bluuebunny/crossref_metadata_2025 huggingface dataset:
Expansive Vascular Remodeling and Increased Vascular Calcification Response to Cholecalciferol in a Murine Model of Obesity and Insulin Resistance
Authors: Carmo Luciana S. , Burdmann Emmanuel A. , Fessel Melissa R. , Almeida Youri E. , Pescatore Luciana A. , Farias-Silva Elisangela , Gamarra Lionel F. , Lopes Gabriel H. , Aloia Thiago P.A. , Liberman Marcel
Published: January 2019

Objective—

We hypothesized that ob/ob mice develop expansive vascular remodeling associated with calcification.

Approach and Results—

We quantified and investigated mechanisms of vascular remodeling and vascular calcification in ob/ob mice after vitamin D
3
(VD) stimulation or PBS (control), compared with C57BL/6 mice. Both ob/ob (OBVD [VD-treated ob/ob mice]) and C57BL/6 (C57VD [VD-treated C57BL/6 mice]) received 8×10
3
IU/day of intraperitoneal VD for 14 days. Control ob/ob (OBCT [PBS-treated ob/ob mice]) and C57BL/6 (C57CT [PBS-treated C57BL/6 mice]) received intraperitoneal PBS for 14 days. Hypervitaminosis D increased the external and internal elastic length in aortae from OBVD, resulting in increased total vascular area and lumen vascular area, respectively, which characterizes expansive vascular remodeling. OBVD decreased the aortic wall thickness, resulting in hypotrophic vascular remodeling. We demonstrated increased collagen deposition, elastolysis, and calcification in aortae from OBVD. Our results showed a positive correlation between expansive vascular remodeling and vascular calcification in OBVD. We demonstrated increased serum calcium levels, augmented Bmp (bone morphogenetic protein)-2 and osteochondrogenic proteins expression in OBVD aortae. Furthermore, aortae from OBVD increased oxidative stress, coincidently with augmented in situ MMP (matrix metalloproteinase) activity and exhibited no VDR (VD receptor) inhibition after VD.

Conclusions—

Our data provide evidence that obese and insulin-resistant mice (ob/ob) developed expansive hypotrophic vascular remodeling correlated directly with increased vascular calcification after chronic VD stimulation. Positive hypotrophic vascular remodeling and vascular calcification in this mouse model is possibly mediated by the convergence of absence VDR downregulation after VD stimulation, increased reactive oxygen species generation, and MMP activation.
Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology
Authors: Lloyd-Jones Donald M. , Braun Lynne T. , Ndumele Chiadi E. , Smith Sidney C. , Sperling Laurence S. , Virani Salim S. , Blumenthal Roger S.
Published: January 2019

Risk assessment is a critical step in the current approach to primary prevention of atherosclerotic cardiovascular disease. Knowledge of the 10-year risk for atherosclerotic cardiovascular disease identifies patients in higher-risk groups who are likely to have greater net benefit and lower number needed to treat for both statins and antihypertensive therapy. Current US prevention guidelines for blood pressure and cholesterol management recommend use of the pooled cohort equations to start a process of shared decision-making between clinicians and patients in primary prevention. The pooled cohort equations have been widely validated and are broadly useful for the general US clinical population. But, they may systematically underestimate risk in patients from certain racial/ethnic groups, those with lower socioeconomic status or with chronic inflammatory diseases, and overestimate risk in patients with higher socioeconomic status or who have been closely engaged with preventive healthcare services. If uncertainty remains for patients at borderline or intermediate risk, or if the patient is undecided after a patient–clinician discussion with consideration of risk enhancing factors (eg, family history), additional testing with measurement of coronary artery calcium can be useful to reclassify risk estimates and improve selection of patients for use or avoidance of statin therapy. This special report summarizes the rationale and evidence base for quantitative risk assessment, reviews strengths and limitations of existing risk scores, discusses approaches for refining individual risk estimates for patients, and provides practical advice regarding implementation of risk assessment and decision-making strategies in clinical practice.
YAP and TAZ Negatively Regulate Prox1 During Developmental and Pathologic Lymphangiogenesis
Authors: Cho Hyunsoo , Kim Jaeryung , Ahn Ji Hoon , Hong Young-Kwon , Mäkinen Taija , Lim Dae-Sik , Koh Gou Young
Published: January 2019

Rationale:

The Hippo pathway governs cellular differentiation, morphogenesis, and homeostasis, but how it regulates these processes in lymphatic vessels is unknown.

