bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury
Authors: Zlatanova Ivana , Pinto Cristina , Bonnin Philippe , Mathieu Jacques R.R. , Bakker Wineke , Vilar Jose , Lemitre Mathilde , Voehringer David , Vaulont Sophie , Peyssonnaux Carole , Silvestre Jean-Sébastien 
Published: January 2019

Background:
Defective systemic and local iron metabolism correlates with cardiac disorders. Hepcidin, a master iron sensor, actively tunes iron trafficking. We hypothesized that hepcidin could play a key role to locally regulate cardiac homeostasis after acute myocardial infarction.

Methods:
Cardiac repair was analyzed in mice harboring specific cardiomyocyte or myeloid cell deficiency of hepcidin and challenged with acute myocardial infarction.

Results:

We found that the expression of hepcidin was elevated after acute myocardial infarction and the specific deletion of hepcidin in cardiomyocytes failed to improve cardiac repair and function. However, transplantation of bone marrow–derived cells from hepcidin-deficient mice (
Hamp
−/−
) or from mice with specific deletion of hepcidin in myeloid cells (LysM
CRE/+
/
Hamp
f/f
) improved cardiac function. This effect was associated with a robust reduction in the infarct size and tissue fibrosis in addition to favoring cardiomyocyte renewal. Macrophages lacking hepcidin promoted cardiomyocyte proliferation in a prototypic model of apical resection–induced cardiac regeneration in neonatal mice. Interleukin (IL)–6 increased hepcidin levels in inflammatory macrophages. Hepcidin deficiency enhanced the number of CD45
+
/CD11b
+
/F4/80
+
/CD64
+
/MHCII
Low
/chemokine (C–C motif) receptor 2 (CCR2)
+
inflammatory macrophages and fostered signal transducer and activator of transcription factor-3 (STAT3) phosphorylation, an instrumental step in the release of IL-4 and IL-13. The combined genetic suppression of hepcidin and IL-4/IL-13 in macrophages failed to improve cardiac function in both adult and neonatal injured hearts.

Conclusions:
Hepcidin refrains macrophage-induced cardiac repair and regeneration through modulation of IL-4/IL-13 pathways.
Early Risks of Death, Stroke/Systemic Embolism, and Major Bleeding in Patients With Newly Diagnosed Atrial Fibrillation
Authors: Bassand Jean-Pierre , Virdone Saverio , Goldhaber Samuel Z. , Camm A. John , Fitzmaurice David A. , Fox Keith A.A. , Goto Shinya , Haas Sylvia , Hacke Werner , Kayani Gloria , Mantovani Lorenzo G. , Misselwitz Frank , Pieper Karen S. , Turpie Alexander G.G. , van Eickels Martin , Verheugt Freek W.A. , Kakkar Ajay K. ,   For the GARFIELD-AF Investigators
Published: January 2019

Background:
Atrial fibrillation is associated with increased risks of death, stroke/systemic embolism, and bleeding (incurred by antithrombotic therapy), which may occur early after diagnosis.

Methods:
We assessed the risk of early events (death, stroke/systemic embolism, and major bleeding) over 12 months and their relation to the time after diagnosis of atrial fibrillation in 52 014 patients prospectively enrolled in the GARFIELD-AF registry (Global Anticoagulant Registry in the FIELD–Atrial Fibrillation) between March 2010 and August 2016.

Results:
Over 12 months, 2140 patients died (mortality rate, 4.3; 95% CI, 4.2–4.5 per 100 person-years), of whom 288 (13.5%) died in the first month (6.8; 95% CI, 6.1–7.6). Over 12 months, 657 patients had a stroke/systemic embolism (1.3; 95% CI, 1.2–1.4) and 411 had a major bleeding (0.8; 95% CI, 0.8–0.9). During the first month, the rates (per 100 person-years) of stroke/systemic embolism and major bleed were 2.3 (95% CI, 1.9–2.8) and 1.5 (95% CI, 1.2–1.9), respectively. The elevated 1-month mortality rate was mostly attributable to cardiovascular mortality (3.5; 95% CI, 3.0–4.1), in particular, heart failure, sudden death, and acute coronary syndromes (1.0 [95% CI, 0.8–1.4], 0.6 [95% CI, 0.4–0.8], and 0.5 [95% CI, 0.3–0.8], respectively). Age, heart failure, prior stroke, history of cirrhosis, vascular disease, moderate-to-severe kidney disease, diabetes mellitus, and living in North or Latin America were independent predictors of a higher risk of early death, whereas anticoagulation and living in Europe or Asia were independent predictors of a lower risk of early death. A predictive model developed for the 1-month risk of death had a C-statistic of 0.81 (95% CI, 0.78–0.83).

