Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis.

Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gram-negative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis.

Calcium Ion Chelation Preserves Platelet Function During Cold Storage.

OBJECTIVE: Platelet transfusion is a life-saving therapy to prevent or treat bleeding in patients with thrombocytopenia or platelet dysfunction. However, for >6 decades, safe and effective strategies for platelet storage have been an impediment to widespread use of platelet transfusion. Refrigerated platelets are cleared rapidly from circulation, precluding cold storage of platelets for transfusion. Consequently, platelets are stored at room temperature with an upper limit of 5 days due to risks of bacterial contamination and loss of platelet function. This practice severely limits platelet availability for transfusion. This study is to identify the mechanism of platelet clearance after cold storage and develop a method for platelet cold storage. Approach and Results: We found that rapid clearance of cold-stored platelets was largely due to integrin activation and apoptosis. Deficiency of integrin ß3 or caspase-3 prolonged cold-stored platelets in circulation. Pretreatment of platelets with EGTA, a cell impermeable calcium ion chelator, reversely inhibited cold storage-induced platelet activation and consequently prolonged circulation of cold-stored platelets. Moreover, transfusion of EGTA-treated, cold-stored platelets, but not room temperature-stored platelets, into the mice deficient in glycoprotein Ibα significantly shortened tail-bleeding times and diminished blood loss. CONCLUSIONS: Integrin activation and apoptosis is the underlying mechanism of rapid clearance of platelets after cold storage. Addition of a cell impermeable calcium ion chelator to platelet products is potentially a simple and effective method to enable cold storage of platelets for transfusion.

Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death.

Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis.

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction.

BACKGROUND: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. METHODS: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. RESULTS: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1ß secretion. The released interleukin-1ß interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes. CONCLUSIONS: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1ß) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.

Value-based assessment of implementing a Pulmonary Embolism Response Team (PERT).

PERTs are a new, multidisciplinary approach to PE care. They were conceived to efficiently identify and risk stratify PE patients and standardize care delivery. More research needs to be conducted to assess the effects that PERTs have had on PE care. This study sought to determine the effects of a PERT on quality and overall value of care. This was a retrospective study of all patients 18 years of age or older who presented with a principal diagnosis of an acute PE based on available ICD codes from January 1, 2010 to December 31, 2018. Patients who did not have an imaging study, i.e., CTPA or ECHO, available were excluded. Patients were divided into pre- (before October 2015) and post-PERT eras (after October 2015) and stratified based on the presence of right heart strain/dysfunction on imaging. All quality outcomes were extracted from the EMR, and cost outcomes were provided by the financial department. 530 individuals (226 pre-PERT and 304 post-PERT) were identified for analysis. Quality outcomes improved between the eras; most notably in-hospital mortality decreased (16.5 vs. 9.6) and hospital LOS decreased (7.7 vs. 4.4) (p < 0.05). Total cost of care also decreased a statistically significant amount between the eras. The implementation of a PERT improved quality and cost of care, resulting in improved value. We hypothesize that this may be due to more timely identification and risk stratification leading to earlier interventions and streamlined decision making, but further research is required to validate these findings in larger cohorts.

Cangrelor in addition to standard therapy reduces cardiac damage and inflammatory markers in patients with ST-segment elevation myocardial infarction.

Although P2Y12 receptor blockers have become a standard, adjunctive therapy in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), the optimal regimen has not been established. We performed a prospective, open-label, randomized study to investigate the effect of cangrelor administration on platelet function and inflammation in patients with primary PCI (PPCI). Twenty-two patients were randomized to receive either cangrelor and ticagrelor or ticagrelor alone (standard group) before PPCI. Platelet reactivity was evaluated at baseline (before PCI), 10 min and the end of the procedure. At baseline, there was no significant difference in platelet reactivity between both groups, whereas platelets were significantly inhibited at 10 min after initiating cangrelor vs. standard (adenosine-diphosphate-induced aggregation 102.2 ± 24.88 vs. 333.4 ± 63.3, P < 0.05 and thrombin-receptor-activating-peptide-induced aggregation 285.8 ± 86.1 vs. 624.8 ± 106.0, P < 0.05). Lower platelet aggregation in the cangrelor group persisted but the difference was reduced by the end of the procedure. Circulating inflammatory cells, pro-inflammatory cytokines, total elastase, and surrogates of neutrophil extracellular traps (total elastase-myeloperoxidase complexes) were significantly lower in the cangrelor compared to the standard therapy group at 6 h after randomization. There was a trend towards reduction in cardiac damage in the cangrelor group as reflected by the changes in late gadolinium enhancement between 48 h and 3 months after STEMI. Early administration of cangrelor in STEMI patients was associated with more effective platelet inhibition during PPCI and significantly dampened the deleterious inflammatory response compared to standard therapy (NCT03043274).