Objective:

We aimed to reveal the role of the final effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), in lymphatic endothelial cell (LEC) differentiation, morphogenesis, and homeostasis.

Methods and Results:

During mouse embryonic development, LEC-specific depletion of
Yap/Taz
disturbed both plexus patterning and valve initiation with upregulated Prox1 (prospero homeobox 1). Conversely, LEC-specific YAP/TAZ hyperactivation impaired lymphatic specification and restricted lymphatic sprouting with profoundly downregulated Prox1. Notably, lymphatic YAP/TAZ depletion or hyperactivation aggravated or attenuated pathological lymphangiogenesis in mouse cornea. Mechanistically, VEGF (vascular endothelial growth factor)-C activated canonical Hippo signaling pathway in LECs. Indeed, repression of
PROX1
transcription by YAP/TAZ hyperactivation was mediated by recruitment of NuRD (nucleosome remodeling and histone deacetylase) complex and endogenous binding activity of TEAD (TEA domain family members) to the
PROX1
promoter. Furthermore, YAP/TAZ hyperactivation enhanced MYC signaling and inhibited
CDKN1C
, leading to cell cycle dysregulation and aberrant proliferation.

Conclusions:

We find that YAP and TAZ play promoting roles in remodeling lymphatic plexus patterning and postnatal lymphatic valve maintenance by negatively regulating Prox1 expression. We further show that YAP and TAZ act as plastic regulators of lymphatic identity and define the Hippo signaling-mediated
PROX1
transcriptional programing as a novel dynamic checkpoint underlying LEC plasticity and pathophysiology.
Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder
Authors: Greaney Jody L. , Saunders Erika F.H. , Santhanam Lakshmi , Alexander Lacy M.
Published: January 2019

Rationale:

In rodent models of depression, oxidative stress-induced reductions in NO bioavailability contribute to impaired endothelium-dependent dilation. Endothelial dysfunction is evident in major depressive disorder (MDD); however, the molecular mediators remain undefined.

Objective:

We sought to translate preclinical findings to humans by testing the role of oxidative stress in mediating microvascular endothelial dysfunction, including potential modulatory influences of sex, in MDD.

Methods and Results:

Twenty-four treatment-naive, otherwise healthy, young adults with MDD (14 women; 18–23 years) and 20 healthy adults (10 women; 19–30 years) participated. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine, alone and in combination with an NO synthase inhibitor (L-NAME), a superoxide scavenger (Tempol), and an NADPH oxidase inhibitor (apocynin), as well as during perfusion of the endothelium-independent agonist sodium nitroprusside. Tissue oxidative stress markers (eg, nitrotyrosine abundance, superoxide production) were also quantified. Endothelium-dependent dilation was blunted in MDD and mediated by reductions in NO-dependent dilation. Endothelium-independent dilation was likewise attenuated in MDD. In MDD, there were no sex differences in either NO-mediated endothelium-dependent dilation or endothelium-independent dilation. Acute scavenging of superoxide or inhibition of NADPH oxidase improved NO-dependent dilation in MDD. Expression and activity of oxidative stress markers were increased in MDD. In a subset of adults with MDD treated with a selective serotonin reuptake inhibitor for their depressive symptoms and in remission (n=8; 7 women; 19–37 years), NO-mediated endothelium-dependent dilation was preserved, but endothelium-independent dilation was impaired, compared with healthy adults.

Conclusions:

Oxidative stress-induced reductions in NO-dependent dilation, as well as alterations in vascular smooth muscle function, directly contribute to microvascular dysfunction in MDD. Strategies targeting vascular oxidative stress may be viable therapeutic options for improving NO-mediated endothelial function and reducing cardiovascular risk in MDD.
Atherosclerotic Conditions Promote the Packaging of Functional MicroRNA-92a-3p Into Endothelial Microvesicles
Authors: Liu Yangyang , Li Qian , Hosen Mohammed Rabiul , Zietzer Andreas , Flender Anna , Levermann Paula , Schmitz Theresa , Frühwald Daniel , Goody Philip , Nickenig Georg , Werner Nikos , Jansen Felix
Published: January 2019

Rationale:

Microvesicle-incorporated microRNAs (miRs) are biomarkers and effectors of cardiovascular disease. Whether microvesicle-miR expression is regulated in coronary artery disease (CAD) or not is unknown.