Conclusions:
The increased hazard of early events, in particular, cardiovascular mortality, in newly diagnosed atrial fibrillation points to the importance of comprehensive care for such patients and should alert clinicians to detect warning signs of possible early mortality.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01090362.
Evaluation of Microvascular Injury in Revascularized Patients With ST-Segment–Elevation Myocardial Infarction Treated With Ticagrelor Versus Prasugrel
Authors: van Leeuwen Maarten A.H. , van der Hoeven Nina W. , Janssens Gladys N. , Everaars Henk , Nap Alexander , Lemkes Jorrit S. , de Waard Guus A. , van de Ven Peter M. , van Rossum Albert C. , ten Cate Tim J.F. , Piek Jan J. , von Birgelen Clemens , Escaned Javier , Valgimigli Marco , Diletti Roberto , Riksen Niels P. , van Mieghem Nicolas M. , Nijveldt Robin , van Royen Niels 
Published: January 2019

Background:
Despite successful restoration of epicardial vessel patency with primary percutaneous coronary intervention, coronary microvascular injury occurs in a large proportion of patients with ST-segment–elevation myocardial infarction, adversely affecting clinical and functional outcome. Ticagrelor has been reported to increase plasma adenosine levels, which might have a protective effect on the microcirculation. We investigated whether ticagrelor maintenance therapy after revascularized ST-segment–elevation myocardial infarction is associated with less coronary microvascular injury compared to prasugrel maintenance therapy.

Methods:
A total of 110 patients with ST-segment–elevation myocardial infarction received a loading dose of ticagrelor and were randomized to maintenance therapy of ticagrelor (n=56) or prasugrel (n=54) after primary percutaneous coronary intervention. The primary outcome was coronary microvascular injury at 1 month, as determined with the index of microcirculatory resistance in the infarct-related artery. Cardiovascular magnetic resonance imaging was performed during the acute phase and at 1 month.

Results:

The primary outcome of index of microcirculatory resistance was not superior in ticagrelor- or prasugrel-treated patients (ticagrelor, 21 [interquartile range, 15–39] U; prasugrel, 18 [interquartile range, 11–29] U;
P
=0.08). Recovery of microcirculatory resistance over time was not better in patients with ticagrelor versus prasugrel (ticagrelor, −13.9 U; prasugrel, −13.5 U;
P
=0.96). Intramyocardial hemorrhage was observed less frequently in patients receiving ticagrelor (23% versus 43%;
P
=0.04). At 1 month, no difference in infarct size was observed (ticagrelor, 7.6 [interquartile range, 3.7–14.4] g, prasugrel 9.9 [interquartile range, 5.7–16.6] g;
P
=0.17). The occurrence of microvascular obstruction was not different in patients on ticagrelor (28%) or prasugrel (41%;
P
=0.35). Plasma adenosine concentrations were not different during the index procedure and during maintenance therapy with ticagrelor or prasugrel.

Conclusions:
In patients with ST-segment–elevation myocardial infarction, ticagrelor maintenance therapy was not superior to prasugrel in preventing coronary microvascular injury in the infarct-related territory as assessed by the index of microcirculatory resistance, and this resulted in a comparable infarct size at 1 month.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02422888.
Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration
Authors: Fan Qin , Tao Rong , Zhang Hang , Xie Hongyang , Lu Lin , Wang Ting , Su Min , Hu Jian , Zhang Qi , Chen Qiujing , Iwakura Yoichiro , Shen Weifeng , Zhang Ruiyan , Yan Xiaoxiang 
Published: January 2019

Background:
Macrophage-associated immune response plays an important role in myocardial ischemia/reperfusion (IR) injury. Dectin-1, expressed mainly on activated myeloid cells, is crucial for the regulation of immune homeostasis as a pattern recognition receptor. However, its effects and roles during the myocardial IR injury remain unknown.