Depression After Open Heart Surgery: Influences of Optimism, Sex, and Event-Related Medical Factors.

ABSTRACT: Postoperative depression is a multifaceted condition that can limit quality of life and potentially decrease the survival benefits of open heart surgery (OHS). We postulated that sex, pre-event character strengths, medical, and certain surgery indicators would predict post-event/myocardial infarction depression. To identify predictors, we collected three-wave survey data from 481 OHS patients at a large academic referral institution (age, 62+; female, 42%) and included key medical and surgical information. The final model (F[7, N = 293] = 28.15, p < 0.001, R2 = 0.408) accounted for over two fifths of the variance in post-OHS depression. Pre-event/OHS optimism mitigated post-OHS depression. Being female, older, living alone, longer surgical perfusion time, absence of left main disease greater than 50%, and pre-OHS depression were associated with the increased likelihood of post-OHS depression. Our findings suggest that teaching optimism to OHS patients might be beneficial in reducing the risk of postoperative depression and that female patients should be monitored more closely for the development of depression through an interdisciplinary approach.

Passive antipyretic therapy is not as effective as invasive hypothermia for maintaining normothermia after cardiac arrest.

AIM OF THE STUDY: Targeted temperature management is a class I indication in comatose patients after a cardiac arrest. While the literature has primarily focused on innovative methods to achieve target temperatures, pharmacologic therapy has received little attention. We sought to examine whether pharmacologic therapy using antipyretics is effective in maintaining normothermia in post cardiac arrest patients. MATERIALS AND METHODS: Patients ≥18 years who were resuscitated after an in-hospital or out-of-hospital cardiac arrest and admitted at our institution from January 2012 to September 2015 were retrospectively included. Patients were divided into groups based on the method of temperature control that was utilized. The primary outcome was temperature control <38 °C during the first 48 h after the cardiac arrest. RESULTS: 671 patients were identified in Group 1 (no hypothermia), 647 in Group 2 (antipyretics), 44 in Group 3 (invasive hypothermia), and 51 in Group 4 (invasive hypothermia and antipyretics). Mean patient age was 59 (SD ±15.7) years with 40.6% being female. Using Group 1 as the control arm, 57.7% of patients maintained target temperature with antipyretics alone (p < 0.001), compared to 69.3% in the control group and 82.1% in the combined hypothermia groups 3&4 (p = 0.01). Patients receiving both invasive hypothermia and antipyretics (Group 4), had the greatest mean temperature decrease of 5.2 °C. CONCLUSIONS: Among patients undergoing targeted temperature management, relying solely on as needed use of antipyretics is not sufficient to maintain temperatures <38 °C. However, antipyretics could be used as an initial strategy if given regularly and/or in conjunction with more aggressive cooling techniques.

Developing and Demonstrating the Viability and Availability of the Multilevel Implementation Strategy for Syncope Optimal Care Through Engagement (MISSION) Syncope App: Evidence-Based Clinical Decision Support Tool.

