Faculty Bibliography

INTRODUCTION/UNASSIGNED:Platelet hyperreactivity is linked to inflammation and cardiovascular risk in nonpregnant populations, but its relationship to placentally mediated pregnancy outcomes is undefined. We prospectively evaluated platelet hyperreactivity in pregnancy and subsequent ischemic placental disease (IPD), and examined aspirin's (ASA) effect on platelet activity by baseline platelet phenotype. METHODS/UNASSIGNED: RESULTS/UNASSIGNED:Of 66 pregnant participants recruited, 61 had first-trimester LTA; 20 (32.8%) had platelet hyperreactivity. Participants with hyperreactivity were more likely to develop IPD than those without (55% versus 24%, adjusted odds ratio [aOR] 3.77 (95% CI [1.05-13.53]), with consistent directionality across individual components despite low event frequencies. Participants with platelet hyperreactivity showed greater platelet aggregation to ADP, collagen, and low-dose AA. Platelet transcriptomic profiling distinguished participants with versus without platelet hyperreactivity and revealed differential expression of pathways related to platelet activity, energy metabolism, and immune regulation. Among 45 high-risk participants recommended ASA, those with hyperreactivity exhibited higher AA-induced aggregation (24% vs 12.5% platelet aggregation, p=0.01) despite similar serum TxB2 levels. CONCLUSION/UNASSIGNED:First-trimester platelet hyperreactivity was present in approximately one-third of participants and was independently associated with increased risk of IPD. Participants with platelet hyperreactivity demonstrated distinct transcriptomic signatures and greater platelet aggregation despite ASA use. Together, these findings support a contributory role for platelets in placental ischemic pathology and highlight the need to elucidate mechanisms and develop platelet-targeted preventive strategies.

BACKGROUND:Microvascular density and endothelial glycocalyx function may provide insights into early atherosclerosis and cardiovascular disease (CVD) risk. Sublingual sidestream darkfield (SDF) microscopy permits imaging of red blood cells (RBC) to assess the microcirculation. We sought to define reference ranges for SDF microscopy parameters in healthy populations and individuals with coronary artery disease (CAD) and to assess factors correlated with microcirculatory abnormalities. METHODS:Adults with and without CVD risk factors and epicardial CAD underwent SDF microscopy using a CapiScope Handheld Video Capillaroscopy System and Glycocheck analytic software to measure the perfused boundary region (a measure of RBC glycocalyx penetration), percent RBC filling (%RBC, a measure of microvascular perfusion) and microvascular density. RESULTS:<0.0001), though values overlapped substantially; after adjustment for demographics and CVD risk factors, obstructive CAD was not independently associated with sublingual microvascular parameters. CONCLUSIONS:Obstructive CAD was not associated with sublingual microvascular parameters after accounting for demographics and CVD risk factors. The overlap of microvascular parameters in patients with and without CAD limits the clinical utility of SDF microscopy to identify traditional CVD.

Despite major advances in medical therapies and prevention strategies, the risk of cardiovascular complications in patients with both type I and type II diabetes remains substantially elevated. In 2019, the American Heart Association sought applications for a Strategically Focused Research Network on Cardiometabolic Health and Type 2 Diabetes. In 2020, 4 centers were named, including Brigham and Women's Hospital, Johns Hopkins University, New York University, and the University of Iowa. These centers performed basic, translational, and clinical studies to provide insights to explain the over 2-fold risk of cardiovascular complications in diabetes. Clinical studies and studies in cells and animals aimed to uncover new mechanisms responsible for disease development. Studies using human populations sought to uncover new biomarkers to prognosticate risk. In this review, we discuss several key issues and current and developing methods to understand why diabetes drives atherosclerotic cardiovascular disease and heart failure. Both human data and experimental models are considered. We integrate a review of these topics with work from the Strategically Focused Research Network and conclude with suggestions for identifying novel risk factors and future experimental research.