Objective:

Here, we explore the expression of circulating microvesicle-miRs in patients with CAD and investigate the role of microvesicle-miR in endothelial cells.

Methods and Results:

Circulating microvesicles were isolated from patients’ plasma by using ultracentrifugation. Electron microscopy was used to determine the size of the microvesicles. A Taqman miR array revealed certain microvesicle-miRs are significantly regulated in patients with stable CAD compared with patients with ACS. To validate the miR array results, 180 patients with angiographically excluded CAD (n=41), stable CAD (n=77), and acute coronary syndrome (n=62) were prospectively studied. Nine miRs involved in regulation of vascular performance—miR-126-3p, miR-222-3p, miR-let-7d-5p, miR-21-5p, miR-26a-5p, miR-92a-3p, miR-139-5p, miR-30b-5p, and miR-199a-5p—were quantified in circulating microvesicles by real-time polymerase chain reaction (PCR). Among these, miR-92a-3p was significantly increased in patients with CAD compared with non-CAD patients. Microvesicle-sorting experiments showed endothelial cells (ECs) were the major cell source for microvesicles containing miR-92a-3p. In vitro oxLDL (oxidized low-density lipoprotein) and IL-6 (interleukin-6) stimulation increased miR-92a-3p expression in parent ECs and upregulated the expression level of endothelial microvesicle (EMV)-incorporated miR-92a-3p. Labeling of miR-92a-3p and EMVs demonstrated that functional miR-92a-3p was transported into recipient ECs, which accelerated cell migration and proliferation. Knockdown of miR-92a-3p in EMVs abrogated EMV-mediated effects on EC migration, proliferation, and blocked vascular network formation in a matrigel plug. Polymerase chain reaction–based gene profiling showed that the expression of THBS1 (thrombospondin 1) protein—a target of miR-92a-3p and an inhibitor of angiogenesis—was significantly reduced in ECs by EMVs. Knockdown of miR-92a-3p in EMVs abrogated EMV-mediated inhibition of the THBS1 gene and protein expression.

Conclusions:

Atherosclerotic conditions promote the packaging of endothelial miR-92a-3p into EMVs. EMV-mediated transfer of functional miR-92a-3p regulates angiogenesis in recipient ECs by a THBS1-dependent mechanism.
Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function
Authors: Hall Ignacio Fernando , Climent Montserrat , Quintavalle Manuela , Farina Floriana Maria , Schorn Tilo , Zani Stefania , Carullo Pierluigi , Kunderfranco Paolo , Civilini Efrem , Condorelli Gianluigi , Elia Leonardo
Published: January 2019

Rationale:

microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs are involved in the modulation of miRNA activity in VSMCs is unknown.

Objective:

We aimed to identify circular RNAs interacting with miRNAs enriched in VSMCs and modulating the cells’ activity.

Methods and Results:

RNA sequencing and bioinformatics identified several circular RNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circular RNA gemmed from alternative splicing of Lrp6 (lipoprotein receptor 6), a gene highly expressed in vessels and implicated in vascular pathologies and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITGβ8 (integrin-β8), FASCIN (fascin actin-bundling protein 1), KLF4 (Kruppel-like factor 4),
Yes1
(YES proto-oncogene 1), and
Lox
(lysyl oxidase). The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR-145 versus unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids.

Conclusions:

circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.
Relationship Between Operator Volume and Long-Term Outcomes After Percutaneous Coronary Intervention
Authors: Fanaroff Alexander C. , Zakroysky Pearl , Wojdyla Daniel , Kaltenbach Lisa A. , Sherwood Matthew W. , Roe Matthew T. , Wang Tracy Y. , Peterson Eric D. , Gurm Hitinder S. , Cohen Mauricio G. , Messenger John C. , Rao Sunil V.
Published: January 2019

Background:

Although many studies show an inverse association between operator procedural volume and short-term adverse outcomes after percutaneous coronary intervention (PCI), the association between procedural volume and longer-term outcomes is unknown.