BACKGROUND: Syncope evaluation and management is associated with testing overuse and unnecessary hospitalizations. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Syncope Guideline aims to standardize clinical practice and reduce unnecessary services. The use of clinical decision support (CDS) tools offers the potential to successfully implement evidence-based clinical guidelines. However, CDS tools that provide an evidence-based differential diagnosis (DDx) of syncope at the point of care are currently lacking. OBJECTIVE: With input from diverse health systems, we developed and demonstrated the viability of a mobile app, the Multilevel Implementation Strategy for Syncope optImal care thrOugh eNgagement (MISSION) Syncope, as a CDS tool for syncope diagnosis and prognosis. METHODS: Development of the app had three main goals: (1) reliable generation of an accurate DDx, (2) incorporation of an evidence-based clinical risk tool for prognosis, and (3) user-based design and technical development. To generate a DDx that incorporated assessment recommendations, we reviewed guidelines and the literature to determine clinical assessment questions (variables) and likelihood ratios (LHRs) for each variable in predicting etiology. The creation and validation of the app diagnosis occurred through an iterative clinician review and application to actual clinical cases. The review of available risk score calculators focused on identifying an easily applied and valid evidence-based clinical risk stratification tool. The review and decision-making factors included characteristics of the original study, clinical variables, and validation studies. App design and development relied on user-centered design principles. We used observations of the emergency department workflow, storyboard demonstration, multiple mock review sessions, and beta-testing to optimize functionality and usability. RESULTS: The MISSION Syncope app is consistent with guideline recommendations on evidence-based practice (EBP), and its user interface (UI) reflects steps in a real-world patient evaluation: assessment, DDx, risk stratification, and recommendations. The app provides flexible clinical decision making, while emphasizing a care continuum; it generates recommendations for diagnosis and prognosis based on user input. The DDx in the app is deemed a pragmatic model that more closely aligns with real-world clinical practice and was validated using actual clinical cases. The beta-testing of the app demonstrated well-accepted functionality and usability of this syncope CDS tool. CONCLUSIONS: The MISSION Syncope app development integrated the current literature and clinical expertise to provide an evidence-based DDx, a prognosis using a validated scoring system, and recommendations based on clinical guidelines. This app demonstrates the importance of using research literature in the development of a CDS tool and applying clinical experience to fill the gaps in available research. It is essential for a successful app to be deliberate in pursuing a practical clinical model instead of striving for a perfect mathematical model, given available published evidence. This hybrid methodology can be applied to similar CDS tool development.

Planning Implementation Success of Syncope Clinical Practice Guidelines in the Emergency Department Using CFIR Framework.

Background and Objectives: Overuse and inappropriate use of testing and hospital admission are common in syncope evaluation and management. Though guidelines are available to optimize syncope care, research indicates that current clinical guidelines have not significantly impacted resource utilization surrounding emergency department (ED) evaluation of syncope. Matching implementation strategies to barriers and facilitators and tailoring strategies to local context hold significant promise for a successful implementation of clinical practice guidelines (CPG). Our team applied implementation science principles to develop a stakeholder-based implementation strategy. Methods and Materials: We partnered with patients, family caregivers, frontline clinicians and staff, and health system administrators at four health systems to conduct quantitative surveys and qualitative interviews for context assessment. The identification of implementation strategies was done by applying the CFIR-ERIC Implementation Strategy Matching Tool and soliciting stakeholders' inputs. We then co-designed with patients and frontline teams, and developed and tested specific strategies. Results: A total of 114 clinicians completed surveys and 32 clinicians and stakeholders participated in interviews. Results from the surveys and interviews indicated low awareness of syncope guidelines, communication challenges with patients, lack of CPG protocol integration into ED workflows, and organizational process to change as major barriers to CPG implementation. Thirty-one patients and their family caregivers participated in interviews and expressed their expectations: clarity regarding their diagnosis, context surrounding care plan and diagnostic testing, and a desire to feel cared about. Identifying change methods to address the clinician barriers and patients and family caregivers expectations informed development of the multilevel, multicomponent implementation strategy, MISSION, which includes patient educational materials, mentored implementation, academic detailing, Syncope Optimal Care Pathway and a corresponding mobile app, and Lean quality improvement methods. The pilot of MISSION demonstrated feasibility, acceptability and initial success on appropriate testing. Conclusions: Effective multifaceted implementation strategies that target individuals, teams, and healthcare systems can be employed to plan successful implementation and promote adherence to syncope CPGs.

Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction.

OBJECTIVE: Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood. APPROACH AND RESULTS: We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3Δ mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson's Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis. CONCLUSION: ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury.

Regulation of PLPP3 gene expression by NF-κB family transcription factors.