BACKGROUND:Coronary microvascular dysfunction (CMD) is present in approximately 40% of patients with ischemia with no obstructive coronary arteries (INOCA) and has been associated with inflammation. We investigated associations between measures of inflammation of the coronary perivascular adipose tissue assessed by coronary computed tomography angiography (CCTA) and results of invasive coronary function testing (CFT) to diagnose CMD. METHODS:Adults referred for clinically indicated invasive coronary angiography who had less than 50% stenosis in all epicardial arteries were prospectively enrolled. CMD was defined as a coronary flow reserve (CFR) less than 2.5 or index of microvascular resistance (IMR) greater than or equal to 25 using bolus thermodilution in the left anterior descending (LAD) coronary artery. Coronary perivascular fat attenuation index was assessed by CCTA in the right coronary artery (RCA) and LAD. T tests were used to evaluate differences in perivascular FAI by CMD status. RESULTS:A total of 31 participants underwent CFT and CCTA. The mean age was 58 ± 11.7 years, 77% were female, and 61% were white. CMD was present in 15 participants (48%). No differences in perivascular FAI were observed in patients with and without CMD, either in the RCA [-74.2 ± 9.8 vs. -69.9 ± 10.3 Hounsfield units (HU), P = 0.24] or LAD (-76.4 ± 10.2 vs. -74.8 ± 12.7 HU, P = 0.69). Perivascular FAI was not correlated with CFR or IMR measurements in the RCA or LAD. CONCLUSION/CONCLUSIONS:There were no associations between CMD diagnosed by invasive CFT and perivascular FAI by CCTA in patients with INOCA. Further research is needed to understand the relationship between vascular inflammation and CMD in INOCA.

BACKGROUNDPlatelets are increasingly recognized as active participants in immune signaling and systemic inflammation. Upon activation, platelets form monocyte platelet aggregates (MPA) representing the crossroads of thrombosis and inflammation. We hypothesized that platelet transcriptomics could capture this thromboinflammatory axis and identify individuals at elevated cardiovascular risk.METHODS: MPA levels, defined as CD14+CD61+ cells, were measured using flow cytometry at 2 time points, 4 weeks apart, in healthy individualsPlatelets were isolated and sequenced. Individuals were categorized as MPAhi or MPAlo based on consistently high or low MPA levels across time points.RESULTSAmong 149 participants (median age 52 years, 57% female, 50% non-White), MPAhi individuals exhibited increased expression of platelet activation markers P-selectin (P < 0.001), PAC-1 (P = 0.021), and CD40L (P < 0.001) and enriched immune signaling pathways. Informed by MPA levels and derived from the platelet transcriptome, we developed a 42-gene thromboinflammation platelet signature (TIPS), which correlated with MPA levels in multiple cohorts and was reproducible over time. TIPS was elevated in patients with COVID-19 (P = 0.0002) and myocardial infarction (Padj = 0.008), and as in predicted future cardiovascular events in patients who underwent lower extremity revascularization after a median follow-up of 18 months (adjusted for age, sex, race, and ethnicity [adjHR] 1.55, P = 0.006). Notably, TIPS was modifiable by ticagrelor (P = 0.002) but not aspirin.CONCLUSIONThese findings establish MPA as a biomarker of thromboinflammation and introduce TIPS, a platelet RNA signature, that captures thromboinflammation and provides a promising tool for cardiovascular risk stratification and a potential therapeutic target.TRIAL REGISTRATIONNCT04369664FUNDINGNIH R35HL144993, NIH R01HL139909, and AHA 16SFRN2873002 to JSB, DFG Walter-Benjamin-Programme 537070747 to AB.

BACKGROUND/UNASSIGNED:compared with the conventional index of microcirculatory resistance (IMR) in a cohort of individuals with INOCA. METHODS/UNASSIGNED:was calculated retrospectively, blinded to CFT results. CMD was defined by IMR ≥25 or CFR <2.5. RESULTS/UNASSIGNED:and IMR. CONCLUSIONS/UNASSIGNED:appears unreliable for identifying CMD in patients with INOCA.

Coronary endothelial dysfunction plays a key role in the pathogenesis of acute coronary syndromes. During myocardial infarction (MI), activated platelets release prothrombotic and proinflammatory factors, contributing to vascular injury and dysfunction. To investigate platelet-mediated endothelial dysfunction, endothelial cells (ECs) were treated with platelet-released factors from patients with MI and non-MI controls undergoing coronary angiography. RNA sequencing revealed that MI platelets induced EC mitochondrial dysfunction, confirmed by reduced mitochondrial membrane potential and disrupted mitochondrial networks. Integrating platelet transcriptomic data, we identified the C-C motif chemokine ligand 3 (CCL3) as significantly up-regulated in MI platelets and a key mediator of EC mitochondrial dysfunction. Blocking its receptor, CCR5, attenuated CCL3 effects. In an independent cohort of 261 patients with established cardiovascular disease, higher circulating CCL3 levels were associated with incident major adverse cardiovascular events. Together, these findings establish a mechanistic link between platelet activation and coronary endothelial dysfunction in MI.