Publications by authors named "Susan S Smyth"

145 Publications

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 Jan 13. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
January 2022

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.

J Med Internet Res 2021 11 16;23(11):e25192. Epub 2021 Nov 16.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.

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.
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http://dx.doi.org/10.2196/25192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663445PMC
November 2021

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

Am J Emerg Med 2021 Dec 2;50:202-206. Epub 2021 Jul 2.

Gill Heart and Vascular Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, United States of America.

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.
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http://dx.doi.org/10.1016/j.ajem.2021.06.069DOI Listing
December 2021

Predicting in-hospital mortality after an in-hospital cardiac arrest: A multivariate analysis.

Resusc Plus 2020 Dec 7;4:100039. Epub 2020 Nov 7.

Gill Heart and Vascular Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, United States.

Aim Of The Study: Most survivors of an in-hospital cardiac arrest do not leave the hospital alive, and there is a need for a more patient-centered, holistic approach to the assessment of prognosis after an arrest. We sought to identify pre-, peri-, and post-arrest variables associated with in-hospital mortality amongst survivors of an in-hospital cardiac arrest.

Methods: This was a retrospective cohort study of patients ≥18 years of age who were resuscitated from an in-hospital arrest at our University Medical Center from January 1, 2013 to September 31, 2016. In-hospital mortality was chosen as a primary outcome and unfavorable discharge disposition (discharge disposition other than home or skilled nursing facility) as a secondary outcome.

Results: 925 patients comprised the in-hospital arrest cohort with 305 patients failing to survive the arrest and a further 349 patients surviving the initial arrest but dying prior to hospital discharge, resulting in an overall survival of 29%. 620 patients with a ROSC of greater than 20 min following the in-hospital arrest were included in the final analysis. In a stepwise multivariable regression analysis, recurrent cardiac arrest, increasing age, time to ROSC, higher serum creatinine levels, and a history of cancer were predictors of in-hospital mortality. A history of hypertension was found to exert a protective effect on outcomes. In the regression model including serum lactate, increasing lactate levels were associated with lower odds of survival.

Conclusion: Amongst survivors of in-hospital cardiac arrest, recurrent cardiac arrest was the strongest predictor of poor outcomes with age, time to ROSC, pre-existing malignancy, and serum creatinine levels linked with increased odds of in-hospital mortality.
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http://dx.doi.org/10.1016/j.resplu.2020.100039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244474PMC
December 2020

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

Medicina (Kaunas) 2021 Jun 3;57(6). Epub 2021 Jun 3.

Center for Health Services Research, University of Kentucky, Waller Health Care Annex, 304A, Lexington, KY 40536, USA.

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. 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. 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. Effective multifaceted implementation strategies that target individuals, teams, and healthcare systems can be employed to plan successful implementation and promote adherence to syncope CPGs.
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http://dx.doi.org/10.3390/medicina57060570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228757PMC
June 2021

Inflammasome activation promotes venous thrombosis through pyroptosis.

Blood Adv 2021 06;5(12):2619-2623

Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY.

Crosstalk between coagulation and innate immunity contributes to the progression of many diseases, including infection and cardiovascular disease. Venous thromboembolism (VTE), including pulmonary embolism and deep vein thrombosis (DVT), is among the most common causes of cardiovascular death. Here, we show that inflammasome activation and subsequent pyroptosis play an important role in the development of venous thrombosis. Using a flow restriction-induced mouse venous thrombosis model in the inferior vena cava (IVC), we show that deficiency of caspase-1, but not caspase-11, protected against flow restriction-induced thrombosis. Interleukin-1β expression increased in the IVC following ligation, indicating that inflammasome is activated during injury. Deficiency of gasdermin D (GSDMD), an essential mediator of pyroptosis, protected against restriction-induced venous thrombosis. After induction of venous thrombosis, fibrin was deposited in the veins of wild-type mice, as detected using immunoblotting with a monoclonal antibody that specifically recognizes mouse fibrin, but not in the caspase-1-deficient or GSDMD-deficient mice. Depletion of macrophages by gadolinium chloride or deficiency of tissue factor also protected against venous thrombosis. Our data reveal that tissue factor released from pyroptotic monocytes and macrophages following inflammasome activation triggers thrombosis.
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http://dx.doi.org/10.1182/bloodadvances.2020003041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270666PMC
June 2021

"Passing Out is a Serious Thing": Patient Expectations for Syncope Evaluation and Management.

