Faculty Bibliography

AIM/OBJECTIVE:To investigate how psychosocial stress contributes to accelerated thrombosis, focusing on platelet activation and hyperreactivity. The specific objective was to identify novel platelet regulators involved in stress-mediated thrombosis, with a particular emphasis on the tetraspanin CD37. METHODS AND RESULTS/RESULTS:To explore how stress contributes to platelet hyperreactivity, platelets were isolated from (1) mice that experienced chronic variable stress and stress-free controls (n=8/group) and (2) human subjects with self-reported high and no stress levels (n=18/group), followed by RNA-sequencing. By comparing mutually expressed transcripts, a subset of genes differentially expressed following psychosocial stress was identified in both human and mouse platelets. In both mice and humans, platelet CD37 positively associates with platelet aggregation responses that underlie thrombosis, with Cd37-/- platelets exhibiting impaired integrin αIIbβ3 signaling, characterized by reduced platelet fibrinogen spreading and decreased agonist-induced αIIbβ3 activation. Consistent with a role for CD37 in regulating platelet activation responses, chimeric mice that received Cd37-/- bone marrow experienced a significantly increased time to vessel occlusion in the carotid artery FeCl3 model compared to mice reconstituted with wild-type bone marrow. CD37 deficiency did not alter hemostasis, as platelet count, coagulation metrics, prothrombin time, and partial thromboplastin time did not differ in Cd37-/- mice relative to wild-type mice. Consistent with this, bleeding time did not differ between wild-type and Cd37-/- mice following tail tip transection. CONCLUSIONS:This study provides new insights into the platelet-associated mechanisms underlying stress-mediated thrombosis. Identifying CD37 as a novel regulator of platelet activation responses offers potential therapeutic targets for reducing the thrombotic risk associated with psychosocial stress. The findings also contribute to understanding how psychosocial stress accelerates thrombotic events and underscore the importance of platelet activation in this process.

Although platelets play a critical pathogenic role in myocardial infarction (MI), few studies have characterized the MI platelet transcriptome in the acute or chronic setting in women. We report that transcripts associated with the actin cytoskeleton, Rho family GTPases, mitochondrial dysfunction, and inflammatory signaling are enriched in platelets from MI patients in the acute setting (n = 40, MI; n = 38, control) and do not significantly change over time. Furthermore, 79 platelet genes chronically elevated or suppressed after MI are associated with future cardiovascular events in an independent high-risk cohort (n = 135). Compared with women with MI with nonobstructive coronary arteries, platelets from women with MI and obstructive coronary artery disease were enriched in neutrophil activation and proinflammatory signaling pathways driven by increased tumor necrosis factor (TNF)-α signaling. Hierarchic clustering of the MI transcriptomic profile identified 3 subgroups with distinctive biological pathways and MI correlates. Our data demonstrate that platelets from MI patients are phenotypically different from MI-naïve patients in the acute and chronic settings and reveal a platelet transcriptomic signature with distinct clinical features.

STUDY OBJECTIVE/OBJECTIVE:To determine whether preoperative LDL-C concentration affects the risk of perioperative major adverse cardiovascular or cerebrovascular events (MACCE) after noncardiac surgery. DESIGN/METHODS:Single center retrospective cohort study. SETTING/METHODS:Hospital (including medical and surgical floor, intensive care unit) and patient disposition location (including the patient's home or any other receiving facility). PATIENTS/METHODS:43,348 non-cardiac surgeries at NYU Langone Health between January 2016 and September 2020. INTERVENTIONS/METHODS:Patients were grouped based on preoperative LDL-C. MEASUREMENTS/METHODS:Complete serum lipid panel obtained within one year prior to the date of noncardiac surgery and rate of perioperative MACCE, defined as a composite of in-hospital non-fatal myocardial infarction, in-hospital acute ischemic stroke, myocardial injury after noncardiac surgery, and death from any cause within 30 days of surgery. MAIN RESULTS/RESULTS:Perioperative MACCE occurred in 1093 patients (2.5 %) overall. After multivariable adjustment, odds of MACCE were significantly lower in patients with higher (≥100 mg/dL) versus lower (<100 mg/dL) LDL-C (adjusted odds ratio [aOR] 0.783, 95 % CI, 0.660-0.926]). CONCLUSIONS:In a large cohort of patients undergoing non-cardiac surgery at a major academic health system in New York City, lower LDL-C concentrations were not associated with a lower incidence of perioperative MACCE. Further investigation into modifiable perioperative cardiovascular risk factors is needed to improve perioperative outcomes.

OBJECTIVE:To investigate the relationship between platelet indices (count, size and production/immaturity) and hypertensive disorders of pregnancy. STUDY DESIGN/METHODS:This was a secondary analysis of a prospective cohort of pregnant individuals followed from first trimester through delivery at an academic tertiary care institution. Routine platelet indices obtained prospectively during prenatal care and delivery were compared between those who developed a hypertensive disorder of pregnancy and those who did not. We assessed platelet count (by trimester), mean platelet volume, and immature platelet fraction measured as percent (%) and absolute count. Data were analyzed using Fisher's Exact test, chi-square test, and multivariable logistic regression. P < 0.05 was considered statistically significant. RESULTS: = 0.01) compared to those without a hypertensive disorder of pregnancy, after adjusting for age, race/ethnicity, obesity, nulliparity, and chronic hypertension. The prevalence and likelihood of a hypertensive disorder of pregnancy increased with increasing mean platelet volume, as well as with both the percent and absolute immature platelet fraction. There was no difference between groups in platelet count in the first trimester, second trimester, or at delivery. CONCLUSIONS:An increase in platelet size and immaturity was observed in those with a hypertensive disorder of pregnancy. These data support further investigation of platelets in the mechanisms of the development of hypertensive disorders of pregnancy and the use of platelet indices to better identify high risk groups in pregnancy.