Lipid phosphate phosphatase 3 (LPP3), encoded by the PLPP3 gene, is an integral membrane enzyme that dephosphorylates phosphate esters of glycero- and sphingophospholipids. Cell surface LPP3 can terminate the signaling actions of bioactive lysophosphatidic acid (LPA) and sphingosine 1 phosphate, which likely explains its role in developmental angiogenesis, vascular injury responses, and cell migration. Heritable variants in the final intron PLPP3 associate with interindividual variability in coronary artery disease risk that may result from disruption of enhancer sequences that normally act in cis to increase expression of the gene. However, the mechanisms regulating PLPP3 expression are not well understood. We show that the human PLPP3 promoter contains three functional NF-κB response elements. All of these are required for maximal induction of PLPP3 promoter activity in reporter assays. The identified sequences recruit RelA and RelB components of the NF-κB transcription complex to chromatin, and these transcription factors bind to the identified target sequences in two different cell types. LPA promotes binding of Rel family transcription factors to the PLPP3 promoter and increases PLPP3 gene expression through mechanisms that are attenuated by an NF-κB inhibitor, LPA receptor antagonists, and inhibitors of phosphoinositide 3 kinase. These findings indicate that up-regulation of PLPP3 during inflammation and atherosclerosis results from canonical activation of the NF-κB signaling cascade to increase PLPP3 expression through nuclear import and binding of RelA and RelB transcription factors to the PLPP3 promoter and suggest a mechanism by which the LPP3 substrate, LPA, can regulate PLPP3 expression.

Translational Implications of Platelets as Vascular First Responders.

Platelets play a vital role in normal hemostasis to stem blood loss at sites of vascular injury by tethering and adhering to sites of injury, recruiting other platelets and blood cells to the developing clot, releasing vasoactive small molecules and proteins, and assembling and activating plasma coagulation proteins in a tightly regulated temporal and spatial manner. In synchrony with specific end products of coagulation, primarily cross-linked fibrin, a stable thrombus quickly forms. Far beyond physiological hemostasis and pathological thrombosis, emerging evidence supports platelets playing a pivotal role in vascular homeostasis, inflammation, cellular repair, regeneration, and wide range of autocrine and paracrine functions. In essence, platelets play both structural and functional roles as reporters, messengers, and active transporters surveying the vasculature for cues of environmental or developmental stimuli and participating as first responders.1 In this review, we will provide a contemporary perspective of platelet physiology, including fundamental, translational, and clinical constructs that apply directly to human health and disease.

Coronary Artery Disease Risk-Associated Plpp3 Gene and Its Product Lipid Phosphate Phosphatase 3 Regulate Experimental Atherosclerosis.

OBJECTIVE: Genome-wide association studies identified novel loci in PLPP3(phospholipid phosphatase 3) that associate with coronary artery disease risk independently of traditional risk factors. PLPP3 encodes LPP3 (lipid phosphate phosphatase 3), a cell-surface enzyme that can regulate the availability of bioactive lysophopsholipids including lysophosphatidic acid (LPA). The protective allele of PLPP3 increases LPP3 expression during cell exposure to oxidized lipids, however, the role of LPP3 in atherosclerosis remains unclear. Approach and Results: In this study, we sought to validate LPP3 as a determinate of the development of atherosclerosis. In experimental models of atherosclerosis, LPP3 is upregulated and co-localizes with endothelial, smooth muscle cell, and CD68-positive cell markers. Global post-natal reductions in Plpp3 expression in mice substantially increase atherosclerosis, plaque-associated LPA, and inflammation. Although LPP3 expression increases during ox-LDL (oxidized low-density lipoprotein)-induced phenotypic modulation of bone marrow-derived macrophages, myeloid Plpp3 does not appear to regulate lesion formation. Rather, smooth muscle cell LPP3 expression is a critical regulator of atherosclerosis and LPA content in lesions. Moreover, mice with inherited deficiency in LPA receptor signaling are protected from experimental atherosclerosis. CONCLUSIONS: Our results identify a novel lipid signaling pathway that regulates inflammation in the context of atherosclerosis and is not related to traditional risk factors. Pharmacological targeting of bioactive LPP3 substrates, including LPA, may offer an orthogonal approach to lipid-lowering drugs for mitigation of coronary artery disease risk.

Reduced dose thrombolysis with ultrasound-facilitated catheter-directed administration for acute pulmonary embolism reduces length of stay.

