bluuebunny/crossref_metadata_2025 huggingface dataset:
Kidney Size, Renal Function, Ang (Angiotensin) Peptides, and Blood Pressure in Young Adults Born Preterm
Authors: Paquette Katryn , Fernandes Rafael Oliveira , Xie Li Feng , Cloutier Anik , Fallaha Catherine , Girard-Bock Camille , Mian Muhammad Oneeb Rehman , Lukaszewski Marie-Amélie , Mâsse Benoit , El-Jalbout Ramy , Lapeyraque Anne-Laure , Santos Robson A. , Luu Thuy Mai , Nuyt Anne Monique
Published: September 2018

Preterm birth incurs a higher risk for adult cardiovascular diseases, including hypertension. Because preterm birth may impact nephrogenesis, study objectives were to assess renal size and function of adults born preterm versus full term and to examine their relationship with blood pressure (BP; 24-hour ambulatory BP monitoring) and circulating renin-Ang (angiotensin) system peptides. The study included 92 young adults born (1987–1997) preterm (≤29 weeks of gestation) and term (n=92) matched for age, sex, and race. Young adults born preterm had smaller kidneys (80±17 versus 90±18 cm
3
/m
2
;
P
<0.001), higher urine albumin-to-creatinine ratio (0.70; interquartile range, 0.47–1.14 versus 0.58, interquartile range 0.42 to 0.78 mg/mmol,
P
=0.007), higher 24-hour systolic (121±9 versus 116±8 mm Hg;
P
=0.001) and diastolic (69±5 versus 66±6 mm Hg;
P
=0.004) BP, but similar estimated glomerular filtration rate. BP was inversely correlated with kidney size in preterm participants. Plasma Ang I was higher in preterm versus term participants (36.3; interquartile range, 13.2–62.3 versus 19.4; interquartile range, 9.9–28.1 pg/mL;
P
<0.001). There was no group difference in renin, Ang II, Ang (1–7), and alamandine. In the preterm, but not in the term group, higher BP was significantly associated with higher renin and alamandine and lower birth weight and gestational age with smaller adult kidney size. Young adults born preterm have smaller kidneys, higher urine albumin-to-creatinine ratio, higher BP, and higher circulating Ang I levels compared with term controls. Preterm young adults with smaller kidneys have higher BP.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT03261609.
Nondipping Blood Pressure Patterns Predict Obstructive Sleep Apnea in Patients Undergoing Ambulatory Blood Pressure Monitoring
Authors: Genta-Pereira Daniel Castanho , Furlan Sofia F. , Omote Daniel Q. , Giorgi Dante M.A. , Bortolotto Luiz A. , Lorenzi-Filho Geraldo , Drager Luciano F.
Published: September 2018

A nondipping blood pressure (BP) pattern is common in patients with obstructive sleep apnea (OSA). However, it is unclear how useful a nondipping BP pattern is in screening for OSA. In this cross-sectional study, we recruited consecutive patients with clinical indications for performing ambulatory BP monitoring evaluating the following dipping patterns: (1) normal: ≥10% but <20%; (2) extreme: ≥20%; (3) reduced: ≥0% but <10%; and (4) reverse (riser): <0%. Sleep questionnaires and sleep studies were performed within 7 days after ambulatory BP monitoring. OSA was defined as an apnea-hypopnea index ≥15 events/h. We evaluated 153 patients (OSA frequency, 50.3%). Patients with OSA had higher BPs during sleep, were taking more antihypertensive drugs, and more frequently used hypertensive drugs during the night than patients without OSA. Considering systolic BP, the frequency of OSA in patients with reverse dippers (73.5%) was higher than normal (37.3%), extreme (46.2%), and reduced dippers (49.1%;
P
=0.012). For diastolic BP, OSA was more common in reduced (66.7%) and reverse dippers (69.6%) as compared to normal (41.4%) or extreme dippers (33.3%;
P
=0.007). In the regression analysis, reverse systolic dipper was independently associated with OSA (odds ratio, 3.92; 95% CI, 1.31–11.78). Both reduced and reverse diastolic dippers increased the likelihood of OSA for 2.7-fold and 3.5-fold, respectively. Snoring and positive sleep questionnaire findings were associated with a modest increase in the accuracy of reverse dipping pattern for predicting OSA. In conclusion, reverse systolic, as well as reduced and reverse diastolic dippers are independently associated with OSA.
Incremental Value of the CRUSADE, ACUITY, and HAS‐BLED Risk Scores for the Prediction of Hemorrhagic Events After Coronary Stent Implantation in Patients Undergoing Long or Short Duration of Dual Antiplatelet Therapy
Authors: Costa Francesco , Tijssen Jan G. , Ariotti Sara , Giatti Sara , Moscarella Elisabetta , Guastaroba Paolo , De Palma Rossana , Andò Giuseppe , Oreto Giuseppe , Zijlstra Felix , Valgimigli Marco
Published: September 2018