Methods:

Using the National Cardiovascular Data Registry CathPCI registry data linked with Medicare claims data, we examined the association between operator PCI volume and long-term outcomes among patients ≥65 years of age. Operators were stratified by average annual PCI volume (counting PCIs performed in patients of all ages): low- (<50 PCIs), intermediate- (50–100), and high- (>100) volume operators. One-year unadjusted rates of death and major adverse coronary events (MACEs; defined as death, readmission for myocardial infarction, or unplanned coronary revascularization) were calculated with Kaplan-Meier methods. The proportional hazards assumption was not met, and risk-adjusted associations between operator volume and outcomes were calculated separately from the time of PCI to hospital discharge and from hospital discharge to 1-year follow-up.

Results:

Between July 1, 2009, and December 31, 2014, 723 644 PCI procedures were performed by 8936 operators: 2553 high-, 2878 intermediate-, and 3505 low-volume operators. Compared with high- and intermediate-volume operators, low-volume operators more often performed emergency PCI, and their patients had fewer cardiovascular comorbidities. Over 1-year follow-up, 15.9% of patients treated by low-volume operators had a MACE compared with 16.9% of patients treated by high-volume operators (
P
=0.004). After multivariable adjustment, intermediate- and high-volume operators had a significantly lower rate of in-hospital death than low-volume operators (odds ratio, 0.91; 95% CI, 0.86–0.96 for intermediate versus low; odds ratio, 0.79; 95% CI, 0.75–0.83 for high versus low). There were no significant differences in rates of MACEs, death, myocardial infarction, or unplanned revascularization between operator cohorts from hospital discharge to 1-year follow-up (adjusted hazard ratio for MACEs, 0.99; 95% CI, 0.96–1.01 for intermediate versus low; hazard ratio, 1.01; 95% CI, 0.99–1.04 for high versus low).

Conclusions:

Unadjusted 1-year outcomes after PCI were worse for older adults treated by operators with higher annual volume; however, patients treated by these operators had more cardiovascular comorbidities. After risk adjustment, higher operator volume was associated with lower in-hospital mortality and no difference in postdischarge MACEs.
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.
Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial
Authors: Fitchett David , Inzucchi Silvio E. , Cannon Christopher P. , McGuire Darren K. , Scirica Benjamin M. , Johansen Odd Erik , Sambevski Steven , Kaspers Stefan , Pfarr Egon , George Jyothis T. , Zinman Bernard
Published: January 2019

Background:

In the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure. We investigated whether these effects varied across the spectrum of baseline cardiovascular risk.

Methods:

Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention.

Results:

Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline (
P
>0.05 for randomized group-by-subgroup interactions).

Conclusions:

Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events. Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01131676.
Anti-Inflammatory Therapy With Canakinumab for the Prevention of Hospitalization for Heart Failure
Authors: Everett Brendan M. , Cornel Jan H. , Lainscak Mitja , Anker Stefan D. , Abbate Antonio , Thuren Tom , Libby Peter , Glynn Robert J. , Ridker Paul M
Published: January 2019

Background:

Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure–related mortality.

Methods:

We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure–related mortality.

Results:

A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively;
P
<0.0001). The unadjusted hazard ratios for HHF with each dose of canakinumab compared with placebo were 1.04 (95% CI, 0.79–1.36) for 50 mg, 0.86 (95% CI, 0.65–1.13) for 150 mg, and 0.76 (95% CI, 0.57–1.01) for 300 mg (
P
for trend=0.025). The composite of HHF or heart failure–related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78–1.29) for 50 mg, 0.88 (95% CI, 0.68–1.13) for 150 mg, and 0.78 (95% CI, 0.60–1.02) for 300 mg (
P
for trend=0.042).

Conclusions:

These randomized double-blind placebo-controlled data suggest that therapy with canakinumab, an interleukin-1β inhibitor, is related to a dose-dependent reduction in HHF and the composite of HHF or heart failure–related mortality in a population of patients with prior myocardial infarction and elevations in high-sensitivity C-reactive protein.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01327846.