Faculty Bibliography

OBJECTIVE:Platelets are mediators of inflammation with immune effector cell properties, and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet associated lectin galactoside-binding soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE, and a potential biomarker associated with clinical phenotypes. METHODS:We performed RNA sequencing on platelets of patients with SLE (n=54) and age, sex, and race-matched controls (n=18) and measured LGALS3BP in platelet releasate and in circulating serum. We investigated the association between levels of LGALS3BP with the prevalence, disease severity, and clinical phenotpyes of SLE, and studied platelet-mediated effects on myeloid inflammation. RESULTS:). Platelet-released LGALS3BP was highly correlated with circulating LGALS3BP (R = 0.69, p < 0.0001). Circulating LGALS3BP correlated with the SLE disease activity index (R = 0.32, p = 0.0006). Specifically, circulating LGALS3BP was higher in SLE patients with lupus nephritis than those with inactive disease (4.0 μg/mL vs 2.3 μg/mL, P < 0.001). IFN-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) cells in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced pro-inflammatory cytokine production by macrophages. CONCLUSIONS:These data support that platelets act as potent effector cells contributing to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity.

Background Psychological well-being is important among individuals with myocardial infarction (MI) given the clear links between stress, depression, and adverse cardiovascular outcomes. Stress and depressive disorders are more prevalent in women than men after MI. Resilience may protect against stress and depressive disorders after a traumatic event. Longitudinal data are lacking in populations post MI. We examined the role of resilience in the psychological recovery of women post MI, over time. Methods and Results We analyzed a sample from a longitudinal observational multicenter study (United States, Canada) of women post MI, between 2016 and 2020. Perceived stress (Perceived Stress Scale-4 [PSS-4]) and depressive symptoms (Patient Health Questionnaire-2 [PHQ-2]) were assessed at baseline (time of MI) and 2 months post MI. Demographics, clinical characteristics, and resilience (Brief Resilience Scale [BRS]) were collected at baseline. Low and normal/high resilience groups were established as per published cutoffs (BRS scores <3 or ≥3). Mixed-effects modeling was used to examine associations between resilience and psychological recovery over 2 months. The sample included 449 women, mean (SD) age, 62.2 (13.2) years, of whom 61.1% identified as non-Hispanic White, 18.5% as non-Hispanic Black, and 15.4% as Hispanic/Latina. Twenty-three percent had low resilience. The low resilience group had significantly higher PSS-4 and PHQ-2 scores than the normal/high resilience group at all time points. In adjusted models, both groups showed a decrease in PSS-4 scores over time. Conclusions In a diverse cohort of women post MI, higher resilience is associated with better psychological recovery over time. Future work should focus on developing strategies to strengthen resilience and improve psychological well-being for women with MI. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02905357; Unique identifier: NCT02905357.

BACKGROUND:The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)-R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features. METHODS:Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes. RESULTS:There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease. CONCLUSIONS:In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.

IMPORTANCE:Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. OBJECTIVE:To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. DESIGN, SETTING, AND PARTICIPANTS:Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. EXPOSURES:Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. MAIN OUTCOMES AND MEASURES:Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. RESULTS:Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. CONCLUSIONS AND RELEVANCE:Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. TRIAL REGISTRATION:ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.

OBJECTIVE:Frailty is an emerging risk factor for adverse outcomes. However, perioperative frailty assessments derived from electronic health records (EHR) have not been studied on a large scale. We aim to estimate the prevalence of frailty and the associated incidence of major adverse cardiovascular events (MACE) among adults hospitalized for non-cardiac surgery. METHODS:Adults aged ≥45 years hospitalized for non-cardiac surgery between 2004-2014 were identified from the National Inpatient Sample. The validated Hospital Frailty Risk Score (HFRS) derived from International Classification of Diseases codes was used to classify patients as low (HFRS <5), medium (5-10), or high (>10) frailty risk. The primary outcome was MACE, defined as myocardial infarction, cardiac arrest, and in-hospital mortality. Multivariable logistic regression was used to estimate the adjusted odds of MACE stratified by age and HFRS. RESULTS:A total of 55,349,978 hospitalizations were identified, of which 81.0%, 14.4%, and 4.6% had low, medium, and high HFRS, respectively. Patients with higher HFRS had more cardiovascular risk factors and comorbidities. MACE occurred during 2.5% of surgical hospitalizations and was common among patients with high frailty scores (high HFRS: 9.1%, medium: 6.9%, low: 1.3%, p<0.001). Medium (adjusted odds ratio [aOR] 2.05, 95% CI 2.02 to 2.08) and high (aOR 2.75, 95% CI 2.70 to 2.79) HFRS were associated with greater odds of MACE versus low HFRS, with the greatest odds of MACE observed in younger individuals 45-64 years (interaction p-value <0.001). CONCLUSIONS:The HFRS may identify frail surgical inpatients at risk for adverse perioperative cardiovascular outcomes.