Background

Multiple scores have been proposed to stratify bleeding risk, but their value to guide dual antiplatelet therapy duration has never been appraised. We compared the performance of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HAS‐BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) scores in 1946 patients recruited in the Prolonging Dual Antiplatelet Treatment After Grading Stent‐Induced Intimal Hyperplasia Study (
PRODIGY
) and assessed hemorrhagic and ischemic events in the 24‐ and 6‐month dual antiplatelet therapy groups.

Methods and Results

Bleeding score performance was assessed with a Cox regression model and C statistics. Discriminative and reclassification power was assessed with net reclassification improvement and integrated discrimination improvement. The C statistic was similar between the
CRUSADE
score (area under the curve 0.71) and
ACUITY
(area under the curve 0.68), and higher than
HAS
−
BLED
(area under the curve 0.63).
CRUSADE
, but not
ACUITY
, improved reclassification (net reclassification index 0.39,
P
=0.005) and discrimination (integrated discrimination improvement index 0.0083,
P
=0.021) of major bleeding compared with
HAS
‐
BLED
. Major bleeding and transfusions were higher in the 24‐ versus 6‐month dual antiplatelet therapy groups in patients with a CRUSADE score >40 (hazard ratio for bleeding 2.69,
P
=0.035; hazard ratio for transfusions 4.65,
P
=0.009) but not in those with CRUSADE score ≤40 (hazard ratio for bleeding 1.50,
P
=0.25; hazard ratio for transfusions 1.37,
P
=0.44), with positive interaction (
P
int
=0.05 and
P
int
=0.01, respectively). The number of patients with high
CRUSADE
scores needed to treat for harm for major bleeding and transfusion were 17 and 15, respectively, with 24‐month rather than 6‐month dual antiplatelet therapy; corresponding figures in the overall population were 67 and 71, respectively.

Conclusions

Our analysis suggests that the
CRUSADE
score predicts major bleeding similarly to ACUITY and better than HAS BLED in an all‐comer population with percutaneous coronary intervention and potentially identifies patients at higher risk of hemorrhagic complications when treated with a long‐term dual antiplatelet therapy regimen.

Clinical Trial Registration

URL
:
http://clinicaltrials.gov
. Unique identifier:
NCT
00611286.
Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy
Authors: Eisele Nicole , Klossner Rahel , Escher Geneviève , Rudloff Stefan , Larionov Alexey , Theilig Franziska , Mohaupt Markus G. , Mistry Hiten D. , Gennari‐Moser Carine
Published: September 2018

Background

In pregnancy, a high plasma volume maintains uteroplacental perfusion and prevents placental ischemia, a condition linked to elevated maternal blood pressure (
BP
). Reducing
BP
by increasing Na
+
intake via plasma volume expansion appears contra‐intuitive. We hypothesize that an appropriate Na
+
intake in pregnancy reduces maternal
BP
and adapts the renin‐angiotensin system in a pregnancy‐specific manner.

Methods and Results

BP
was measured by implanted telemetry in Sprague‐Dawley rats before and throughout pregnancy. Pregnant and nonpregnant animals received either a normal‐salt (0.4%;
NS
), high‐salt (8%;
HS
), or low‐salt (0.01%;
LS
) diet, or
HS
(days 1–14) followed by
LS
(days 14–20) diet (
HS
/
LS
). Before delivery (day 20), animals were euthanized and organs collected. Food, water, and Na
+
intake were monitored in metabolic cages, and urinary creatinine and Na
+
were analyzed. Na
+
intake and retention increased in pregnancy (
NS
,
LS
), leading to a positive Na
+
balance (
NS
,
LS
).
BP
was stable during
LS
, but reduced in
HS
conditions in pregnancy. The renin‐angiotensin system was adapted as expected. Activating cleavage of α‐ and γ‐subunits of the renal epithelial Na
+
channel and expression of‐full length medullary β‐subunits, accentuated further in all
LS
conditions, were upregulated in pregnancy.