Patient Prefer Adherence 2021 4;15:1213-1223. Epub 2021 Jun 4.

Center for Health Services Research, College of Medicine, Lexington, KY, USA.

Purpose: Syncope is a complex symptom requiring thoughtful evaluation. The ACC/AHA/HRS published syncope management guidelines in 2017. Effective guideline implementation hinges on overcoming multilevel barriers, including providers' perceptions that patients prefer aggressive diagnostic testing when presenting to the emergency department (ED) with syncope, which conflicts with the 2017 Guideline on Syncope. To better understand this perceived barrier, we explored patient and family caregiver expectations and preferences when presenting to the ED with syncope.

Patients And Methods: We conducted semi-structured focus groups (N=12) and in-depth interviews (N=19) with patients presenting to the ED with syncope as well as with their family caregivers. Interviews were recorded, transcribed verbatim, and analyzed by a team of researchers following a directed content analysis. Results were reviewed and shared iteratively with all team members to confirm mutual understanding and agreement.

Results: Syncope patients and caregivers discussed three main desires when presenting to the ED with syncope: 1) clarity regarding their diagnosis,; 2) context surrounding their care plan and diagnostic approach; and 3) to feel seen, heard and cared about by their health care team.

Conclusion: Clinicians have cited patient preferences for aggressive diagnostic testing as a barrier to adhering to the 2017 Guideline on Syncope, which recommends against routine administration of imaging testing (eg, echocardiograms). Our results suggest that while participants preferred diagnostic testing as a means to achieve clarity and even a feeling of being cared for, other strategies, such as a patient-engaged approach to communication and shared decision-making, may address the spectrum of patient expectations when presenting to the ED with syncope while adhering to guideline recommendations.
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http://dx.doi.org/10.2147/PPA.S307186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187096PMC
June 2021

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

J Nerv Ment Dis 2021 03;209(3):212-217

Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, Kentucky.

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.
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http://dx.doi.org/10.1097/NMD.0000000000001285DOI Listing
March 2021

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

J Thromb Thrombolysis 2021 Oct 30;52(3):934-940. Epub 2020 Nov 30.

Cardiovascular Interventions, Coronary Artery Disease Center, Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, USA.

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).
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http://dx.doi.org/10.1007/s11239-020-02345-8DOI Listing
October 2021

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

J Nerv Ment Dis 2020 12;208(12):966-973

Department of Cardiology, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, Kentucky.

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.
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http://dx.doi.org/10.1097/NMD.0000000000001236DOI Listing
December 2020

Training the translational workforce: Expanding beyond translational research to include translational science.

J Clin Transl Sci 2020 Apr 6;4(4):360-362. Epub 2020 Apr 6.

Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, USA.

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http://dx.doi.org/10.1017/cts.2020.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681113PMC
April 2020

Calcium Ion Chelation Preserves Platelet Function During Cold Storage.

Arterioscler Thromb Vasc Biol 2021 01 12;41(1):234-249. Epub 2020 Nov 12.

Gill Heart and Vascular Institute, Division of Cardiovascular Medicine, College of Medicine (B.X., G.Z., Y.Z., C.W., A.J.M., S.S.S., Z.L.), University of Kentucky, Lexington.

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 β3 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.
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http://dx.doi.org/10.1161/ATVBAHA.120.314879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158249PMC
January 2021

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

J Mol Cell Cardiol 2020 12 2;149:95-114. Epub 2020 Oct 2.

Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky and the Lexington VA Medical Center, Lexington, KY, USA. Electronic address:

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-Plpp3) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3 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.
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http://dx.doi.org/10.1016/j.yjmcc.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744112PMC
December 2020

CYP2C19 Genotyping to Guide Antiplatelet Therapy After Percutaneous Coronary Interventions: One Size Rarely Fits All.

