a mouse model of peripheral arterial disease by quantification of blood perfusion recovery and capillary density. In the ischemic hind limb, treatment of
CEP
03 encapsulated within Matrigel significantly enhanced blood perfusion by 2‐fold after 14 days compared with those treated with Matrigel alone. Moreover, these results concurred with histological finding that treatment of
CEP
03 in Matrigel resulted in a significant increase in microvessel density compared with Matrigel alone.

Conclusions

Our data suggest that
CEP
03 has a profound positive effect on angiogenesis and neovessel formation and thus has therapeutic potential for treatment of peripheral arterial disease.
Life Course Trajectories of Cardiovascular Risk Factors in Women With and Without Hypertensive Disorders in First Pregnancy: The HUNT Study in Norway
Authors: Haug Eirin B. , Horn Julie , Markovitz Amanda R. , Fraser Abigail , Vatten Lars J. , Macdonald‐Wallis Corrie , Tilling Kate , Romundstad Pål R. , Rich‐Edwards Janet W. , Åsvold Bjørn O. 
Published: September 2018

Background
Women with hypertensive pregnancy disorders have adverse levels of cardiovascular risk factors. It is unclear how this adverse risk factor profile evolves during adult life. We compared life course trajectories of cardiovascular risk factors in women with preeclampsia or gestational hypertension in their first pregnancy to normotensive women.

Methods and Results

We linked information on cardiovascular risk factors from the population‐based
HUNT
(Nord‐Trøndelag Health Study) surveys with pregnancy information from the Medical Birth Registry of Norway. Trajectories of cardiovascular risk factors were constructed for 22 308 women with a normotensive first pregnancy; 1092 with preeclampsia, and 478 with gestational hypertension in first pregnancy. Already before first pregnancy, women with preeclampsia in their first pregnancy had higher measures of adiposity, blood pressure, heart rate, and serum lipids and glucose compared with women with a normotensive first pregnancy. After first pregnancy, there was a parallel development in cardiovascular risk factor levels, but women with a normotensive first pregnancy had a time lag of >10 years compared with the preeclampsia group. There were no clear differences in risk factor trajectories between women with gestational hypertension and women with preeclampsia.

Conclusions
Women with hypertensive pregnancy disorders in their first pregnancy had an adverse cardiovascular risk factor profile before pregnancy compared with normotensive women, and the differences persisted beyond 50 years of age. Hypertensive disorders in pregnancy signal long‐term increases in modifiable cardiovascular risk factors, and may be used to identify women who would benefit from early prevention strategies.
Efficacy and Safety of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients With Impaired Liver Function: A Retrospective Cohort Study
Authors: Wang Chun‐Li , Wu Victor Chien‐Chia , Kuo Chang‐Fu , Chu Pao‐Hsien , Tseng Hsiao‐Jung , Wen Ming‐Shien , Chang Shang‐Hung 
Published: September 2018

Background

Patients with impaired liver function (
ILF
) were excluded from clinical trials that investigated non–vitamin K antagonist oral anticoagulants (
NOAC
s) for stroke prevention in patients with atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of
NOAC
s in atrial fibrillation patients with
ILF
.

Methods and Results

A cohort study based on electronic medical records was conducted from 2009 to 2016 at a multicenter healthcare provider in Taiwan and included 6451 anticoagulated atrial fibrillation patients (aged 76.7±7.0 years, 52.5% male). Patients were classified into 2 subgroups: patients with normal liver function (n=5818) and patients with ILF (n=633, 9.8%). Cox regression analysis was performed to investigate the risks of thromboembolism, bleeding, and death associated with use of
NOAC
s and warfarin in patients with normal liver function and
ILF
, respectively. In patients with normal liver function, compared with warfarin therapy (n=2928),
NOAC
therapy (n=4048) was associated with significantly lower risks of stroke or systemic embolism (adjusted hazard ratio: 0.75; 95% confidence interval, 0.65–0.88;
P
<0.001) and death (adjusted hazard ratio: 0.69; 95% confidence interval, 0.60–0.80;
P
<0.001) with no difference in major bleeding or gastrointestinal bleeding. In patients with
ILF
, compared with warfarin therapy (n=394),
NOAC
therapy (n=342) was associated with significantly lower risk of death (adjusted hazard ratio: 0.64; 95% confidence interval, 0.49–0.83;
P
<0.001), but no difference in stroke or systemic embolism, major bleeding, or gastrointestinal bleeding.

Conclusions

In atrial fibrillation patients with
ILF
,
NOAC
therapy and warfarin therapy were associated with similar risks of stroke or systemic embolism, major bleeding, and gastrointestinal bleeding.