Conclusions

Pregnancy led to Na
+
retention adapted to dietary changes.
HS
exposure paradoxically reduced
BP
. Na
+
uptake while only modestly linked to the renin‐angiotensin system is enhanced in the presence of posttranslational renal epithelial Na
+
channel modifications. This suggests (1) storage of Na
+
in pregnancy upon
HS
exposure, bridging periods of
LS
availability; and (2) that potentially non–renin‐angiotensin–related mechanisms participate in
EN
aC activation and consecutive Na
+
retention.
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.
Prognostic Significance of Pulse Pressure Variability During Mechanical Thrombectomy in Acute Ischemic Stroke Patients
Authors: Maïer Benjamin , Turc Guillaume , Taylor Guillaume , Blanc Raphaël , Obadia Michael , Smajda Stanislas , Desilles Jean‐Philippe , Redjem Hocine , Ciccio Gabriele , Boisseau William , Sabben Candice , Ben Machaa Malek , Hamdani Mylene , Leguen Morgan , Gayat Etienne , Blacher Jacques , Lapergue Bertrand , Piotin Michel , Mazighi Mikael ,   the Endovascular Treatment in Ischemic Stroke (ETIS) Investigators, Escalard Simon , Piotin Michel , Fahed Robert , Corabianu Ovide , de Broucker Thomas , Smadja Didier , Ille Olivier , Manchon Eric , Garcia Pierre‐Yves , Decroix J. P. , Wang A. , Wang A. , Evrard S. , Tchikviladzé M. , Bourdain F. , Coskun O. , Di Maria F. , Rodesch G. , Consoli A. , Tisserand M. , Pico F. , Rakotoharinandrasana H. , Tassan P. , Poll R. , Nighoghossian Norbert , Gory Benjamin , Riva Roberto , Eker O. , Derex Laurent , Cho Tae‐Hee , Mechtouff Laura , Lukaszewicz Anne‐Claire , Philippeau Frédéric , Cakmak Serkan , Blanc‐Lasserre Karine , Vallet Anne‐Evelyne
Published: September 2018

Background

Studies on the role of blood pressure (
BP
) variability specifically during mechanical thrombectomy (
MT
) are sparse and limited. Moreover, pulse pressure (
PP
) has not been considered as a potent hemodynamic parameter to describe
BP
variability during
MT
. We assessed the impact of
PP
variability on functional outcome in acute ischemic stroke patients with large vessel occlusion during
MT
.

Methods and Results

Acute ischemic stroke patients presenting with large vessel occlusion from January 2012 to June 2016 were included.
BP
data during
MT
were prospectively collected in the ETIS (Endovascular Treatment in Ischemic Stroke) registry. Logistic regression models were used to assess the association between
PP
coefficients of variation and functional outcome at 3 months (modified Rankin Scale). Among the 343 included patients,
PP
variability was significantly associated with worse 3‐month modified Rankin Scale in univariable (odds ratio
[OR]
=1.56, 95% confidence interval [CI]: 1.24–1.96 per 1‐unit increase,
P
=0.0002) and multivariable ordinal logistic regression (adjusted
OR
=1.40, 95%
CI
: 1.09–1.79,
P
=0.008).
PP
variability was also associated with unfavorable outcome (modified Rankin Scale 3–6) in univariable (
OR
=1.53, 95%
CI
: 1.17–2.01,
P
=0.002) and multivariable analysis (adjusted
OR
=1.42, 95%
CI
: 1.02–1.98,
P
=0.04). There was an association between
PP
variability and 3‐month all‐cause mortality in univariable analysis (
OR
= 1.37, 95%
CI
: 1.01–1.85 per 1‐unit increase of the coefficient of variation of the
PP
,
P
=0.04), which did not remain significant after adjustment for potential confounders.

Conclusions

PP
variability during
MT
is an independent predictor of worse clinical outcome in acute ischemic stroke patients. These findings support the need for a close monitoring of
BP
variability during
MT
. Whether pharmacological interventions aiming at reducing
BP
variability during
MT
could impact functional outcome needs to be determined.
Pathoanatomic Findings Associated With Duty‐Related Cardiac Death in US Firefighters: A Case–Control Study
Authors: Smith Denise L. , Haller Jeannie M. , Korre Maria , Fehling Patricia C. , Sampani Konstantina , Grossi Porto Luiz Guilherme , Christophi Costas A. , Kales Stefanos N.
Published: September 2018

Background

Sudden cardiac death accounts for the greatest proportion of duty‐related deaths among US firefighters. Increased understanding of the pathoanatomic causes of sudden cardiac death and the risk associated with underlying cardiac pathologies is needed to develop evidence‐based screening recommendations.