JAMA 2020 08;324(8):747-749

Gill Heart Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington.

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http://dx.doi.org/10.1001/jama.2020.13094DOI Listing
August 2020

Securing the Future for a Major Academic Cardiovascular Program: Hardwiring a Referral Network and Preparing for a Transition to Value-Based Reimbursement.

Hosp Top 2020 Oct-Dec;98(4):163-171. Epub 2020 Aug 17.

Department of Medicine, University of Kentucky, Lexington, KY, USA.

The University of Kentucky College of Medicine and Albert B. Chandler Hospital opened over 50 years ago to serve Kentucky. After initial growth and expansion, both were struggling clinically, academically, and financially in the early 2000s. Difficulties were apparent in cardiovascular (CV) services, which captured only 11% of the regional patients hospitalized for cardiac disease. Over the next 15 years, CV services dynamically transformed to become the leading provider with a large network of regional partners, garnering 42% of market share. This article describes strategic plans and initiatives leading to clinical and academic growth. Future value-based initiatives are also described.
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http://dx.doi.org/10.1080/00185868.2020.1803777DOI Listing
June 2021

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

Am J Emerg Med 2020 09 16;38(9):1867-1874. Epub 2020 May 16.

Center for Health Services Research, Department of Medicine, University of Kentucky, Lexington, KY, USA; Division of Hospital Medicine, Department of Medicine, University of Kentucky, Lexington, KY, USA.

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.
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http://dx.doi.org/10.1016/j.ajem.2020.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572884PMC
September 2020

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

J Thromb Thrombolysis 2021 Jan;51(1):217-225

Gill Heart and Vascular Institute, Division of Cardiovascular Medicine, University of Kentucky, 900 S. Limestone, CTW 320, Lexington, KY, 40536, USA.

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.
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http://dx.doi.org/10.1007/s11239-020-02188-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325945PMC
January 2021

Roles for lysophosphatidic acid signaling in vascular development and disease.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 08 3;1865(8):158734. Epub 2020 May 3.

Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY 40536, United States of America; Veterans Affairs Medical Center, Lexington, KY 40511, United States of America.

The bioactive lipid lysophosphatidic acid (LPA) is emerging as an important mediator of inflammation in cardiovascular diseases. Produced in large part by the secreted lysophospholipase D autotaxin (ATX), LPA acts on a series of G protein-coupled receptors and may have action on atypical receptors such as RAGE to exert potent effects on vascular cells, including the promotion of foam cell formation and phenotypic modulation of smooth muscle cells. The signaling effects of LPA can be terminated by integral membrane lipid phosphate phosphatases (LPP) that hydrolyze the lipid to receptor inactive products. Human genetic variants in PLPP3, that predict lower levels of LPP3, associate with risk for premature coronary artery disease, and reductions of LPP3 expression in mice promote the development of experimental atherosclerosis and enhance inflammation in the atherosclerotic lesions. Recent evidence also supports a role for ATX, and potentially LPP3, in calcific aortic stenosis. In summary, LPA may be a relevant inflammatory mediator in atherosclerotic cardiovascular disease and heightened LPA signaling may explain the cardiovascular disease risk effect of PLPP3 variants.
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http://dx.doi.org/10.1016/j.bbalip.2020.158734DOI Listing
August 2020

Lysophospholipids and their receptors: New data and new insights into their function.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 07 13;1865(7):158697. Epub 2020 Mar 13.

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http://dx.doi.org/10.1016/j.bbalip.2020.158697DOI Listing
July 2020

Contemporary Meta-Analysis of Extended Direct-Acting Oral Anticoagulant Thromboprophylaxis to Prevent Venous Thromboembolism.

Am J Med 2020 09 6;133(9):1074-1081.e8. Epub 2020 Mar 6.

Gill Heart & Vascular Institute, University of Kentucky, Lexington.