BACKGROUND/UNASSIGNED:Elevated perceived stress is associated with adverse outcomes following myocardial infarction (MI) and may account for poorer recovery among women vs men. OBJECTIVES/UNASSIGNED:This randomized controlled trial tested effects of a mindfulness-based intervention on stress levels among women with MI. METHODS/UNASSIGNED:Women with elevated stress (Perceived Stress Scale [PSS-4]≥6) at least 2 months after MI were enrolled from 12 hospitals in the United States and Canada and via community advertising. Participants were randomized to a remotely delivered mindfulness intervention (MBCT-Brief) or heart disease education, both 8 weeks long. Follow-up was 6 months. Changes in stress (PSS-10; primary outcome) and secondary outcomes (depressive symptoms, anxiety, quality of life, disease-specific health status, actigraphy-assessed sleep) were compared between groups. RESULTS/UNASSIGNED: = 0.036). CONCLUSIONS/UNASSIGNED:MBCT-Brief was associated with greater 6-month reductions in stress than an active control among adherent participants. More frequent mindfulness practice was associated with greater improvements in psychological outcomes. Strategies to engage women with MI in mindfulness training and support regular home practice may enhance these effects.

BACKGROUND/UNASSIGNED:Reported results of clinical trials assessing higher-dose anticoagulation in patients hospitalized for COVID-19 have been inconsistent. PURPOSE/UNASSIGNED:To estimate the association of higher- versus lower-dose anticoagulation with clinical outcomes. DATA SOURCES/UNASSIGNED:Randomized trials were identified from the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov with no restriction by trial status or language. STUDY SELECTION/UNASSIGNED:Eligible randomized trials assigned patients hospitalized for COVID-19 to higher- versus lower-dose anticoagulation. DATA EXTRACTION/UNASSIGNED:20 eligible trials provided data in a prospectively agreed format. Two further studies were included based on published data. The primary outcome was all-cause mortality 28 days after randomization. Secondary outcomes were progression to invasive mechanical ventilation or death, thromboembolic events, and major bleeding. DATA SYNTHESIS/UNASSIGNED: = 0%; 10 trials, 3897 patients, 2935 receiving no or low oxygen at randomization) for intermediate- versus prophylactic-dose anticoagulation. Treatment effects appeared broadly consistent across predefined patient subgroups, although some analyses were limited in power. Higher- compared with lower-dose anticoagulation was associated with fewer thromboembolic events, but a greater risk for major bleeding. CONCLUSION/UNASSIGNED:Therapeutic-dose compared with prophylactic-dose anticoagulation reduced 28-day mortality. Mortality was similar for intermediate-dose compared with prophylactic-dose anticoagulation and higher for therapeutic-dose compared with intermediate-dose anticoagulation, although this comparison was not estimated precisely. PRIMARY FUNDING SOURCE/UNASSIGNED:No direct funding. (PROSPERO: CRD42020213461).

Cardiometabolic risk factors, obesity, diabetes and hyperlipidemia contribute to cardiovascular disease (CVD). While platelets are involved in CVD pathogenesis, the relationship between risk factor burden on platelet indices and the platelet transcriptome remains uncertain. Blood was collected from CVD-free adults, measuring platelet count, mean platelet volume (MPV), immature platelet fraction (IPF), and absolute immature platelet fraction (AIPF) by hemogram. Platelets were isolated and analyzed via RNA sequencing. Participants were stratified by number of cardiometabolic risk factors (diabetes, obesity, hyperlipidemia). We calculated median (IQR) values of platelet indices and p-for-trend via linear regression across risk factor burden. To evaluate the association between risk factor burden and platelet transcripts, we performed multivariable linear regression adjusting for age, sex, and race/ethnicity. Among 141 participants, (50.5 ± 14.8 years, 42% male, 26% Black) risk factor burden was associated with increasing platelet size, IPF, and AIPF but not platelet count. Platelet RNA sequencing identified 100 differentially expressed transcripts (p < .01; 66 upregulated, 34 downregulated). Gene ontology enrichment analysis demonstrated upregulated pathways of secondary metabolic processes (NES = 1.96, p < .01), and hematopoietic stem cell proliferation (NES = 1.95, p < .01). Greater cardiometabolic risk factor burden is associated with increased platelet size and immaturity and suggesting novel platelet-mediated mechanisms linking risk factor burden with CVD.

BACKGROUND:Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response. METHODS:CHOlesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) >100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein (a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and western blotting. We examined the change in Lp(a) levels from baseline to 30 days. RESULTS:Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < 0.001). Among 73 (49%) participants with Lp(a) ≥30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < 0.001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = 0.59), apo(a) size directly correlated with Lp(a) reduction (P < 0.001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < 0.001). CONCLUSION/CONCLUSIONS:Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.