The optimal dose and duration of tissue plasminogen activator (tPA) administered with ultrasound-facilitated catheter-directed thrombolysis (USCDT) to patients with acute PE remains to be determined. Our institution recently adopted a shorter duration (4 h) of USCDT and lower dosing strategy (tPA 1 mg/h) based on data from the OPTALYSE PE Trial. The purpose was to evaluate the implementation at our institution of shorter duration (4 h) of USCDT and lower dosing strategy (tPA 1 mg/h) as outlined by OPTALYSE PE Trial. This was a retrospective, single-center, observational study included patients from 01/01/2017 to 12/31/2018 in a large, academic medical center. Group 1 represented patients who underwent USCDT prior to 01/18/18. Group 2 represented patients who underwent USCDT after 01/18/18 and received 4 h of USCDT and tPA 1 mg/h/catheter. The primary outcome was intensive care unit (ICU) length of stay (LOS). Secondary outcomes were the proportion of patients experiencing a composite of major adverse events (death, recurrent PE, major bleeding, or stroke), change in right ventricle size/function and pulmonary artery pressures, need for mechanical respiratory or hemodynamic support, hospital LOS and drug cost. A total of 31 patients were included in the study: twenty patients in Group 1 and eleven patients in Group 2. Median ICU LOS was 3.5 days in Group 1 and 1 day in Group 2. Group 2 had reduced MACE, requirement for mechanical respiratory or hemodynamic support, hospital LOS, drug costs and adverse events. Implementation of a shorter duration of USCDT and lower dosing strategy for tPA in patients with acute PE may be one strategy to reduce the total ICU LOS and costs associated with care.

Preoperative Optimism Related to Low Anxiety in Patients 1 Month After Open Heart Surgery.

Anxiety can contribute to poor prognosis in cardiac patients. Few studies have examined the role of optimism in anxiety after open heart surgery (OHS). This study investigated the influence of preoperative optimism on post-OHS anxiety, adjusting cardiac indices used by cardiac surgeons. Data were collected before and 1 month after OHS in 481 patients (58% men; age, 62.4 ± 11.94 years). Optimism was measured using the Life Orientation Test. Anxiety was measured using the Trait Anxiety Inventory. Medical and cardiac indices were retrieved from the Society of Thoracic Surgeon's national database. Multiple regression analyses showed that greater pre-OHS optimism was associated with lower levels of post-OHS anxiety (F[6, N = 306] = 50.18, p < 0.001, R = 0.502). No other factors showed similar protection. Pre-OHS anxiety, younger age, and minority status were associated with anxiety in the critical recovery month. The findings demonstrate the potential benefit of optimism against post-OHS anxiety, which may have clinical implications for improving disease management.

Value-based syncope evaluation and management: Perspectives of health care professionals on readiness, barriers and enablers.

BACKGROUND: Syncope is a common condition seen in the emergency department. Given the multitude of etiologies, research exists on the evaluation and management of syncope. Yet, physicians' approach to patients with syncope is variable and often not value based. The 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients with Syncope includes a focus on unnecessary medical testing. However, little research assesses implementation of the guidelines. METHODS: Mixed methods approach was applied. The targeted provider specialties include emergency medicine, hospital medicine and cardiology. The Evidence-based Practice Attitude Scale-36 and the Organizational Readiness to Change Assessment surveys were distributed to four different hospital sites. We then conducted focus groups and key informant interviews to obtain more information about clinicians' perceptions to guideline-based practice and barriers/facilitators to implementation. Descriptive statistics and bivariate analyses were used for survey analysis. Two-stage coding was used to identify themes with NVivo. RESULTS: Analysis of surveys revealed that overall attitude toward evidence-based practices was moderate and implementation of new guidelines were seen as a burden, potentially decreasing compliance. There were differences across hospital settings. Five common themes emerged from interviews: uncertainty of a syncope diagnosis, rise of consumerism in health care, communication challenge with patient, provider differences in standardized care, and organizational processes to change. CONCLUSIONS: Despite recommendations for the use of syncope guidelines, adherence is suboptimal. Overcoming barriers to use will require a paradigm shift. A multifaceted approach and collaborative relationships are needed to adhere to the Guidelines to improve patient care and operational efficiency.

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid.