Background: Medically ill patients remain at risk of venous thromboembolism for up to 6 weeks after hospital discharge due to factors such as immobilization and inflammation.

Methods: We conducted a meta-analysis and systematic review of Phase III randomized controlled trials comparing extended use of direct oral anticoagulation (DOAC) post discharge for venous thromboembolism prophylaxis with placebo.

Results: The primary efficacy outcome (composite of venous thromboembolism and mortality) occurred in 373/13,099 patients in the DOAC group (2.9%) and 477/13,309 patients in the placebo group (3.6%), with an odds ratio (OR) of 0.79 (95% confidence interval [CI], 0.69-0.91). The secondary efficacy outcome (nonfatal symptomatic venous thromboembolism) occurred in 75/15,573 patients in the DOAC group (0.48%) and 120/15,599 in the placebo group (0.77%) with an OR of 0.62 (95% CI, 0.47-0.83). The primary safety outcome (major bleeding) occurred in 90/15,474 patients in the DOAC group (0.58%) and in 47/15,418 patients in the placebo group (0.3%) with an OR of 1.92 (95% CI, 1.35-2.73). The secondary safety (clinically relevant nonmajor bleeding) outcome occurred in 333/15,474 patients in the DOAC group (2.2%) and 191/15,418 patients in the placebo group (1.2%) with an OR of 1.75 (95% CI, 1.46-2.1). The extended use of venous thromboembolism prophylaxis post discharge results in decreased venous thromboembolism events but increased bleeding risk. Our cost-effective analysis of extended DOAC use vs placebo showed superiority of the DOAC group.

Conclusion: In conclusion, given the mortality benefit and cost benefit, extended thromboprophylaxis is a beneficial strategy to efficiently reduce the risk of venous thromboembolism.
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http://dx.doi.org/10.1016/j.amjmed.2020.01.037DOI Listing
September 2020

Inflammatory properties of diet mediate the effect of depressive symptoms on Framingham risk score in men and women: Results from the National Health and Nutrition Examination Survey (2007-2014).

Nutr Res 2020 02 23;74:78-86. Epub 2019 Nov 23.

College of Public Health, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA.

Depression is common in patients with cardiovascular disease (CVD) and associated with inflammation. Inflammation contributes to the development of CVD and can be modulated by diet. However, the role of inflammatory properties of diet in the relationship between depressive symptoms and CVD risk is not well understood. We hypothesized that the inflammatory properties of diet mediate the relationship between depressive symptoms and CVD risk in men and women. Cross-sectional data collected by the National Health and Nutrition Examination Survey (2007-2014) were used for the study. Depressive symptoms scores, inflammatory properties of diet, and CVD risk were measured by the Patient Health Questionnaire-9 (PHQ-9), the Dietary Inflammatory Index (DII), and the Framingham risk score (FRS), respectively. Generalized linear models were used for the mediation analysis. There were significant differences in the proportions of men and women in the depressed group (PHQ-9 ≥ 10; 5.24 ± 0.65% vs 9.36 ± 0.87%, P < .001) and high CVD risk group (FRS >20%; 16.47 ± 0.79% vs 6.03 ± 0.32%, P < .001). The DII partially mediated the relationship between depressive symptoms and CVD risk in men (indirect effect: 0.06, P = .010) but fully mediated the relationship between depressive symptoms and CVD risk in women (indirect effect: 0.10, P < .001). These findings confirmed our hypothesis that inflammatory properties of diet at least partially mediate the relationship between depressive symptoms and CVD risk in men and women. Our findings suggest that interventions designed to reduce depressive symptoms should contain strategies to reduce pro-inflammatory and increase anti-inflammatory properties of diet to decrease CVD risk.
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http://dx.doi.org/10.1016/j.nutres.2019.11.008DOI Listing
February 2020

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

Circulation 2020 03 16;141(13):1080-1094. Epub 2020 Jan 16.

Department of Surgery (G.S., B.A., P.R.N.), Ohio State University Wexner Medical Center, Columbus.