Methods and Results

Using autopsy data for duty‐related firefighter fatalities occurring between 1999 and 2014, this retrospective case–control study compared cardiac findings of male firefighters aged 18 to 65 years who died on duty of cardiac‐related causes with those who died of noncardiac trauma‐related causes. Data from 276 cardiac cases and 351 noncardiac trauma controls were analyzed. Among cardiac cases, the most prevalent (82%) underlying pathoanatomic substrate was comorbid coronary heart disease and cardiomegaly/left ventricular hypertrophy. Cardiac cases had a higher prevalence of cardiomegaly (heart weight >450 g), left ventricular hypertrophy (left ventricular wall thickness ≥1.2 cm), and severe coronary artery stenosis (≥75%) than trauma controls (all
P
<0.001). In multivariate analyses, heart weight >450 g, coronary artery stenosis ≥75%, and evidence of a prior myocardial infarction were strong independent predictors of cardiac death, with odds ratios of 6.1 (95% confidence interval, 3.6–10.4), 9.3 (95% confidence interval, 5.3–16.1), and 6.2 (95% confidence interval, 3.4–11.3), respectively.

Conclusions

The majority of cardiac fatalities had evidence of both coronary heart disease and increased heart mass, and each condition was independently associated with a markedly elevated risk of cardiac death. Targeted screening for coronary heart disease, increased heart mass, and evidence of prior myocardial infarction should be considered to reduce duty‐related cardiac deaths among firefighters.
Long‐Term Blood Pressure Level and Variability From Midlife to Later Life and Subsequent Cognitive Change: The ARIC Neurocognitive Study
Authors: Yano Yuichiro , Griswold Michael , Wang Wanmei , Greenland Philip , Lloyd‐Jones Donald M. , Heiss Gerardo , Gottesman Rebecca F. , Mosley Thomas H.
Published: September 2018

Background

To understand how blood pressure (
BP
) from midlife and beyond is related to cognition in older age, a lifespan approach is needed. We assessed the associations of
BP
levels and variability from midlife on with subsequent cognitive change.

Methods and Results

The ARIC (Atherosclerosis Risk in Communities) Study participants underwent 4 clinic
BP
measurements (visit 1, 2, 3, and 4
BP
s) between 1987 and 1998, and their mean levels and average real variability (
ARV
) were assessed as exposures. A global cognitive
z
score, estimated from the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test scores, was calculated at 1996 to 1998 (visit 4) and 2011 to 2013 (visit 5). Among 11 408 participants (mean age, 54 years; 56% women; 21% black race), mean systolic
BP
(
SBP
)/diastolic
BP
(
DBP
) level was 123/72 mm Hg, and

ARV
SBP

/

ARV
DBP

was 11/7 mm Hg. With linear mixed models, 1‐
SD
increases of

ARV
SBP

(standardized regression coefficient [95% confidence interval], −0.03 [−0.04 to −0.01] points) and

ARV
DBP

(standardized regression coefficient [95% confidence interval], −0.02 [−0.03 to −0.002] points; both
P
<0.05), but not mean
SBP
or
DBP
levels, were associated with lower global cognitive
z
scores at visit 4. In contrast, mean
SBP
(standardized regression coefficient [95% confidence interval], −0.04 [−0.06 to −0.02] points) or
DBP
(standardized regression coefficient [95% confidence interval], 0.04 [0.02–0.06] points; both
P
<0.001) level, but not

ARV
SBP

or

ARV
DBP

, was associated with change in global cognitive
z
scores from visits 4 to 5.

Conclusions

Greater visit‐to‐visit
SBP
or
DBP
variability from midlife on is modestly associated with lower cognitive function, whereas higher mean
SBP
and lower
DBP
levels from midlife to later life are modestly associated with cognitive decline in later life.
Causes and Predictors of 30‐Day Readmission in Patients With Syncope/Collapse: A Nationwide Cohort Study
Authors: Kadri Amer N. , Abuamsha Hasan , Nusairat Leen , Kadri Nazih , Abuissa Hussam , Masri Ahmad , Hernandez Adrian V.
Published: September 2018

Background

Syncope accounts for 0.6% to 1.5% of hospitalizations in the United States. We sought to determine the causes and predictors of 30‐day readmission in patients with syncope.