Methods:

Genetic ablation, antibody blockade, or Dectin-1 activation, along with the adoptive bone marrow transfer chimeric model, was used to determine the functional significance of Dectin-1 in myocardial IR injury. Immune cell filtration and inflammation were examined by flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Moreover, Dectin-1
+
cells were analyzed by flow cytometry in the blood of patients with ST-segment–elevation myocardial infarction and stable patients with normal coronary artery (control).

Results:

We demonstrated that Dectin-1 expression observed on the bone marrow–derived macrophages is increased in the heart during the early phase after IR injury. Dectin-1 deficiency and antibody-mediated Dectin-1 inhibition led to a considerable improvement in cardiac function, accompanied by a reduction in cardiomyocyte apoptosis, which was associated with a decrease in M1 macrophage polarization and Ly-6C
+
monocyte and neutrophil infiltration. Activation of Dectin-1 with its agonist had the opposite effects. Furthermore, Dectin-1 contributed to neutrophil recruitment through the regulation of Cxcl1 and granulocyte colony-stimulating factor expression. In addition, Dectin-1–dependent interleukin-23/interleukin-1β production was shown to be essential for interleukin-17A expression by γδT cells, leading to neutrophil recruitment and myocardial IR injury. Furthermore, we demonstrated that circulating Dectin-1
+
CD14
++
CD16
−
and Dectin-1
+
CD14
++
CD16
+
monocyte levels were significantly higher in patients with ST-segment–elevation myocardial infarction than in controls and positively correlated with the severity of cardiac dysfunction.

Conclusions:
Our results reveal a crucial role of Dectin-1 in the process of mouse myocardial IR injury and provide a new, clinically significant therapeutic target.
Idarucizumab for Dabigatran Reversal in the Management of Patients With Gastrointestinal Bleeding
Authors: Van der Wall Sake J. , Lopes Renato D. , Aisenberg James , Reilly Paul , van Ryn Joanne , Glund Stephan , Elsaesser Amelie , Klok Frederikus A. , Pollack Charles V. , Huisman Menno V. 
Published: January 2019

Background:
Although dabigatran has a favorable risk-benefit profile compared with vitamin K antagonist therapy for venous thromboembolism and nonvalvular atrial fibrillation, major bleeding events, including gastrointestinal (GI) bleeding, may occur. Therefore, our aim was to provide insights into the efficacy and safety of idarucizumab for urgent dabigatran reversal in patients with major GI bleeding.

Methods:
Patients with uncontrollable GI bleeding requiring reversal were enrolled from June 2014 through July 2016 in the RE-VERSE AD study (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab), a prospective, multicenter, open-label study of idarucizumab, and were followed up for 90 days for primary and secondary outcomes. Patients were to receive a 5-g dose of intravenous idarucizumab, administered as 2 bolus infusions of 2.5 g no more than 15 minutes apart. The primary end point was the maximum reversal of dabigatran anticoagulation within 4 hours after administration of idarucizumab as measured by the dabigatran-specific assays diluted thrombin time and ecarin clotting time. Further end points included investigator-reported bleeding cessation within the first 24 hours and incidence of rebleeding, thromboembolic events, or mortality.

Results:
GI bleeding occurred in 137 patients enrolled in RE-VERSE AD, of which 84% was adjudicated as major or life-threatening, 48 (35.0%) was upper GI tract in origin, 43 (31.4%) was lower GI in origin, and 46 (33.6%) was either both or unknown. Complete reversal of dabigatran was observed in 118 of 121 patients (97.5%) with an elevated diluted thrombin time at presentation and 95 of 131 patients (72.5%) with an elevated ecarin clotting time and was similar for upper and lower GI bleeding. Bleeding cessation within 24 hours was reported in 92 of 134 evaluable patients (68.7%) after a median duration of 2.4 hours (interquartile range, 2.0–3.9 hours). During the 90-day follow-up, 6 patients (4.4%) had a postreversal thromboembolic event, and 20 patients (14.6%) died.