Lysophosphatidic acids (LPAs) are bioactive radyl hydrocarbon-substituted derivatives of glycerol 3-phosphate. LPA metabolism and signaling are implicated in heritable risk of coronary artery disease. Genetic and pharmacological inhibition of these processes attenuate experimental atherosclerosis. LPA accumulates in atheromas, which may be a consequence of association with LDLs. The source, regulation, and biological activity of LDL-associated LPA are unknown. We examined the effects of experimental hyperlipidemia on the levels and distribution of circulating LPA in mice. The majority of plasma LPA was associated with albumin in plasma from wild-type mice fed normal chow. LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6). Adipose-specific deficiency of the ENPP2 gene encoding the LPA-generating secreted lysophospholipase D, autotaxin (ATX), attenuated these Western diet-dependent increases in LPA. ATX-dependent increases in LDL-associated LPA were observed in isolated incubated plasma. ATX acted directly on LDL-associated lysophospholipid substrates in vitro. LDL from all human subjects examined contained LPA and was decreased by lipid-lowering drug therapies. Human and mouse plasma therefore contains a diet-sensitive LDL-associated LPA pool that might contribute to the cardiovascular disease-promoting effects of LPA.

LPA receptor 4 deficiency attenuates experimental atherosclerosis.

The widely expressed lysophosphatidic acid (LPA) selective receptor 4 (LPAR4) contributes to vascular development in mice and zebrafish. LPAR4 regulates endothelial permeability, lymphocyte migration, and hematopoiesis, which could contribute to atherosclerosis. We investigated the role of LPAR4 in experimental atherosclerosis elicited by adeno-associated virus expressing PCSK9 to lower LDL receptor levels. After 20 weeks on a Western diet, cholesterol levels and lipoprotein distribution were similar in WT male and Lpar4Y/- mice (P = 0.94). The atherosclerotic lesion area in the proximal aorta and arch was ∼25% smaller in Lpar4Y/- mice (P = 0.009), and less atherosclerosis was detected in Lpar4Y/- mice at any given plasma cholesterol. Neutral lipid accumulation in aortic root sections occupied ∼40% less area in Lpar4Y/- mice (P = 0.001), and CD68 expression was ∼25% lower (P = 0.045). No difference in α-smooth muscle actin staining was observed. Bone marrow-derived macrophages isolated from Lpar4Y/- mice displayed significantly increased upregulation of the M2 marker Arg1 in response to LPA compared with WT cells. In aortic root sections from Lpar4Y/- mice, heightened M2 "repair" macrophage marker expression was detected by CD206 staining (P = 0.03). These results suggest that LPAR4 may regulate the recruitment of specific sets of macrophages or their phenotypic switching in a manner that could influence the development of atherosclerosis.

Outcomes of fibrinolytic therapy for patients with metastatic cancer and acute pulmonary embolism.

INTRODUCTION: Malignancy is a common cause of morbidity and mortality in the United States and around the world and the second leading cause of death in the United States. There is little data on the impact of metastatic cancer on the risk of hemorrhagic stroke or mortality among patients undergoing fibrinolytic therapy (FT) for acute PE. METHODS: Using the National Inpatient Sample (NIS) database, we extracted admissions with a primary diagnosis of acute pulmonary embolism that underwent FT from 2010 to 2014. We performed a case control matched analysis between patients with and without metastatic cancer. Our primary outcome of interest was Mortality and our secondary outcome of interest was hemorrhagic stroke (HS). RESULTS: Of the 883,183 patients with a primary diagnosis of acute PE between 2010 and 12014, 23,690 patients (2.7%) underwent FT. After exclusion, 22,592 patients were included in the analysis. Of these, 941 patients (4.2%) were reported to have metastatic cancer. There was a higher incidence of cerebrovascular accidents and intubation/mechanical ventilation in the metastatic cancer arm. Mortality was significantly higher in the metastatic cancer arm with no difference in the incidence of HS. In multivariate regression analysis, among all patients that underwent FT for acute PE, metastatic cancer was associated with a significant odds for mortality (OR 1.91, 95% CI 1.11-5.82, p < .001). CONCLUSION: The presence of metastatic cancer in patients undergoing fibrinolytic therapy for acute pulmonary embolism is associated with increase mortality.