Methods and Results

We identified 323 250 encounters with a primary diagnosis of syncope/collapse in the 2013–2014 Nationwide Readmissions Database. We excluded patients younger than 18 years, those discharged in December, those who died during hospitalization, hospital transfers, and those whose length of stay was missing. We used multivariable logistic regression analysis to evaluate the association between baseline characteristics and 30‐day readmission. A total of 282 311 syncope admissions were included. The median age was 72 years (interquartile range, 58–83), 53.9% were women, and 9.3% had 30‐day readmission. The most common cause of 30‐day readmissions was syncope/collapse, followed by cardiac, neurological, and infectious causes. Characteristics associated with 30‐day readmissions were age 65 years and older (odds ratio [OR], 0.7; 95% confidence interval [
CI
], 0.6–0.7), female sex (OR, 0.9; 95% CI, 0.8–0.9), congestive heart failure (OR, 1.5; 95% CI, 1.2–1.9), atrial fibrillation/flutter (OR, 1.3; 95% CI, 1.3–1.4), diabetes mellitus (OR, 1.2; 95% CI, 1.2–1.3), coronary artery disease (OR, 1.2; 95% CI, 1.2–1.3), anemia (OR, 1.4; 95% CI, 1.4–1.5), chronic obstructive pulmonary disease (OR, 1.4; 95% CI, 1.3–1.4), home with home healthcare disposition (OR, 1.5; 95% CI, 1.5–1.6), leaving against medical advice (OR, 1.7; 95% CI, 1.6–1.9), length of stay of 3 to 5 days (OR, 1.5; 95% CI, 1.4–1.6) or >5 days (OR, 2; 95% CI, 1.8–2), and having private insurance (OR, 0.6; 95% CI, 0.6–0.7).

Conclusions

The 30‐day readmission rate after syncope/collapse was 9.3%. We identified causes and risk factors associated with readmission. Future prospective studies are needed to derive risk‐stratification models to reduce the high burden of readmissions.
Skin Autofluorescence–Indicated Advanced Glycation End Products as Predictors of Cardiovascular and All‐Cause Mortality in High‐Risk Subjects: A Systematic Review and Meta‐analysis
Authors: Cavero‐Redondo Ivan , Soriano‐Cano Alba , Álvarez‐Bueno Celia , Cunha Pedro G. , Martínez‐Hortelano Jose A. , Garrido‐Miguel Miriam , Berlanga‐Macías Carlos , Martínez‐Vizcaíno Vicente
Published: September 2018

Background

Chronic deposits of advanced glycation end products produced by enzymatic glycation have been suggested as predictors of atherosclerotic‐related disorders. This study aimed to estimate the relationship between advanced glycation end products indicated by skin autofluorescence levels and the risk of cardiovascular and all‐cause mortality based on data from observational studies.

Methods and Results

We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Web of Science databases from their inceptions until November 2017 for observational studies addressing the association of advanced glycation end products by skin autofluorescence levels with cardiovascular and all‐cause mortality. The DerSimonian and Laird random‐effects method was used to compute pooled estimates of hazard ratios and their respective 95% confidence intervals for the risk of cardiovascular and all‐cause mortality associated with levels of advanced glycation end products by skin autofluorescence. Ten published studies were included in the systematic review and meta‐analysis. Higher skin autofluorescence levels were significantly associated with a higher pooled risk estimate for cardiovascular mortality (hazard ratio: 2.06; 95% confidence interval, 1.58–2.67), which might not be important to moderate heterogeneity (I
2
=34.7%;
P
=0.163), and for all‐cause mortality (hazard ratio: 1.91; 95% confidence interval, 1.42–2.56) with substantial heterogeneity (I
2
=60.8%;
P
=0.0.18).

Conclusions

Our data suggest that skin autofluorescence levels could be considered predictors of all‐cause mortality and cardiovascular mortality in patients at high and very high risk.
Frailty and Outcomes After Myocardial Infarction: Insights From the CONCORDANCE Registry
Authors: Patel Ashish , Goodman Shaun G. , Yan Andrew T. , Alexander Karen P. , Wong Camilla L. , Cheema Asim N. , Udell Jacob A. , Kaul Padma , D'Souza Mario , Hyun Karice , Adams Mark , Weaver James , Chew Derek P. , Brieger David , Bagai Akshay
Published: September 2018

Background

Little is known about the prognostic implications of frailty, a state of susceptibility to stressors and poor recovery to homeostasis in older people, after myocardial infarction (
MI
).