INTRODUCTION/BACKGROUND:The healthcare resource utilization (HRU) and costs of oral anticoagulant-naïve patients with non-valvular atrial fibrillation (NVAF) and diabetes initiated on rivaroxaban or warfarin in the United States (US) has not been previously evaluated. METHODS:Data Mart Database (1 January, 2012 to 30 September, 2021) to evaluate the HRU and costs of adult patients with NVAF and diabetes newly initiated on rivaroxaban or warfarin (on or after January 2013). Inverse probability of treatment weighting (IPTW) was used to adjust for confounding between cohorts. HRU and costs (USD 2021) were assessed per patient-year (PPY) post-treatment initiation. Weighted cohorts were compared using rate ratios (RR) from Poisson regression models, odds ratios (OR) from logistic regression models, and cost differences; 95% confidence intervals (CI) and p values were generated using non-parametric bootstrap procedures. RESULTS:After IPTW, 17,881 and 19,274 patients initiated on rivaroxaban and warfarin were included, respectively (mean age: 73 years; 40% female). During 12 months of follow-up, the rivaroxaban cohort had lower all-cause HRU PPY across all components, including lower rates of inpatient stays (RR: 0.84, 95% CI 0.81, 0.88), outpatient visits (RR: 0.67, 95% CI 0.66, 0.68), and 30 day hospital readmission (OR: 0.75, 95% CI 0.66, 0.83; all p < 0.001) compared to the warfarin cohort. Moreover, rivaroxaban was associated with medical cost savings PPY (mean cost difference: - $9306, 95% CI - $11,769, - $6607), which compensated for higher pharmacy costs relative to warfarin (mean cost difference: $5518, 95% CI $5193, $5839), resulting in significantly lower all-cause total healthcare costs for rivaroxaban versus warfarin (mean cost difference: - $3788, 95% CI - $6258, - $1035; all p < 0.001). CONCLUSION/CONCLUSIONS:Among NVAF patients with diabetes in a real-world US setting, rivaroxaban was associated with lower healthcare costs compared to warfarin.

BACKGROUND:Perioperative bleeding is a common and potentially life-threatening complication after surgery. We sought to identify the frequency, patient characteristics, causes, and outcomes of perioperative bleeding in patients undergoing noncardiac surgery. METHODS:In a retrospective cohort study of a large administrative database, adults aged ≥45 years hospitalized for noncardiac surgery in 2018 were identified. Perioperative bleeding was defined using ICD-10 diagnosis and procedure codes. Clinical characteristics, in-hospital outcomes, and first hospital readmission within 6 months were assessed by perioperative bleeding status. RESULTS:We identified 2,298,757 individuals undergoing noncardiac surgery, among which 35,429 (1.54%) had perioperative bleeding. Patients with bleeding were older, less likely to be female, and more likely to have renal and cardiovascular disease. All-cause, in-hospital mortality was higher in patients with vs without perioperative bleeding (6.0% vs 1.3%; adjusted OR [aOR] 2.38, 95% CI 2.26-2.50). Patients with vs without bleeding had a prolonged inpatient length of stay (6 [IQR 3-13] vs 3 [IQR 2-6] days, P < .001). Among those who were discharged alive, hospital readmission was more common within 6 months among patients with bleeding (36.0% vs 23.6%; adjusted HR 1.21, 95% CI 1.18-1.24). The risk of in-hospital death or readmission was greater in patients with vs without bleeding (39.8% vs 24.5%; aOR 1.33, 95% CI 1.29-1.38). When stratified by revised cardiac risk index , there was a stepwise increase in surgical bleeding risk with increasing perioperative cardiovascular risks. CONCLUSIONS:Perioperative bleeding is reported in 1 out of every 65 noncardiac surgeries, with a higher incidence in patients at elevated cardiovascular risk. Among postsurgical inpatients with perioperative bleeding, approximately 1 of every 3 patients died during hospitalization or were readmitted within 6-months. Strategies to reduce perioperative bleeding are warranted to improve outcomes following non-cardiac surgery.

BACKGROUND: Monocyte-platelet aggregates (MPAs) represent the crossroads between thrombosis and inflammation, and targeting this axis may suppress thromboinflammation. While antiplatelet therapy (APT) reduces platelet-platelet aggregation and thrombosis, its effects on MPA and platelet effector properties on monocytes are uncertain. OBJECTIVES/OBJECTIVE: To analyze the effect of platelets on monocyte activation and APT on MPA and platelet-induced monocyte activation. METHODS:, GP IIb/IIIa, and COX-1 inhibitors and assessed for platelet and monocyte activity via flow cytometry. RNA-Seq of monocytes incubated with platelets was used to identify platelet-induced monocyte transcripts and was validated by RT-qPCR in monocyte-PR co-incubation ± APT. RESULTS:inhibition attenuates platelet-induced monocyte activation.

AIM/OBJECTIVE:The Diabetes risk index (DRI) is a composite of NMR-measured lipoproteins and branched chain amino acids predictive of diabetes mellitus development. Bariatric surgery is indicated in patients with severe obesity, many of whom are at high-risk for developing diabetes. Substantial weight loss occurs following bariatric surgery and sustained weight loss likely contributes to reductions in the development of diabetes and cardiovascular disease. However, some evidence suggests that bariatric surgical procedures themselves may contribute to reducing risk of these conditions independent of weight loss. We aimed to investigate DRI and its association with reductions in body weight and adiposity over one year following bariatric surgery. METHODS:; n = 15). RESULTS:, but DRI decreased so that it no longer differed from that of normal BMI controls (1.9 [1, 17] vs control 12 [1, 20]; p = 0.35). Subjects continued to lose weight, whereas DRI remained similar, throughout follow-up with DRI 1.0 [1, 7] at 12 months. Changes in DRI did not correlate with changes in BMI, body weight or waist circumference at any time during follow-up. There was no difference in change in DRI between surgical procedures or pre-operative metabolic syndrome status. CONCLUSIONS:Our analysis of DRI scores supports the capacity of bariatric surgery to reduce risk of developing diabetes in severely obese individuals. Our findings suggest that bariatric surgical techniques may have inherent effects that improve cardiometabolic risk independent of reductions in body weight or adiposity.