Conclusions:
Idarucizumab showed a rapid and complete reversal of dabigatran activity in nearly all patients presenting with GI bleeding, facilitating emergency patient care without the additional presence of anticoagulation.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02104947.
Physiological and Clinical Assessment of Resting Physiological Indexes
Authors: Lee Joo Myung , Choi Ki Hong , Park Jonghanne , Hwang Doyeon , Rhee Tae-Min , Kim Jinseob , Park Jinhyoung , Kim Hyung Yoon , Jung Hae Won , Cho Yun-Kyeong , Yoon Hyuck-Jun , Song Young Bin , Hahn Joo-Yong , Nam Chang-Wook , Shin Eun-Seok , Doh Joon-Hyung , Hur Seung-Ho , Koo Bon-Kwon 
Published: January 2019

Background:
Recently, resting pressure–derived indexes such as resting full-cycle ratio (RFR) and diastolic pressure ratio (dPR) have been introduced to assess the functional significance of epicardial coronary stenosis. The present study sought to investigate the agreement of RFR or dPR with other pressure-derived indexes (instantaneous wave-free ratio [iFR] or fractional flow reserve), the sensitivity of RFR or dPR for anatomic or hemodynamic stenosis severity, and the prognostic implications of RFR or dPR compared with iFR

Methods:

RFR and dPR were calculated from resting pressure tracings by an independent core laboratory in 1024 vessels (435 patients). The changes in resting physiological indexes according to diameter stenosis were compared among iFR, RFR, and dPR. Among 115 patients who underwent
13
N-ammonia positron emission tomography, the changes in those indexes according to basal and hyperemic stenosis resistance and absolute hyperemic myocardial blood flow were compared. The association between resting physiological indexes and the risk of 2-year vessel-oriented composite outcomes (a composite of cardiac death, vessel-related myocardial infarction, and vessel-related ischemia-driven revascularization) was analyzed among 864 deferred vessels.

Results:

Both RFR and dPR showed a significant correlation with iFR (
R
=0.979,
P
<0.001 for RFR; and
R
=0.985,
P
<0.001 for dPR), which was higher than that with fractional flow reserve (
R
=0.822,
P
<0.001; and
R
=0.819,
P
<0.001, respectively). RFR and dPR showed a very high agreement with iFR (C index, 0.987 and 0.993). Percent difference of iFR, RFR, and dPR according to the increase in anatomic and hemodynamic severity was almost identical. The diagnostic performance of iFR, RFR, and dPR was not different in the prediction of myocardial ischemia defined by both low hyperemic myocardial blood flow and low coronary flow reserve by
13
N-ammonia positron emission tomography. All resting physiological indexes showed significant association with the risk of 2-year vessel-oriented composite outcomes (iFR per 0.1 increase: hazard ratio, 0.514 [95% CI, 0.370–0.715],
P
<0.001; RFR per 0.1 increase: hazard ratio, 0.524 [95% CI, 0.378–0.725],
P
<0.001; dPR per 0.1 increase: hazard ratio, 0.587 [95% CI, 0.436–0.791],
P
<0.001) in deferred vessels.

Conclusions:
All resting pressure–derived physiological indexes (iFR, RFR, and dPR) can be used as invasive tools to guide treatment strategy in patients with coronary artery disease.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01621438.
Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation
Authors: Kang Duk-Hyun , Park Sung-Ji , Shin Sung-Hee , Hong Geu-Ru , Lee Sahmin , Kim Min-Seok , Yun Sung-Cheol , Song Jong-Min , Park Seung-Woo , Kim Jae-Joong 
Published: January 2019

Background:
The morbidity and mortality of patients with functional mitral regurgitation (MR) remain high, but no pharmacological therapy has been proven effective. The hypothesis of this study was that sacubitril/valsartan would be superior to valsartan alone in improving functional MR via dual inhibition of the renin-angiotensin system and neprilysin.

Methods:
In this double-blind trial, we randomly assigned 118 patients with heart failure with chronic functional MR secondary to left ventricular (LV) dysfunction to receive either sacubitril/valsartan or valsartan, in addition to standard medical therapy for heart failure. The primary end point was the change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, LV end-systolic volume, LV end-diastolic volume, and incomplete mitral leaflet closure area.

Results:

The decrease in effective regurgitant orifice area was significantly greater in the sacubitril/valsartan group than in the valsartan group (–0.058±0.095 versus –0.018±0.105 cm
2
;
P
=0.032) in an intention-to-treat analysis including 117 (99%) patients. Regurgitant volume was also significantly decreased in the sacubitril/valsartan group in comparison with the valsartan group (mean difference, –7.3 mL; 95% CI, –12.6 to –1.9;
P
=0.009). There were no significant between-group differences regarding the changes in incomplete mitral leaflet closure area and LV volumes, with the exception of LV end-diastolic volume index (
P
=0.044). We noted no significant difference in the change of blood pressure between the treatment groups, and 7 patients (12%) in the sacubitril/valsartan group and 9 (16%) in the valsartan group had ≥1 serious adverse events (
P
=0.54).