Methods and Results

We studied 3944
MI
patients aged ≥65 years treated at 41 Australian hospitals from 2009 to 2016 in the CONCORDANCE (
Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events
) registry. Frailty index (
FI
) was determined using the health deficit accumulation method. All‐cause and cardiac‐specific mortality at 6 months were compared between frail (
FI
>0.25) and nonfrail (
FI
≤0.25) patients. Among 1275 patients with ST‐segment–elevation MI (STEMI), 192 (15%) were frail, and among 2669 non‐STEMI (
NSTEMI)
patients, 902 (34%) were frail. Compared with nonfrail counterparts, frail
STEMI
patients received 30% less reperfusion therapy and 22% less revascularization during index hospitalization; frail
NSTEMI
patients received 30% less diagnostic angiography and 39% less revascularization. Unadjusted 6‐month all‐cause mortality (
STEMI
: 13% versus 3%;
NSTEMI
: 13% versus 4%) and cardiac‐specific mortality (
STEMI
: 6% versus 1.4%,
NSTEMI
: 3.2% versus 1.2%) were higher among frail patients. After adjustment for known prognosticators,
FI
was significantly associated with higher 6‐month all‐cause (
STEMI
:
odds ratio:
1.74 per 0.1
FI [
95% confidence interval, 1.37–2.22],
P
<0.001;
NSTEMI
:
odds ratio:
1.62 per 0.1
FI
[95%
confidence interval,
1.40–1.87],
P
<0.001) but not cardiac‐specific mortality (
STEMI
:
P
=0.99;
NSTEMI
:
P
=0.93).

Conclusions

Frail patients receive lower rates of invasive cardiac care during
MI
hospitalization. Increased frailty was independently associated with increased postdischarge all‐cause mortality but not cardiac‐specific mortality. These findings inform identification of frailty during
MI
hospitalization as a potential opportunity to address competing risks for mortality in this high‐risk population.
Thirty‐Day Readmission Rates, Timing, Causes, and Costs after ST‐Segment–Elevation Myocardial Infarction in the United States: A National Readmission Database Analysis 2010–2014
Authors: Kim Luke K. , Yeo Ilhwan , Cheung Jim W. , Swaminathan Rajesh V. , Wong S. Chiu , Charitakis Konstantinos , Adejumo Oluwayemisi , Chae John , Minutello Robert M. , Bergman Geoffrey , Singh Harsimran , Feldman Dmitriy N.
Published: September 2018

Background

Readmission after ST‐segment–elevation myocardial infarction (
STEMI
) poses an enormous economic burden to the
US
healthcare system. Efforts to prevent readmissions should be based on understanding the timing and causes of these readmissions. This study aimed to investigate contemporary causes, timing, and cost of 30‐day readmissions after
STEMI
.

Methods and Results

All
STEMI
hospitalizations were selected in the Nationwide Readmissions Database (
NRD
) from 2010 to 2014. The 30‐day readmission rate as well as the primary cause and cost of readmission were examined. Multivariate regression analysis was performed to identify the predictors of 30‐day readmission and increased cumulative cost. From 2010 to 2014, the 30‐day readmission rate after
STEMI
was 12.3%. Within 7 days of discharge, 43.9% were readmitted, and 67.3% were readmitted within 14 days. The annual rate of 30‐day readmission decreased by 19% from 2010 to 2014 (
P
<0.001). Female sex,
AIDS
, anemia,
chronic kidney disease
, collagen vascular disease, diabetes mellitus, hypertension, pulmonary hypertension,
congestive heart failure
, atrial fibrillation, and increased length of stay were independent predictors of 30‐day readmission. A large proportion of patients (41.6%) were readmitted for noncardiac reasons. After multivariate adjustment, 30‐day readmission was associated with a 47.9% increase in cumulative cost (
P
<0.001).

Conclusions

Two thirds of patients were readmitted within the first 14 days after
STEMI
, and a large proportion of patients were readmitted for noncardiac reasons. Thirty‐day readmission was associated with an ≈50% increase in cumulative hospitalization costs. These findings highlight the importance of closer surveillance of both cardiac and general medical conditions in the first several weeks after
STEMI
discharge.