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-1β secretion. The released interleukin-1β 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-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122461PMC
March 2020

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

J Thromb Thrombolysis 2020 May;49(4):540-544

University of Kentucky HealthCare, Gill Heart and Vascular Institute, 800 Rose St, Lexington, KY, 40536, USA.

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.
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http://dx.doi.org/10.1007/s11239-019-02009-2DOI Listing
May 2020

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

Arterioscler Thromb Vasc Biol 2019 11 19;39(11):2261-2272. Epub 2019 Sep 19.

From the Division of Cardiovascular Medicine, The Gill Heart & Vascular Institute, University of Kentucky, Lexington (P.A.M., L.Y., M.U., G.M., J.B., J.V., A.J.M., S.S.S.).

Objective: Genome-wide association studies identified novel loci in (phospholipid phosphatase 3) that associate with coronary artery disease risk independently of traditional risk factors. 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 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 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 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.
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http://dx.doi.org/10.1161/ATVBAHA.119.313056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812632PMC
November 2019

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

J Lipid Res 2019 11 4;60(11):1818-1828. Epub 2019 Sep 4.

Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY

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 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.
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http://dx.doi.org/10.1194/jlr.M093096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824489PMC
November 2019

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

J Biol Chem 2019 09 30;294(38):14009-14019. Epub 2019 Jul 30.

Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky College of Medicine, Lexington, Kentucky 40536

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 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.
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http://dx.doi.org/10.1074/jbc.RA119.009002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755815PMC
September 2019

Outcomes and Characteristics of Myocardial Infarction in Patients With Cirrhosis.

J Invasive Cardiol 2019 Jul;31(7):E162-E169

University of Kentucky College of Health Sciences, 900 S. Limestone, CTW 326, Lexington KY 40536 USA.

Objectives: Patients with cirrhosis have increased bleeding risk due to coagulopathy and platelet sequestration, as well as inherent cardiovascular risk. We aim to assess the impact of cirrhosis on the revascularization rates and in-hospital outcomes in patients with acute myocardial infarction (AMI).

Methods: We queried the National Inpatient Sample Database from 2010 to 2014 and identified hospitalizations with a primary diagnosis of AMI (n = 612,547); of these, a total of 3135 patients had a concomitant diagnosis of cirrhosis. We compared clinical outcomes between patients with cirrhosis and a propensity-score matched cohort without cirrhosis (n = 3086).

Results: Patients with cirrhosis had a lower rate of ST-elevation MI (18.9% vs 26.7% in the cohort with no cirrhosis; P<.001), a lower rate of coronary angiography (51.4% vs 63.9% in the cohort with no cirrhosis; P<.001), and lower rates of revascularization by percutaneous coronary intervention (PCI) (28.7% vs 39.2% in the cohort with no cirrhosis; P<.001) or coronary artery bypass grafting (6.0% vs 12.9% in the cohort with no cirrhosis; P<.001). Gastrointestinal and postprocedural hemorrhage was more common in patients with cirrhosis (12.3% vs 7.1% in the cohort with no cirrhosis; P<.001), regardless of revascularization status, and cirrhosis patients also had a higher in-hospital mortality rate (8.7% vs 6.9% in the cohort with no cirrhosis; P<.01). PCI was independently associated with lower mortality in patients with cirrhosis (odds ratio, 0.57; 95% confidence interval, 0.33-0.98; P=.04).

Conclusion: Patients with cirrhosis presenting with AMI were highly selected to undergo coronary angiography and subsequent revascularization, and had higher mortality than those without cirrhosis. However, PCI was independently associated with lower mortality in patients with cirrhosis, although to less effect than non-cirrhotics, perhaps due to higher bleeding rates.
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July 2019

Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis.

Immunity 2019 06 7;50(6):1401-1411.e4. Epub 2019 May 7.

Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, KY, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.immuni.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791531PMC
June 2019

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

Pulm Pharmacol Ther 2019 06 5;56:104-107. Epub 2019 Apr 5.

University of Kentucky Medical Center, Lexington, KY, USA.

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.
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http://dx.doi.org/10.1016/j.pupt.2019.04.001DOI Listing
June 2019
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