Conclusions:
Among patients with secondary functional MR, sacubitril/valsartan reduced MR to a greater extent than did valsartan. Our findings suggest that an angiotensin receptor-neprilysin inhibitor might be considered for optimal medical therapy of patients with heart failure and functional MR.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02687932.
Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials
Authors: Fanaroff Alexander C. , Clare Robert , Pieper Karen S. , Mahaffey Kenneth W. , Melloni Chiara , Green Jennifer B. , Alexander John H. , Jones W. Schuyler , Harrison Robert W. , Mehta Rajendra H. , Povsic Thomas J. , Moreira Humberto G. , Al-Khatib Sana M. , Roe Matthew T. , Kong David F. , Mathews Robin , Tricoci Pierluigi , Holman Rury R. , Wallentin Lars , Held Claes , Califf Robert M. , Alexander Karen P. , Lopes Renato D. 
Published: January 2019

Background:
Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed.

Methods:
Data from 9 global clinical trials (2009–2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre–diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model.

Results:
Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre–diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause.

Conclusions:
In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.
Glucose-Sensitive Myokine/Cardiokine MG53 Regulates Systemic Insulin Response and Metabolic Homeostasis
Authors: Wu Hong-Kun , Zhang Yan , Cao Chun-Mei , Hu Xinli , Fang Meng , Yao Yuan , Jin Li , Chen Gengjia , Jiang Peng , Zhang Shuo , Song Ruisheng , Peng Wei , Liu Fenghua , Guo Jiaojiao , Tang Lifei , He Yanyun , Shan Dan , Huang Jin , Zhou Zhuan , Wang Dao Wen , Lv Fengxiang , Xiao Rui-Ping 
Published: January 2019

Background:
Mitsugumin 53 (MG53 or TRIM72), a striated muscle-specific E3 ligase, promotes ubiquitin-dependent degradation of the insulin receptor and insulin receptor substrate-1 and subsequently induces insulin resistance, resulting in metabolic syndrome and type 2 diabetes mellitus (T2DM). However, it is unknown how MG53 from muscle regulates systemic insulin response and energy metabolism. Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that regulate systemic metabolic processes. We hypothesize that MG53 may act as a myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic homeostasis.

Methods:

Using perfused rodent hearts or skeletal muscle, we investigated whether high glucose, high insulin, or their combination (conditions mimicking metabolic syndrome or T2DM) alters MG53 protein concentration in the perfusate. We also measured serum MG53 levels in rodents and humans in the presence or absence of metabolic diseases, particularly T2DM. The effects of circulating MG53 on multiorgan insulin response were evaluated by systemic delivery of recombinant MG53 protein to mice. Furthermore, the potential involvement of circulating MG53 in the pathogenesis of T2DM was assessed by neutralizing blood MG53 with monoclonal antibodies in diabetic
db/db
mice. Finally, to delineate the mechanism underlying the action of extracellular MG53 on insulin signaling, we analyzed the potential interaction of MG53 with extracellular domain of insulin receptor using coimmunoprecipitation and surface plasmon resonance assays.

Results:

Here, we demonstrate that MG53 is a glucose-sensitive myokine/cardiokine that governs the interorgan regulation of insulin sensitivity. First, high glucose or high insulin induces MG53 secretion from isolated rodent hearts and skeletal muscle. Second, hyperglycemia is accompanied by increased circulating MG53 in humans and rodents with diabetes mellitus. Third, systemic delivery of recombinant MG53 or cardiac-specific overexpression of MG53 causes systemic insulin resistance and metabolic syndrome in mice, whereas neutralizing circulating MG53 with monoclonal antibodies has therapeutic effects in T2DM
db/db
mice. Mechanistically, MG53 binds to the extracellular domain of the insulin receptor and acts as an allosteric blocker.

Conclusions:
Thus, MG53 has dual actions as a myokine/cardiokine and an E3 ligase, synergistically inhibiting the insulin signaling pathway. Targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.